WO2011074791A2 - Pharmaceutical composition containing telmisartan and hydrochlorothiazide - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing telmisartan and hydrochlorothiazide, and particularly, the present invention relates to a pharmaceutical composition containing telmisartan (an angiotensin II receptor antagonist) and hydrochlorothiazide (a diuretic). The pharmaceutical composition of the present invention, having a compound containing polyvinylpyrrolidone (an inactive water soluble polymer) primarily coated on a telmisartan core, and a compound of hydrochlorothiazide (a diuretic) and polyvinylpyrrolidone secondarily coated thereon, can have a good diuretic dissolution rate, and is significantly smaller and lighter than commercial drugs of the prior art, so that administering dosages to patients can be easier, and the composition can be effectively used in the medical industry.

Description

 【Specification】

 [Name of invention]

 Pharmaceutical composition containing telmisartan and hydrochlorothiazide

 The present invention relates to a pharmaceutical composition containing telmisartan, an angiotensin π receptor antagonist, and hydrochlorothiazide, a diuretic. It includes a first coating layer, and a pharmaceutical composition comprising a second coating layer comprising hydrochlorothiazide.

Background Art

 Telmisartan is known as angiotensin Π receptor antagonist developed to treat hypertension and other medical indications (European Publication No. 502314). The telmisartan

4 '-[(1,4'-dimethyl-2'-propyl [2,6'-bi-1H-benzimidazolyl) methyl]-[1,1'-biphenyl] -2-carboxylic acid or 4' -[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazole-1-ylmethyl] -biphenyl-2-carboxylic acid, described molecularly chemically It is a non-peptide, the empirical formula is C ₃₃ H ₃₀ N ₄ 0 ₂ , and the molecular weight is 514.63.

 Hydrochlorothiazide is also a thiazide diuretic administered orally for the treatment of edema and hypertension. The chemical names 6-chloro-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine _7- Sulfonamide-1, 1-dioxide

 Since the combination treatment of telmisartan and hydrochlorothiazide, a diuretic, has been shown to show synergistic therapeutic effects in the treatment of hypertension, a study attempting to properly structurally combine telmisartan and hydrochlorothiazide, a diuretic, A lot has been going on.

Generally, in order to combine heterogeneous drugs, excipients may be added to the first drug component. Many methods have been used in which powders are prepared by simply adding the second drug component contained therein or by simultaneously granulating the second drug component containing the system 1 drug component and the excipient.

 However, it is not desirable to use this method to prepare pharmaceutical compositions in which telmisartan and dichlorohydride hydrochlorothiazide are mixed. Because dichlorohydride hydrochlorothiazide is incompatible with basic compounds such as meglumine (N-methyl-D-glucamine), which is a component of the telmisartan formulation, and furthermore when the telmisartan and hydrochlorothiazide are mixed, There is a problem that the pharmaceutical composition is in the form of a dissolution matrix, thereby reducing the rate of dissolution of the hydrochlorothiazide.

 In order to solve the non-combustibility problem, studies have been made to coat the hydrochlorothiazide particles with a water-soluble polymer such as hydroxypropylsallos to improve the contact area between hydrochlorothiazide and telmisartan, but storage problems, It is pointed out that the rate at which the coated hydrochlorothiazide dissolves is further reduced by the gel-forming properties of the polymer.

 Various methods have been attempted to overcome the non-combustibility problem as described above, while solving the incompatibility problem of the basic compound of the telmisartan formulation and the hydrochlorothiazide, it is appropriately blended and the elution characteristics of the hydrochlorothiazide are improved. There is no research report suggesting a clear solution.

[Detailed Description of the Invention]

 [Technical problem]

 Therefore, the present inventors have solved the problem of incompatibility between telmisartan and dichloromide hydrochlorothiazide, and improved the dissolution properties of the diuretic as well as reducing the size of the final tablet to develop an easy-to-use pharmaceutical preparation. By this, the present invention was completed.

Therefore, the present invention provides telmisartan and hydrochlorothiazide as a diuretic. It is an object of the present invention to provide a pharmaceutical composition which can be easily taken by improving the dissolution rate of diuretics and further reducing the size of tablets while solving the problem of non-combustibility. Technical Solution

 In order to achieve the above object, the present invention is a core of a dissolution tablet matrix form containing telmisartan and a basic substance; A first coating layer coated on the core and comprising a polyvinylpyridone-based polymer; And a second coating layer coated on the first coating layer and comprising a hydrochlorothiazide and a polyvinylpyridone-based polymer.

 In another aspect,

 Preparing a core in the form of a dissolved tablet matrix comprising telmisartan and a basic substance;

 Forming a first coating layer comprising a polyvinylpyrrolidone-based polymer on the core; And

 Forming a second coating layer including hydrochlorothiazide and polyvinylpyridone-based polymer on the first coating layer

It provides a method for producing a telmisartan and a hydrochlorothiazide complex comprising a. Hereinafter, the present invention will be described in more detail. The pharmaceutical composition of the present invention comprises a core in the form of a soluble tablet matrix comprising telmisartan and a basic substance; A first coating layer coated on the core and comprising a polyvinylpyrrolidone-based polymer; And a second coating layer coated on the first coating layer and including a hydrochlorothiazide and a polyvinylpyridone-based polymer. The core in the form of the dissolution tablet matrix includes telmisartan and basic substances dispersed in a dissolution tablet matrix that is immediate release. The basic material which may be contained in the core in the form of the dissolution matrix is not limited thereto, but preferably alkali metal hydroxides (e.g., NaOH, KOH), basic amino acids (e.g. arginine, lysine) and meglumine (N-methyl- D-glucamine) may be one or more selected from the group consisting of.

 The core of the dissolved tablet matrix form is not limited thereto, and may preferably further include a water-soluble diluent, an excipient and / or an adjuvant.

 The water-soluble diluent is not limited thereto, but may preferably be one or more selected from the group consisting of glucose, sucrose, lactose, sorbitol, mannnisoc, dulci, liby and xylitol, and more preferably sorbent. It can be rain.

 The excipients and / or auxiliaries may be selected, for example, from binders, carriers, layering agents, lubricants, flow control agents, crystallization retardants, solubilizers, colorants, pH adjusters, surfactants and emulsifiers.

 Since telmisartan is included in the dissolution tablet matrix including the basic substance, telmisartan may be stably included in the pharmaceutical composition and may have immediate release characteristics.

 The dissolved tablet matrix form of the core may be prepared according to the core preparation method of pharmaceutical preparations known in the art, for example, may be prepared with reference to Korean Patent Registration No. 851770 (the document is described herein It is included as a reference), the manufacturing method is not particularly limited.

The pharmaceutical composition of the present invention may include, but is not limited to, 20 mg to 80 mg telmisartan and 6.25 mg to 25 mg hydrochlorothiazide per unit dosage form, once administered as a pharmaceutically active ingredient, The total weight of the unit dosage form may be 260-520 mg. In addition, the first coating layer is coated on the core, and includes a polyvinylpyridone-based polymer.

 The core in the form of the dissolved tablet matrix contains a basic substance, and if the hydrochlorothiazide is directly coated on the core, hydrochlorothiazide cannot be stably contained in the pharmaceutical composition, thereby causing an incompatibility problem.

 The solubility of telmisartan is 0.00351 mg / mL, which is difficult to dissolve in water, and the pka value is 4.45, which is a weakly acidic substance. In order to increase the solubility of telmisartan with low solubility in water, basic substances such as meglumine (N-methyl-D-glucamine) as described above are used. On the other hand, hydrochlorothiazide has a solubility of 2.24 mg / mL, which is well soluble in water, and a pka value of 7.9, indicating weak basicity. When the tablets are formulated by combining telmisartan and hydrochlorothiazide having these properties, the rate of dissolution of hydrochlorothiazide is reduced by meglumine in the telmisartan formulation, which is why telmisart is intended for immediate release. The problem of non-combustion occurs that sufficient efficacy of the tan and hydrochlorothiazide combination agent is not expressed.

 In order to solve the above problem, the present invention does not apply a hydrochlorothiazide coating layer directly to the core of the dissolution tablet matrix form containing telmisartan, and the poly between the core and the hydrochlorothiazide coating layer (second coating layer) It is characterized by introducing a first coating layer containing a vinylpyridone-based polymer. The polyvinylpyridone-based polymer (PVP) of the first coating layer is not limited thereto, and preferably 10: 1 to 2: 1 (HCTZ weight :) relative to the hydrochlorothiazide (HCTZ) increase in the pharmaceutical composition. PVP weight), and more preferably 5: 1 to 2: 1 (HCTZ weight: PVP weight). If it is out of the numerical range may cause a problem in the dissolution of hydrochlorothiazide and telmisartan, and when the pharmaceutical composition is prepared in the form of tablets, the weight or size of the tablet may increase, so it is preferable to limit to the numerical range Do.

The first coating layer, together with the polyvinylpyrrolidone-based polymer, a plasticizer, It may further include a filler and other additives, the details of which are substantially the same as the description of the second coating layer to be described later.

 In addition, the second coating layer is coated on the first coating layer, and includes hydrochlorothiazide and polyvinylpyridone-based polymer.

 The polyvinylpyridone-based polymer (PVP) of the second coating layer is not limited thereto, and preferably 2: 1 to 1: 1 (HCTZ weight: PVP) based on the weight of hydrochlorothiazide (HCTZ) contained in the pharmaceutical composition. Weight). If it is out of the numerical range may cause a problem in the dissolution of hydrochlorothiazide and telmisartan, and when the pharmaceutical composition is prepared in the form of tablets, the weight or size of the tablet may increase, so it is preferable to limit to the numerical range Do.

The second coating layer, but are not limited to preferably the disintegrating agent may further include, and further more preferably further comprises a plasticizer, talc, titanium oxide, silicon dioxide and at least one selected from ^'the group consisting of surface active agent can do.

 The disintegrant may be, but is not limited to, at least one selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, carboxymethylsalose, anhydrous corn starch and sodium starch glycolate, and more preferably. Preferably croscarmellose sodium. The disintegrant may include, but is not limited to, 1.5: 1 to 0.2: 1 (HCTZ weight: disintegrant weight) relative to the weight of hydrochlorothiazide (HCTZ) contained in the pharmaceutical composition. Preferably from 1.13: 1 to 0.5: 1. If it is out of the numerical range may cause a problem in the dissolution of hydrochlorothiazide and telmisartan, and when the pharmaceutical composition is prepared in the form of tablets, the weight or size of the tablet may increase, so it is preferable to limit to the numerical range Do.

The plasticizers are pluronic, polyethylene glycol, sodium carboxymethyl cellulose, polyethoxylated castor oil, hydrogenated castor oil, lauryl sulfate At least one selected from the group consisting of sodium, propylene glycol, glycerin, glycerine monostearate, polymethacrylate, triacetin tributyl citrate, triethanolamine, triethyl citrate, polyvinyl butyrate and polyvinylacetate phthalate And preferably polyethylene glycol.

 The surfactant may be, but is not limited to, at least one selected from the group consisting of polysorbate, polyoxyethylene glycol ester, and polyoxyethylene castor oil derivative.

 The pharmaceutical composition of the present invention contains telmisartan in a core of a dissolution tablet matrix form, and the core is first coated with a polyvinylpyridone-based polymer, followed by hydrochlorothiazide and the polyvinylpyridone-based polymer. By re-coating with the polymer again, the basic material and hydrochlorothiazide contained in the core are separated to minimize the contact between them, thereby solving the existing non-combustibility problem as described above, and at the same time, By containing a zide, the solubility of hydrochlorothiazide and telmisartan is improved and the dissolution rate is very high.

 In particular, in the present invention, polyvinylpyrrolidone-based polymers were used for primary and secondary coatings as inert water-soluble polymers, and for example, polyvinylpyrrolidone (PVP) may be used. The molecular weight of the polyvinylpyridone-based polymer (eg, polyvinylpyridone) is not particularly limited, and may be, for example, about 2,500 to 3,000,000, but is not limited thereto.

The polyvinylpyridone-based polymer is an inert polymer having no reaction to telmisartan and hydrochlorothiazide, and is a water-soluble polymer that can most effectively induce the disintegration of telmisartan and hydrochlorothiazide. Compared to hydroxypropyl methylcel lulose, which has been used as a water-soluble polymer, it is a polymer that can further improve the dissolution rate of hydrochlorothiazide (see Comparative Example 3). The pharmaceutical composition of the present invention having the composition and composition ratio as described above is also compared with conventional commercial preparations (Miccardis plus tablets, Boehringer Ingelheim) or formulations which differ from the compositions and composition ratios set forth in the present invention. It shows a better effect on the dissolution rate of the zide and telmisartan.

 In particular, the pharmaceutical composition of the present invention effectively elutes telmisartan, a diuretic hydrochlorothiazide, which is an active ingredient that should act in combination for the treatment of hypertension, and is more useful for treating hypertension than conventional commercial preparations. Can be used.

 Specifically, in one experimental example of the present invention, the surface of the core containing telmisartan was first coated with polyvinylpyridone, an inert water-soluble polymer, and secondly coated with polyvinylpyridone and hydrochlorothiazide. In the case (see <Example 1> to <Example 3>), in the <Example 1> to <Example 3> in the case of further secondary coating by further including a disintegrant and a plasticizer (<Example 4> to The elution rate of the hydrochlorothiazide of (see <Example 5>) was measured at various pHs.

 In addition, when the surface of the core containing telmisartan was only subjected to primary coating with polyvinylpyridone (see Comparative Example 2) or hydroxypropylmethylcell (see Comparative Example 1), Various pH values of the surface of the core were first coated with hydroxypropylmethylcell with an inert water-soluble polymer and then second coated with polyvinylpyridone and hydrochlorothiazide (see <Comparative Example 3>). The dissolution rate of hydrochlorothiazide at was measured and compared with that of the present invention.

 As a result, as in <Comparative Example 1> and <Comparative Example 2>, the dissolution rate of the monolayer tablet was 80% or less, and as shown in <Comparative Example 3>, hydroxypropylmethylsalose was used as the inert water-soluble polymer in the first coating. It can be seen that even when the dissolution rate is 80% or less. However, as in <Example 1> to <Example 5>,

When polyvinylpyridone is used as an inert water-soluble polymer for the first coating At most pH, the dissolution rate was 80% or more, preferably 90% or more. In particular, polyvinylpyrrolidone was used as the inert water-soluble polymer in the first coating as in <Example 4> to <Example 5>. It can be seen that the polyvinylpyridone disintegrant and the plasticizer were mixed and used together in the primary coating to give the best dissolution rate (see <Experimental Example 1>).

 Therefore, the pharmaceutical composition of the present invention is not limited thereto, but preferably the hydrochlorothiazide has a dissolution rate of 80% or more within 15 minutes in an aqueous solution of pH 7 or less, and the telmisartan within 30 minutes in an aqueous solution of pH 7.5. It may have a dissolution rate of 80% or more.

 The pharmaceutical composition of the present invention has a better effect on the dissolution rate of diuretics by optimizing the composition and composition ratio as described above, and at the same time as compared to conventional commercial preparations (Micardis plus tablet, Boehringer Ingelheim), telmisartan (80 mg or 40 mg) and hydrochlorothiazide (12.5 mg) in the same amount, the overall pharmaceutical composition is much smaller in size and weight, making it easier for patients to take, and thus can be used more effectively in the medical industry. (See <Experiment 2>).

 The pharmaceutical composition of the present invention is not limited thereto, but preferably the total weight of the unit dosage form may be 6 to 8 times the weight of telmisartan and more preferably 6.3 to 7.4 times.

Furthermore, the pharmaceutical composition of the present invention may be preferably, but not limited to, tablets, and when the unit dosage form is in tablet form, for example, in the case of tablets containing 80 mg of telmisartan and 12.5 mg of hydrochlorothiazide The planar long axis of has a length of 14mm to 15mm, the short axis has a length of 7.0mm to 7.5mm, and the tablet may have a thickness of 5.0mm to 5.5mm, which is the size and weight of the tablet compared to conventional commercially available formulations. This is much smaller and the patient's dose is easier (see FIG. 1). As described above, the pharmaceutical composition of the present invention is coated on the telmisartan core polyvinylpyridone which is an inert water-soluble polymer and thereon By coating a diuretic hydrochlorothiazide and polyvinylpyrrolidone mixture, it can have excellent dissolution rate of diuretic, and the size and weight of the pharmaceutical composition is much smaller than that of commercially available formulations, so it is easier for patients to take. It can be used more effectively in the medical industry.

[Brief Description of Drawings]

 1 is a photograph comparing the size of the tablet and the commercial formulation according to <Example 1>.

 FIG. 2 is a diagram showing a criterion comparing the sizes of tablets and commercial preparations according to <Example 1> (A: shorter length (，), B: long axis length (，), C: thickness (隱)).

[Form for implementation of invention]

 Hereinafter, the present invention will be described in detail by way of examples.

 However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

Reference Example 1

 Manufacture of telmisartan core

 The telmisartan core may use a method used for preparing a conventional pharmaceutical composition. Specifically, in order to prepare a core in the form of a dissolved tablet matrix containing telmisartan and a basic substance, ethane anhydrous is placed in a stainless container. The telmisartan, alkaline substance and binder were slowly added and stirred to obtain a tan coating solution and granulated. The telmisartan granules and D-sorbate obtained above were mixed in a blender and mixed with magnesium stearate, followed by compression molding of tablet hardness to 15 to 20 kp using a rotary tableting machine (eg KISAN, KP-100). Telmisartan core tablets were prepared.

In the compression molding, the telmisartan core containing 80 mg of telmisartan based on one tablet was 480 mg, and the telmisartan core containing 40 mg of telmisartan was molded to be 240 mg. <Example 1>

 Preparation of Bilayer Tablets Comprising Telmisartan and Diuretics (I)-Use of Povidone (polyvinylpyriOlidone) as Water-Soluble Polymer in Primary Coatings

 Ethanol and purified water were added to a stainless container while povidone 29/32, polyethylene glycol 6000, and talc were slowly added thereto, followed by vigorous stirring until complete dissolution and suspension, thereby preparing a primary coating solution. In addition, while adding ethanol and purified water to a stainless container while stirring, HCTZ, povidone 29/32, talc was added slowly, and vigorously stirred until completely dissolved and suspended to prepare a secondary coating solution.

 The coated tablet was prepared by injecting the telmisartan core tablet manufactured in <Reference Example 1> in a coating machine (eg, SEJONG, SFC-30) and spraying the coating solution evenly at an air supply temperature of 60 degrees and an exhaust temperature of 35 to 40 degrees. The composition of the tablets prepared was as described in Table 1 below.

 Table 1

 Bilayer Tablet Composition (I) of Example 1 (Unit: mg, 507 mg / l tablets)

<Example 2>

Preparation of bilayer tablets containing telmisartan and diuretics (Π)-Use of povidone (polyvinylpyrrolidone) as a water-soluble polymer for primary coating The telmisartan core prepared in <Reference Example 1> was coated with primary and secondary methods in the same manner as in <Example 1> as shown in Table 2, to prepare a bilayer tablet including telmisartan and a diuretic. It was.

 [Table 2].

 Bilayer Tablet Composition (Π) of Example 2 (unit: mg, 510 mg / l tablets)

<Example 3>

 Preparation of bilayer tablets containing telmisartan and diuretics (m)-Use of povidone (polyvinylpyrrolidone) as a water-soluble polymer for primary coating

 The telmisartan core prepared in <Reference Example 1> was coated with primary and secondary methods in the same manner as in <Example 1> as in the composition of Table 3 to prepare a bilayer tablet including telmisartan and a diuretic. It was.

 Table 3

 Bilayer Tablet Composition (ΠΙ) of Example 3 (unit: mg, 512.7 mg / l tablets)

<실시예 4>

<Example 4>

 Preparation of bilayer tablets containing telmisartan and diuretics (IV)-Use of povidone (polyvinylpyrrolidone) as a water-soluble polymer for primary coating

 The telmisartan core prepared in <Reference Example 1> was coated in the same manner as in <Example 1> in the same manner as the composition of Table 4 to prepare a bilayer tablet including telmisartan and a diuretic. It was.

 Table 4

 Bilayer Tablet Composition (IV) of Example 4 (in mg, 275.5 mg / l tablets)

Example 5

 Preparation of Bilayer Tablets Containing Telmisartan and Diuretics (V)-Use of Povidone (polyvinylpyrrolidone) as Water-Soluble Polymer in Primary Coatings

 The telmisartan core prepared in <Reference Example 1> was coated with primary and secondary methods in the same manner as in <Example 1>, as shown in Table 5, to prepare a distillation layer containing telmisartan and a diuretic. Prepared.

 Table 5

 Bilayer Tablet Composition (V) of Example 5 (Unit: mg, 295 mg / l tablets)

 Telmisartan Core Tablets 240

 Primary Coated Povidone 29/32 2.5

 Polyethylene Glycol 6000 0.4

Talc 0.1 Ethane (volatile) 85

 Purified water (volatile) 10

 Second Coating HCTZ 12.5

 Povidone K29 / 32 12

 Croscarmellose Sodium 25

 Polyethylene Glycol 6000 2.5

 Ethanol (volatile) 700

 Purified Water (volatile) 60

Comparative Example 1

 Preparation of monolayer tablets containing telmisartan and diuretics (1)-Use of HPMC as a water-soluble polymer for monolayer coatings

 The telmisartan core prepared in <Reference Example 1> was first coated as shown in Table 6 to prepare a single layer tablet including telmisartan and a diuretic. The specific coating method for the core is as described in <Example 1>.

 Table 6

 Preparation of monolayer tablets of Comparative Example 1 (I) (unit: mg, 510 mg / l tablets)

Comparative Example 2

 Preparation of monolayer tablets containing telmisartan and diuretics (Π)-use of povidone as a water-soluble polymer in monolayer coatings

 The telmisartan core prepared in <Reference Example 1> was first coated as shown in Table 7 to prepare a monolayer tablet including telmisartan and a diuretic. The specific coating method for the core is as described in <Example 1>.

 Table 7

Preparation of a monolayer tablet of Comparative Example 2 (Π) (unit: mg, 508.5 mg / l tablets) Telmisartan Core Tablets 480

 Primary Coating HCTZ 12.5

 Povidone K29 / 32 14.5

 Talc 1.5

 Ethane (volatile) 700

 Purified water (volatile) 300

Comparative Example 3

 Preparation of bilayer tablets containing telmisartan and diuretics-use fflC as water-soluble polymer for primary coating

 The telmisartan core prepared in <Reference Example 1> was coated with primary and secondary as in the composition of Table 8 to prepare a bilayer tablet including telmisartan and a diuretic. The specific coating method for the core is as described in <Example 1>.

 Table 8

 Bilayer Tablet Composition of Comparative Example 3 (Unit: mg, 510.5mg / l tablets)

Experimental Example 1

 Evaluation by Dissolution Test

 After eluting at 900 rpm for 15 minutes in 900 ml of pH1.2, pH4.0 and pH6.8 dissolution test solution according to the method 2 of the Korean Pharmacopoeia General Test Methods, the dissolution rate of HCTZ, a diuretic, was measured. It is listed in Table 9 below.

In addition, the dissolution rate of telmisartan was eluted after eluting at a speed of 75 revolutions for 30 minutes in 900 ml of the elution test solution of pH 7.5 according to the second method of the general test method dissolution test method. The measurement results are shown in Table 9 below. The following commercially available formulations contain 80 mg or 40 mg of telmisartan and 12.5 mg of HCTZ, a diuretic.

 Table 9

 Dissolution Test Results (Unit: ¾)

 -Commercially available formulations: Mycardis plus tablet (manufacturer: Boehringer Ingelheim) As shown in Table 9, the commercially available formulations had a dissolution rate of HCTZ, which is a diuretic for 15 minutes or more, in a dissolution test solution. And in the case of single-layer tablet as in <Comparative Example 2> dissolution rate is 80% or less. In addition, as shown in <Comparative Example 3> it can be seen that the dissolution rate is 80% or less when HPMC 2910 is used as an inert water-soluble polymer in one pack.

 However, when povidone (polyvinylpyrrolidone) was used as the inert water-soluble polymer in the first layer as in <Example 1> to <Example 3>, the dissolution rate of HCTZ was about 90% at most pH, in particular < As in Example 4 to <Example 5>, a povidone (polyvinylpyrrolidone) was used as the inert water-soluble polymer in the first layer, and a water-soluble polymer, a disintegrating agent (sodium chromosomal sodium) and a plasticizer ( When polyethylene glycol) is mixed together, it can be seen that better elution is obtained.

 In addition, in the case of <Example 1> to <Example 5> it can be seen that the very excellent effect in the dissolution rate of telmisartan compared to <Comparative Example 1> to <Comparative Example 3>.

Taken together, the bilayer containing telmisartan and diuretics In preparing tablets, the dissolution rate (HCTZ and telmisartan) is superior to commercially available products by coating a telmisartan core with povidone (polyvinylpyrrolidone), an inert water-soluble polymer, and coating a diuretic and povidone on it. Furthermore, when the telmisartan core is coated with an inert water-soluble polymer, povidone (polyvinylpyrrolidone) and mixed with a diuretic, povidone, disintegrant, and a plasticizer on it, it has the best dissolution rate. Can be.

Experimental Example 2

 Tablet Size and Weight Comparison

 The size of the tablet prepared in <Example 1> and the commercial preparation used in <Experimental Example 1> were measured according to FIGS. 1 and 2 and the results are shown in Table 10 below.

Table 10

¬임) 상기 표 10에 기재한 바와 같이， <실시예 1>의 정제 시판제제보다 매우 작아 복용이 용이함을 알 수 있다.

¬)) As shown in Table 10 above, it can be seen that the dosage is much smaller than the tablet commercial preparation of <Example 1>.

 In addition, the weight according to the content of the drug of the commercial formulation and <Example

 The weights of <Example 4> were compared and the results are shown in Table 11.

 Table 111

 Tablet weight comparison

 As shown in Table 11, it can be seen that the tablet weight of <Example 2> or <Example 4> is much less than the commercially available formulations, and thus easy to take.

Claims

[Range of request]  1. a core in the form of a dissolved tablet matrix comprising telmisartan and a basic substance;  A first coating layer coated on the core and comprising a polyvinylpyrrolidone-based polymer; And  A pharmaceutical composition comprising a second coating layer coated on the first coating layer and comprising a hydrochlorothiazide and a polyvinylpyridone-based polymer. 2. The pharmaceutical composition of claim 1 comprising 20 mg to 80 mg telmisartan and 6.25 mg to 25 mg hydrochlorothiazide per unit dosage form. 3. The pharmaceutical composition according to item 2, wherein the hydrochlorothiazide: the weight ratio of the polyvinylpyrrolidone-based polymer of the first coating layer is from 10: 1 to 2: 1. 4. The pharmaceutical composition according to item 2, wherein the hydrochlorothiazide: the weight ratio of the polyvinylpyridone-based polymer of the second coating layer is from 2: 1 to 1: 1. 5. The pharmaceutical composition of claim 1, wherein the second coating layer further comprises a disintegrant. 6. The pharmaceutical composition of claim 5, wherein the second coating layer further comprises at least one selected from the group consisting of plasticizer, talc, titanium oxide, silicon dioxide, and surfactant. 7. The method according to claim 5, wherein the hydrochlorothiazide: A pharmaceutical composition comprising the weight ratio of the disintegrants to be 1.5: 1 to 0.2: 1. 8. The method of claim 1, wherein the hydrochlorothiazide has a dissolution rate of 80% or more within 15 minutes in an aqueous solution having a pH of 7 or less, The telmisartan has a dissolution rate of 80% or more in 30 minutes in an aqueous solution of _P H 7.5. 9. The pharmaceutical composition according to any one of items 1 to 8, wherein the total weight of the unit dosage form is 6 to 8 times the weight of telmisartan.