KR101823071B1 - Process for preparing telmisartan-containing tablets - Google Patents

Abstract

The present invention provides a process for preparing telmisartan-containing tablets by wet granulation, which method comprises using telmisartan-containing tablets comprising colloidal silicon dioxide as an adsorbent and a specific diluent.

Description

TECHNICAL FIELD The present invention relates to a process for preparing telmisartan-containing tablets,

The present invention relates to a process for preparing telmisartan-containing tablets by wet granulation and more particularly to a process for the preparation of telmisartan-containing tablets comprising using colloidal silicon dioxide and a specific diluent as adsorbents .

Telmisartan is known to be an angiotensin II receptor antagonist developed to treat hypertension and other medical indications (EP-A-502314). The chemical name of telmisartan is 4 '- [(1,4'-dimethyl-2'-propyl [2,6'- -Biphenyl] -2-carboxylic acid or 4'- [2-n-propyl-4-methyl-6- (1- methylbenzimidazol- Carboxylic acid, and has the following chemical structure.

Telmisartan is used in the form of the free acid and is known to have very low solubility in the physiological pH range of the gastrointestinal tract at pH 1-7. The presently available method of preparing telmisartan formulations comprises the steps of preparing an aqueous solution comprising a basic agent and optionally a solubilizing agent and a water-soluble polymer, spray-drying the resulting aqueous solution to obtain spray-dried granules, With a water soluble diluent to obtain a premix, mixing the premix with a lubricant to obtain the final mixture. However, the above-described manufacturing method has a problem in that the process itself is complicated and requires an expensive spray drying process.

In order to solve the problems of the conventional preparation method, Korean Patent Registration No. 10-0960953 discloses a method for producing telmisartan-containing tablets by the wet granulation method. The above method solves the problem that when the wet granulation method is applied to the conventional composition (i.e., the composition of Korean Patent Registration No. 876302), the granulation is not performed in the form of a slurry. Specifically, telmisartan 13-18 weight % Of alkali metal hydroxide and 6 to 15% by weight of meglumine, 4 to 12% by weight of a crystallization retarding agent (for example, polyvinylpyrrolidone), diluent (for example, microcrystalline cellulose (Avicel PH102) And 6 to 32% by weight of a high wetting rate solidifying agent (croscarmellose sodium, low-substituted hydroxypropylcellulose, starch glycolic acid, crospovidone, etc.) into wet granules . However, when the telmisartan-containing tablets are prepared according to the above-described preparation method, the properties of the tablets obtained during storage are changed to brown, resulting in low stability. In addition, A diluent is required. As a result, when the tablet is formulated in a two-ply tablet or the like, the size of the tablet increases and the compliance with the medication is lowered.

In particular, conventional telmisartan-containing tablets containing currently available telmisartan-containing tablets contain a strong alkalizing agent such as sodium hydroxide, and because of their strong self-melting properties (i.e., deliquescence) by absorbing moisture in the air, Storage stability is low. Therefore, special packaging such as Alu-Alu package is used to avoid such low stability problem.

The present inventors have found that a simple preparation method, that is, a method for producing telmisartan-containing tablets by a conventional wet granulation method, is characterized in that the tablets obtained have not only superior stability, but also have telmisartan-containing tablets showing biological equivalence with commercially available telmisartan- Various studies have been conducted to develop a method for producing a carbon-containing tablet. The present inventors have found that when a specific adsorbent (i.e., colloidal silicon dioxide) is used, a combined process can be carried out without slurry formation, so that the wet granulation method can be effectively applied and the size of the resulting tablet can be reduced. Further, the inventors of the present invention have found that browning of the tablets obtained is due to the interaction of sodium hydroxide and microcrystalline cellulose used for dissolving telmisartan, and when preparations are carried out using a diluent other than the microcrystalline cellulose series It has been found that it is possible to prepare telmisartan-containing tablets which not only have excellent stability but also exhibit biological equivalence with commercially available telmisartan-containing tablets.

Accordingly, it is an object of the present invention to provide a process for preparing telmisartan-containing tablets by wet granulation comprising using colloidal silicon dioxide as the adsorbent and also using a diluent other than the microcrystalline cellulose series.

According to one aspect of the present invention, there is provided a method for preparing a solution, comprising the steps of: (a) dissolving a water-soluble polymer as an aqueous solution of telmisartan, an alkali metal hydroxide and a meglumine as solubility aids, and a crystallization retarding agent in an ethanol aqueous solution to obtain a solution; (b) mixing a mixture of (i) colloidal silicon dioxide as the adsorbent, (ii) a diluent selected from the group consisting of starch, starch, mannitol, and isomalt, and (iii) a disintegrant to obtain a mixture; (c) performing a combined process using the solution obtained in step (a) and the mixture obtained in step (b) to obtain wet granules and drying the obtained wet granules to obtain granules; and (d) containing granule mixture obtained by mixing the granules obtained in step (c) with a lubricant, and then tableting the resulting mixture to form tablets, or (d2) mixing the granules obtained in step (c) with a lubricant; And tabletting a mixture comprising amlodipine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive using a bilayer tablet press to form a bilayer tablet, .

In the production method of the present invention, step (a) is carried out by mixing 7 to 9 parts by weight of an alkali metal hydroxide, 10 to 15 parts by weight of meglumine and 2 to 15 parts by weight of a water-soluble polymer with 100 parts by weight of telmisartan in an aqueous ethanol solution And then dissolving it to obtain a solution. The water-soluble polymer may be selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, and hydroxypropylcellulose. The volume ratio of water to ethanol in the aqueous ethanol solution is 1: 2 to 3, and the total amount of the aqueous ethanol solution may be 120 to 130 parts by volume based on 100 parts by weight of telmisartan.

The colloidal silicon dioxide may be used in an amount of 30 to 60 parts by weight, preferably 55 to 60 parts by weight, based on 100 parts by weight of telmisartan. The diluent may be used in an amount of 140 to 220 parts by weight based on 100 parts by weight of telmisartan, and may be a mixture of starch and starch. The disintegrant may be selected from the group consisting of carboxymethylcellulose calcium, sodium starch glycolate, croscarmellose sodium, and crospovidone, and may be in the range of 50 to 130 parts by weight per 100 parts by weight of telmisartan Can be used.

In the preparation method of the present invention, the pharmaceutically acceptable salt of amlodipine may be an amlodipine nicotinic acid salt. In addition, the pharmaceutically acceptable additive of step (d) may be a diluent selected from the group consisting of a mixture of starch and starch, mannitol, calcium hydrogen phosphate, or a mixture thereof; And disintegrants selected from the group consisting of carboxymethylcellulose calcium, sodium starch glycolate, or mixtures thereof.

The method for preparing telmisartan-containing tablets according to the present invention can use a colloidal silicon dioxide as an adsorbent to perform a combined process without forming a slurry, thereby effectively applying the wet granulation method, . It has also been found by the present invention that the reduction in the stability of the telmisartan-containing tablet (i.e. browning) is due to the interaction of sodium hydroxide and microcrystalline cellulose used for the dissolution of telmisartan and the microcrystalline cellulose series It has been found by the present invention that a tablets containing telmisartan having excellent stability can be prepared when formulations are carried out using other diluents. Thus, through the manufacturing method of the present invention, the telmisartan-containing tablet can be produced by a simple method, that is, a conventional wet granulation method. In particular, it is possible to provide a tablet containing a telmisartan- A telmisartan-containing tablet exhibiting equivalence can be prepared. In addition, the total weight of the resulting telmisartan-containing tablet can be effectively reduced, and the patient's compliance with medicines can be improved.

1 to 4 are graphs showing comparative dissolution tests of telmisartan (twin tablets of Preparation Examples 1 to 7) prepared in Example 3 and telmisartan / amlodipine combination Twins Tablet 80/5 mg ^TM as a comparative preparation And the results are shown in Fig.
Fig. 5 shows the blood concentration profile of telmisartan for the two-layer tablets (Example 6 of Example 3) prepared according to the present invention and Twins Tablets 80 / 5mg ^TM , a telmisartan / amlodipine combination, as a comparative agent.

(A) dissolving a water-soluble polymer in an aqueous ethanol solution as telmisartan, an alkali metal hydroxide and a meglumine as solubility aids, and a crystallization retarding agent to obtain a solution; (b) mixing a mixture of (i) colloidal silicon dioxide as the adsorbent, (ii) a diluent selected from the group consisting of starch, starch, mannitol, and isomalt, and (iii) a disintegrant to obtain a mixture; (c) performing a combined process using the solution obtained in step (a) and the mixture obtained in step (b) to obtain wet granules and drying the obtained wet granules to obtain granules; and (d) containing granule mixture obtained by mixing the granules obtained in step (c) with a lubricant, and then tableting the resulting mixture to form tablets, or (d2) mixing the granules obtained in step (c) with a lubricant; And tabletting a mixture comprising amlodipine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive using a bilayer tablet press to form a bilayer tablet, .

In the preparation method of the present invention, telmisartan used as an active ingredient can be used as a therapeutically effective amount, for example, 20 to 80 mg per unit tablet or unit two-layer tablet (double layer tablet) , ≪ / RTI > In one embodiment, the telmisartan can be used in an amount of about 80 mg.

The step (a) is carried out by dissolving the water-soluble polymer in aqueous ethanol solution as telmisartan, alkali metal hydroxide and meglumine as solubility aids, and crystallization retarding agent to obtain a solution.

The water-soluble polymer is used as a crystallization retarder and also functions as a binder for carrying out a combined process. The water-soluble polymer may be at least one selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, and hydroxypropylcellulose, preferably polyvinylpyrrolidone. In the conventional preparation method, the water-soluble polymer is used in an amount of 25 to 35 parts by weight based on 100 parts by weight of telmisartan. However, there is a problem that it is difficult to carry out the association process because the viscosity of the combined liquid containing the water-soluble polymer in the above range is too high. Surprisingly, even if a water-soluble polymer is used in a small amount (for example, 2 to 15 parts by weight based on 100 parts by weight of telmisartan), not only the effective function as a crystallization retarding function and a binder but also an appropriate viscosity 15 to 20 CP) is obtained by the present invention. In one embodiment, step (a) comprises dissolving 7 to 9 parts by weight of an alkali metal hydroxide, 10 to 15 parts by weight of a meglumine, and 2 to 15 parts by weight of a water soluble polymer in an aqueous solution of ethanol, relative to 100 parts by weight of telmisartan ≪ / RTI > solution.

The volume ratio of water to ethanol in the aqueous ethanol solution is preferably in the range of 1: 2 to 3 for effective dissolution of telmisartan. In addition, the total amount of the aqueous ethanol solution is preferably in the range of 120 to 130 parts per 100 parts by weight of telmisartan, and when used in this range, it is possible to provide an appropriate viscosity for effective performance of the combined process .

Wherein step (b) comprises mixing (i) a colloidal silicon dioxide as the adsorbent, (ii) a diluent selected from the group consisting of starch, starch, mannitol, and isomalt, and (iii) a disintegrant, ≪ / RTI >

It has been found by the present invention that colloidal silicon dioxide exhibits a significantly higher adsorption power to the associate liquid, thereby enabling the performance of an effective coalescing process while avoiding slurry formation, as well as reducing the size of the resulting tablet. The colloidal silicon dioxide, e.g., as eotaxin chamber ^TM (Aerosil ^TM), Evonik Co.] may be used in a range of 30 to 60 parts by weight based on 100 parts by weight of carbon telmisartan, preferably 55 to 60 parts by weight of Lt; / RTI >

It has also been found by the present invention that the decrease in the stability of the telmisartan-containing tablet (i.e. browning) is due to the interaction of sodium hydroxide and microcrystalline cellulose used for dissolving telmisartan, and the microcrystalline cellulose series It has been found by the present invention that a tablets containing telmisartan having excellent stability can be prepared when formulations are carried out using other diluents. The diluent may be selected from the group consisting of starch (corn starch, potato starch, etc.), starch, mannitol, and isomalt, preferably a mixture of starch and starch, more preferably corn starch corn starch) as a mixture of gelatinized starch (pregelatinized starch) may be e.g., star cap ^{1500 TM (StarCap 1500 TM),} Colorcon Inc.]. The diluent may be used in an amount of 140 to 220 parts by weight based on 100 parts by weight of telmisartan.

The disintegrant may be selected from the group consisting of carboxymethylcellulose calcium, sodium starch glycolate, croscarmellose sodium, and crospovidone, preferably carboxymethylcellulose calcium, croscarmellose sodium, And crospovidone. The disintegrant may be used in an amount of 50 to 130 parts by weight based on 100 parts by weight of telmisartan.

The step (c) is carried out by performing a combined process using the solution obtained in step (a) and the mixture obtained in step (b) to obtain wet granules and drying the obtained wet granules to obtain granules. The combined process may be carried out by a method usually performed in the field of pharmaceuticals, and the drying process may also be carried out by a method usually performed in the pharmaceutical field.

The step (d) comprises the steps of: (d1) mixing the granules obtained in step (c) with a lubricant (for example, magnesium stearate) Containing granules and a glidant; And amlodipine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, using a bilayer tablet press to form a bilayer tablet.

In step d2 above, amlodipine or a pharmaceutically acceptable salt thereof may be used as a therapeutically effective amount. For example, the pharmaceutically acceptable salt of amlodipine may be an amlodipine nicotinic acid salt and is in the range of 1.5 to 7.0 mg, preferably 1.625 to 6.5 mg per unit bi-layer tablet (double layered tablet), more preferably, Can be used in an amount of about 3.25 mg.

In addition, the pharmaceutically acceptable additives used in step (d2) include, without limitation, additives commonly used in amlodipine-containing bilayers. In one embodiment, the pharmaceutically acceptable excipient is selected from the group consisting of a mixture of starch and starch, a diluent selected from the group consisting of mannitol, calcium hydrogen phosphate, or mixtures thereof; And disintegrants selected from the group consisting of carboxymethylcellulose calcium, sodium starch glycolate, or mixtures thereof.

In one embodiment of the present invention, 80 g of (a ') telmisartan, 6.7 g of sodium hydroxide, 10 g of meglumine and 4 g of polyvinylpyrrolidone per unit double-layer tablet are mixed in a volume ratio of water to ethanol of 3: 7 Ethanol solution (100 mL) to obtain a solution; (b ') Mixing 45 g of colloidal silicon dioxide per unit double-layer tablet, 114.3 g of a mixture of starch and starch, 25 g of carboxymethylcellulose, 20 g of croscarmellose sodium and 20 g of crospovidone to obtain a mixture; (c ') performing a combined process using the solution obtained in step (a') and the mixture obtained in step (b ') to obtain wet granules and drying the obtained wet granules to obtain granules; (d ') a telmisartan-containing granule mixture obtained by mixing the granules obtained in step (c') with a lubricant; And a step of tableting the mixture comprising S-amlodipine nicotinate and a pharmaceutically acceptable additive using a bilayer tablet press to form a bilayer tablet.

Hereinafter, the present invention will be described in more detail through examples and test examples. However, these examples and test examples are for illustrating the present invention, and the present invention is not limited to these examples and test examples.

Example  1. Adhesive force evaluation for combined process

40 g of polyvinylpyrrolidone (PVP K30) was dissolved in a mixture of 300 ml of purified water and 700 ml of ethanol. 50 g each of colloidal silicon dioxide, microcrystalline cellulose, silicified microcrystalline cellulose, corn starch, potato starch, star capsule 1500, lactose, mannitol, and isomalt was used to prepare a solution (that is, The combined sum was added. The amount of the associative solution capable of adsorbing 50 g of each component is shown in Table 1 below.

ingredient Amount of solution used in association Amount of adsorbable associative liquid Colloidal silicon dioxide 50 g 170 g Microcrystalline cellulose 50 g 35 g Silicified microcrystalline cellulose 50 g 35 g Corn starch 50 g 20 g Potato starch 50 g 20 g Star Cap 1500 50 g 20 g Lactose 50 g 15 g Mannitol 50 g 10 g Isomalt 50 g 15 g

From the results shown in the above Table 1, it is surprisingly found that the colloidal silicon dioxide exhibits remarkably excellent adsorption power.

Example  2. Viscosity evaluation of associate liquid

Sodium hydroxide, meglumine, PVP K30 and telmisartan were dissolved in the order of the ingredients shown in the following Table 2 to prepare a telmisartan solution, and the viscosity thereof was confirmed. The viscosity was measured at 25 ° C using a Brookfield rotary viscometer, Dv2T, and the time taken for complete dissolution was recorded using a mechanical stirrer at a stirring rate of 1000 rpm. The results are shown in Table 2 below.

Ingredients A B C D E F chief ingredient Telmisartan (g) 80 80 80 80 80 80 Dissolution aid
Sodium hydroxide (g) 6.7 6.7 6.7 6.7 6.7 6.7 Meglumine (g) 24 24 12 10 10 4 Crystallization retarder PVP K30 (g) 24 24 12 8 4 4 menstruum
Purified water (mL) 50 40 30 30 30 30 Ethanol (mL) 120 80 70 70 70 70 Viscosity (CP) 18.5 36.4 27.5 22.2 16.4 16.5 Dissolving time (min) 40 minutes 60 minutes 45 minutes 45 minutes 30 minutes 30 minutes

From the results in the above Table 2, it can be seen that A, E, and F show suitable viscosity and dissolution time for the preparation of the combined liquid, and that the combined amount of E and F can be used preferably because the amount of the solvent used is too much Able to know.

Example  3. Telmisartan  And Amlodipine  Manufacture of two layer definition

On the basis of the results of Examples 1 and 2, a two-layer tablet containing telmisartan and amlodipine was prepared by the components and contents of Tables 3 and 4 below. The contents of the following Tables 3 and 4 show the content (g) of each component of the unit two-layer system.

Sodium hydroxide, meglumine, and PVP K30 were dissolved in an ethanol aqueous solution (a mixture of 30 ml of purified water and 70 ml of ethanol per 80 g of telmisartan) and dissolving telmisartan to prepare a solution. Separately, the mixture was obtained by mixing the adsorbent (colloidal silicon dioxide), the diluent, and the disintegrant, and then the solution was used as a combined liquid to obtain wet granules. The resulting wet granules were dried and sized at 60 占 폚, and then the lubricant was mixed to prepare a mixture (mixture A) for the formation of the tellysatellite layer.

The amlodipine nicotinate salt and Star Cap 1500 were mixed, and the diluent, disintegrant, and coloring agent were uniformly mixed and then mixed with magnesium stearate to prepare a mixture (mixture B) for amlodipine layer formation.

Mixture A and Mixture B were tableted with a bilayer tablet press (JC-DH-23D, JCMCO) to prepare a two-layer tablet.

Formulation Example 1
(g) Formulation Example 2
(g) Formulation Example 3
(g) Formulation Example 4
(g) The first layer chief ingredient Telmisartan 80 80 80 80 Dissolution aid Sodium hydroxide 6.7 6.7 6.7 6.7 Meglumine 16 10 10 10 Water-soluble polymer PVP K30 12 8 4 4 absorbent Colloidal silicon dioxide 10 35 20 5 diluent Silicified microcrystalline cellulose 154.3 50 119.3 189.3 Isomalt - 49.3 - - Disintegration Carboxymethylcellulose calcium 46 46 25 30 Sodium croscarmellose sodium - - 30 20 Crospovidone 50 40 20 30 Lubricant Magnesium stearate 5 5 5 5 sub Total 380 330 320 380 Second layer chief ingredient S-amlodipine nicotinate 3.25 3.25 3.25 3.25 diluent Star Cap 1500 107.95 107.95 107.95 107.95 D-mannitol 40 40 40 40 Anhydrous calcium hydrogen phosphate 10 10 10 10 Disintegration Starch glycolate sodium 6.5 6.5 6.5 6.5 Carboxymethylcellulose calcium 10 10 10 10 Lubricant Magnesium stearate 2 2 2 2 coloring agent Blue No. 2 Aluminum Lake 0.3 0.3 0.3 0.3 sub Total 180 180 180 180 Sum 560 510 500 560

Formulation Example 5
(g) Formulation Example 6
(g) Formulation Example 7
(g) The first layer chief ingredient Telmisartan 80 80 80 Dissolution aid Sodium hydroxide 6.7 6.7 6.7 Meglumine 10 10 10 Water-soluble polymer PVP K30 4 4 4 absorbent Colloidal silicon dioxide 25 45 25 diluent Corn starch 114.3 - - Star Cap 1500 - 114.3 144.3 Isomalt 40 - - Disintegration Carboxymethylcellulose calcium 30 25 35 Sodium croscarmellose sodium 20 20 20 Crospovidone 30 20 30 Lubricant Magnesium stearate 5 5 5 sub Total 365 330 360 Second layer chief ingredient S-amlodipine nicotinate 3.25 3.25 3.25 diluent Star Cap 1500 107.95 107.95 107.95 D-mannitol 40 40 40 Anhydrous calcium hydrogen phosphate 10 10 10 Disintegration Starch glycolate sodium 6.5 6.5 6.5 Carboxymethylcellulose calcium 10 10 10 Lubricant Magnesium stearate 2 2 2 coloring agent Blue No. 2 Aluminum Lake 0.3 0.3 0.3 sub Total 180 180 180 Sum 545 510 540

Test Example  1. Comparative dissolution test

Twins Tablet 80 / 5mg ^TM (telmisartan / amlodipine combination) as a two-layer tablet (two-layer tablets of Formulation Examples 1 to 7) prepared in Example 3 and a comparative preparation (Comparative Example 1) ) Was subjected to a comparative dissolution test of telmisartan. Using a pH 1.2 solution, water, and 900 mL of pH 7.5 phosphate buffer as the elution test liquid, 50 rpm (pH 1.2, water) was prepared according to the dissolution test method second method paddle method in the Korean Pharmacopoeia General Test Methods, The elution test was carried out for 1 hour each with stirring at 75 rpm (pH 7.5 phosphate buffer solution). A test sample was taken at a given time and the concentration of telmisartan was analyzed using high performance liquid chromatography (HPLC) under the following conditions.

<HPLC Conditions>

- Detector: UV absorptiometer

- Column: Capsule pack C18, 4.6mm * 150mm, 5um

- Mobile phase: 0.5 mL of triethylamine was added to the mixture of acetonitrile, methanol and 0.1 mol / L ammonium acetate solution (250/350/400, v / v / v), and adjusted to pH 7.1 ± 0.1 with acetic acid

- Flow rate: 1.6 mL / min

- Wavelength: 298 nm

- Amount of injection: 20 uL

The results of the dissolution test performed as described above are shown in FIGS. 1 to 4. As can be seen from Figs. 1 to 4, the two-layered tablets prepared in Preparation Examples 1 to 7 exhibited dissolution rates similar to those of the comparative preparation in a pH 1.2 solution, water, and a pH 7.5 buffer.

Test Example  2. Stability evaluation

The stability of the two-layered tablets prepared in Example 3 (two-layered tablets of Examples 1 to 8) under severe conditions was evaluated. That is, the two-layered tablets of Formulation Examples 1 to 8 were stored for 5 days in an enclosed state at 60 캜 in severe condition, and the amount of the constituents and the amount of the flexible substance were measured. The base matrix material is amlodipine impurity D (2-propyl 4-methyl-6- (1-methylimidazol-2-yl) benzimidazole) derived from telmisartan and amlodipine impurity D The amount of untransformed and total flexible materials was measured by the following method. The amount of [(2-Aminoethoxy) methyl] -4- (2-chlorophenyl) -6-methyl-3,6-pyridinedicarboxylic Acid 3-Ethyl 5-Methyl Ester &Lt; / RTI &gt; using high performance liquid chromatography (HPLC).

<HPLC conditions of telmisartan-derived flexible material>

- Detector: UV absorptiometer

- Column: Nova Pack C18 3.9mm * 150mm, 4um

- mobile phase: mixture of acetonitrile, methanol, ^* buffer (135: 315: 550, v: v: v)

* Buffer: 0.2 g of sodium hydroxide is dissolved in 500 mL of water, then 500 mL of methanol is added and mixed

- Flow rate: 1.0 mL / min

- Wavelength: 298 nm

- dose: 50 uL

&Lt; HPLC conditions of the succinimidyl nicotinate-derived flexible material >

- Detector: UV absorptiometer

- Column: Capsule pack C18 4.6mm * 150mm, 5um

- Mobile phase A: ^* Mixture of buffer, methanol, acetonitrile (550: 300: 150, v: v: v)

- Mobile phase B: ^* Mixture of buffer, methanol and acetonitrile (300: 600: 100, v: v: v)

* Buffer: 1000 mL of water is added to 7.0 mL of triethylamine and adjusted to pH 3.0 ± 0.1 with phosphoric acid

- Flow rate: 1.2 mL / min

- wavelength: 237 nm

- Injection volume: 80uL

- concentration gradient

The results of the measurement as described above are shown in Tables 5 and 6 below.

Formulation Example 1 Formulation Example 2 Formulation Example 3 Formulation Example 4 Storage conditions Room temperature Harshness Room temperature Harshness Room temperature Harshness Room temperature Harshness Flexible material Base flexible material 0.10 0.11 0.10 0.10 0.11 0.11 0.11 0.10 Unknown flexible substance 0.05 0.05 0.06 0.06 0.06 0.06 0.06 0.05 Total flexible material 0.23 0.22 0.24 0.23 0.22 0.23 0.22 0.22 Constellation change Telmisartan White → Brown White → Brown White → Brown White → Brown Amlodipine layer Blue → Blue Blue → Blue Blue → Blue Blue → Blue

Formulation Example 5 Formulation Example 6 Formulation Example 7 Storage conditions Room temperature Harshness Room temperature Harshness Room temperature Harshness Flexible material Base flexible material 0.10 0.10 0.09 0.09 0.10 0.09 Unknown flexible substance 0.06 0.07 0.06 0.07 0.06 0.06 Total flexible material 0.22 0.23 0.23 0.24 0.24 0.24 Constellation change Telmisartan White → White White → White White → White Amlodipine layer Blue → Blue Blue → Blue Blue → Blue

As can be seen from the results of Table 5 and Table 6, the two-layer formulations of Formulation Examples 1 to 7 all had no change in the amount of the flexible substance detected during storage at room temperature and in the severe condition, The color of the telmisartan layer changed from white to brown.

From the results of Table 5 and Table 6, the interaction between the main component and various additives was evaluated. That is, the respective components were mixed as shown in Table 7 below, and the amount of the flexible material was measured while being kept in a closed state at 60 DEG C for 5 days. The results are shown in Table 7 below.

Mixing information Storage at 60 ℃ in severe condition Early After 5 days Telmisartan + sodium hydroxide (1: 0.1) White White The meglumine + sodium hydroxide (1: 1) White White Colloidal silicon dioxide + sodium hydroxide (1: 0.5) White White Silicified microcrystalline cellulose + sodium hydroxide (1: 0.5) White Dark brown Microcrystalline cellulose + sodium hydroxide (1: 0.5) White Dark brown Corn starch + sodium hydroxide (1: 0.5) Light yellow Light yellow Potato starch + sodium hydroxide (1: 0.5) White White Star Cap 1500 + sodium hydroxide (1: 0.5) White White Isomalt + sodium hydroxide (1: 0.5) White White Crospovidone + sodium hydroxide (1: 0.5) White White Sodium starch glycolate + sodium hydroxide (1: 0.5) White White Carboxymethylcellulose calcium + sodium hydroxide (1: 0.5) Light yellow color Sodium croscarmellose sodium + sodium hydroxide (1: 0.5) Light yellow Light yellow Magnesium stearate + sodium hydroxide (1: 1) White White

(): Mixing ratio (weight ratio)

From the results in Table 7, it can be seen that the changes in the two-layered positive-working formulations of Formulation Examples 1 to 7 are due to the interaction of microcrystalline cellulose or microcrystalline cellulose with sodium hydroxide. Therefore, it can be seen that excellent stability can be achieved by using a diluent other than the microcrystalline cellulose series.

Test Example  3. Pharmacokinetics pharmacokinetic ) exam

A pharmacokinetic study of telmisartan of Twins Tatjut 80/5 mg ^TM (manufactured / imported: Boehringer Ingelheim, Korea) as telmisartan / amlodipine combination was conducted as a two-layer tablet and a comparative preparation prepared according to the present invention.

Twelve healthy adults (weight: 70 ± 10 kg) per group were treated with 0.25, 0.5, 0.75, 1, 1.25, 1.5, After 2, 2.5, 3, 4, 6, 8, and 12 hours, blood was collected with a heparinized syringe. The collected blood was centrifuged at 4000 rpm for 10 minutes, and the separated plasma was taken and stored frozen at -70 ° C until analysis. The concentration of telmisartan in plasma was quantitated using LC-MS / MS. The LC-MS / MS analysis conditions were as follows.

<Conditions for LC-MS / MS analysis>

The blood concentration profile obtained from the pharmacokinetics test is shown in FIG. 5, and the drug entrapment parameters obtained from the results are shown in Table 8 below.

Twins Tablets 80 / 5mg ^TM Formulation Example 6 of Example 3 PK parameter AUC _{0 ? 12 hr} (ng · hr / ml) 1619.95 ± 805.10 1644.98 ± 899.43 Cmax (ng / ml) 441.49 +/- 290.96 438.68 ± 267.59 Tmax (hr) 1.45 ± 2.13 1.38 ± 1.99 Average ratio AUC _{0 ? 12 hr} (Ratio) 1,000 1.015 Cmax (Ratio) 1,000 0.994

5 and 8, it was found that the two-layered tablets prepared according to the present invention exhibited biological equivalence with the comparative formulation Twins Tablets _80/5 mg ^TM with an average ratio of AUC _{0 ? 12 hr} of 1.015 and an average ratio of Cmax of 0.994 have.

Claims (13)

(a) dissolving a water-soluble polymer in an aqueous ethanol solution as telmisartan, an alkali metal hydroxide and a meglumine as solubility aids, and a crystallization retarding agent to obtain a solution;
(b) at least one diluent selected from the group consisting of (i) colloidal silicon dioxide as the adsorbent, (ii) starch, starch, mannitol, and isomalt, and (iii) sodium carboxymethylcellulose, sodium starch glycolate, Wherein the adsorbent, diluent, and disintegrant are present in an amount of from 30 to 60 wt% based on 100 wt% of telmisartan, respectively, to obtain a mixture comprising at least one disintegrant selected from the group consisting of croscarmellose sodium and crospovidone, 140 to 220 parts by weight, and 50 to 130 parts by weight;
(c) performing a combined process using the solution obtained in step (a) and the mixture obtained in step (b) to obtain wet granules and drying the obtained wet granules to obtain granules; and
(d) a telmisartan-containing granule mixture obtained by mixing the granules obtained in step (c) with a lubricant; And amlodipine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive are formed into tablets using a double-layer tableting machine to form a bilayer tablet
Containing bilayer tablet. The method of claim 1, wherein step (a) comprises dissolving 7 to 9 parts by weight of an alkali metal hydroxide, 10 to 15 parts by weight of a meglumine, and 2 to 15 parts by weight of a water-soluble polymer in an aqueous ethanol solution with respect to 100 parts by weight of telmisartan &Lt; / RTI &gt; in a solvent. The production method according to claim 1, wherein the water-soluble polymer is at least one selected from the group consisting of polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, and hydroxypropyl cellulose. The method of claim 1, wherein the volume ratio of water to ethanol in the aqueous ethanol solution of step (a) is 1: 2 to 3, and the total amount of the aqueous ethanol solution is 120 to 130 parts by volume relative to 100 parts by weight of telmisartan . delete The method according to claim 1, wherein the colloidal silicon dioxide is used in a range of 55 to 60 parts by weight based on 100 parts by weight of telmisartan. delete The method according to claim 1, wherein the diluent is a mixture of starch and starch. delete delete The method according to any one of claims 1 to 4, 6, and 8, wherein the pharmaceutically acceptable salt of amlodipine is s-amlodipine nicotinate. 9. A method according to any one of claims 1 to 4, 6 and 8, wherein the pharmaceutically acceptable excipient of step (d) is a mixture of starch and starch, mannitol, calcium hydrogen phosphate, A diluent selected from the group consisting of mixtures; And a disintegrant selected from the group consisting of carboxymethylcellulose calcium, sodium starch glycolate, or mixtures thereof. (a ') unit bilayer tablet 80 g of telmisartan, 6.7 g of sodium hydroxide, 10 g of meglumine and 4 g of polyvinylpyrrolidone were dissolved in 100 mL of a 3: 7 by volume aqueous ethanol solution of ethanol to prepare a solution ;
(b ') a mixture of 45 g of colloidal silicon dioxide per unit double-layered tablet, 114.3 g of a mixture of starch and starch, 20 g of croscarmellose sodium, 25 g of carboxymethylcellulose calcium and 20 g of crospovidone to obtain a mixture;
(c ') performing a combined process using the solution obtained in step (a') and the mixture obtained in step (b ') to obtain wet granules and drying the obtained wet granules to obtain granules;
(d ') a telmisartan-containing granule mixture obtained by mixing the granules obtained in step (c') with a lubricant; And amlodipine nicotinate salt and a pharmaceutically acceptable additive are tableted using a bilayer tablet press to form a bilayer tablet
Containing bilayer tablet.

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