KR20170095525A - Process for preparing telmisartan-containing tablets - Google Patents
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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Abstract
Description
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
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
(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 discovered 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.
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.
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.
(g)
(g)
(g)
(g)
(g)
(g)
(g)
Test Example 1. Comparative dissolution test
<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 a harsh condition, and the amount of the constituent 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 ≪ / RTI > 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
≪ 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.
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 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
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.
From the results of FIG. 5 and Table 8 shows the average ratio of the two-ply Chung AUC 0 → 12hr made according to the present invention refers to the 1.015, compared to the formulation of Twins tableting 80 / 5mg TM and bioequivalence to the average ratio of 0.994 of Cmax have.
Claims (13)
(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) (d1) mixing the granules obtained in the step (c) with a glidant, and then tableting the resulting mixture to form tablets, or
(d2) 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
Lt; RTI ID = 0.0 > of telmisartan-containing < / RTI >
(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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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2019098540A1 (en) * | 2017-11-15 | 2019-05-23 | Chong Kun Dang Pharmaceutical Corp. | Formulation having improved hygroscopic property and dissolution rate comprising telmisartan or its pharmaceutically acceptable salt |
KR20210079003A (en) * | 2019-12-19 | 2021-06-29 | 대원제약주식회사 | A pharmaceutical composition comprising angiotensin receptor blocker and preparation method thereof |
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RS53141B (en) * | 2004-11-05 | 2014-06-30 | Boehringer Ingelheim International Gmbh | Bilayer tablet comprising telmisartan and amlodipine |
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2019098540A1 (en) * | 2017-11-15 | 2019-05-23 | Chong Kun Dang Pharmaceutical Corp. | Formulation having improved hygroscopic property and dissolution rate comprising telmisartan or its pharmaceutically acceptable salt |
KR20210079003A (en) * | 2019-12-19 | 2021-06-29 | 대원제약주식회사 | A pharmaceutical composition comprising angiotensin receptor blocker and preparation method thereof |
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