JP2019001782A - Bilayer tablet - Google Patents

Abstract

To provide a bilayer tablet containing azilsartan and amlodipine besylate, where the stability of amlodipine besylate is improved, and the generation of its N-formyl body is inhibited.SOLUTION: A bilayer tablet contains an azilsartan-containing layer and an amlodipine-containing layer, where, in the weight of the bilayer tablet, the weight of the amlodipine-containing layer is 35-85%.SELECTED DRAWING: None

Description

  The present invention relates to a tablet containing two active ingredients, and specifically to a tablet containing amlodipine and azilsartan.

  For the treatment of hypertension, various compounds classified into calcium antagonists, ARBs (angiotensin II receptor antagonists), ACE (angiotensin converting enzyme) inhibitors, alpha blockers, beta blockers, diuretics, etc. It is used clinically as an antihypertensive agent, alone or in combination. For example, many calcium antagonists are known as amlodipine, nifedipine, nicardipine and other dihydropyridine drugs, and various other phenylalkylamines, benzodiazepines and other drugs are known. As ARB, azilsartan, irbesartan, losartan and others are known.

  These drugs are selected according to the patient's general condition in consideration of their pharmacological characteristics, and are used alone or in combination of two or more. Various preparations containing two or more of these drugs are also known.

  As such a compounding agent, as an angiotensin II receptor antagonist, for example, azilsartan (following Formula 1)

And a calcium antagonist such as amlodipine (Formula 2)

There is known a tablet composed of two layers with a layer containing sucrose (Patent Document 1).

Japanese Patent No. 5666471

  In the above background, the present inventor contains 20 mg of azilsartan and amlodipine besylate (5 mg as amlodipine) in each layer (hereinafter referred to as “azylsultan-containing layer” and “amlodipine-containing layer”, respectively). When a layered tablet was prototyped and evaluated, the amlodipine besylate salt of the bilayer tablet was destabilized and subjected to formylation of the primary amino group in the amlodipine molecule during storage, and an analog (N-formylamlodipine. In the following, it was found that “N-formyl” was formed. An object of the present invention is to provide a bilayer tablet containing azilsartan and amlodipine besylate, which can improve the stability of amlodipine besylate and suppress the formation of its N-formyl body. And

  As a result of the examination for the above purpose, a specific excipient selected within a certain range is contained in the amlodipine-containing layer side of the bilayer tablet in a predetermined ratio or more to increase the weight ratio of the amlodipine-containing layer in the bilayer tablet As a result, it was found that the formation of N-formyl bodies can be remarkably suppressed, and further studies were made to complete the present invention. That is, the present invention provides the following.

1. A bilayer tablet comprising an azilsartan-containing layer and an amlodipine-containing layer, wherein the weight of the amlodipine-containing layer accounts for 35 to 85% of the weight of the bilayer tablet.
2. The bilayer tablet according to 1 above, wherein the azilsartan content in the azilsartan-containing layer is 11 to 60% by weight, and the amlodipine besylate content in the amlodipine-containing layer is 1.4 to 8% by weight.
3. The bilayer tablet according to the above 1 or 2, comprising an excipient, wherein the excipient accounts for 75 to 95% by weight of the bilayer tablet.
4). The bilayer tablet according to 3 above, wherein 35 to 95% by weight of the excipient is contained in the amlodipine-containing layer.
5. The bilayer tablet according to 3 or 4 above, wherein the excipient is selected from the group consisting of D-mannitol, sucrose, erythritol, lactose hydrate, crystalline cellulose, corn starch, partially pregelatinized starch, and ethylcellulose. .
6). The bilayer tablet according to any one of 1 to 7 above, wherein the azilsartan-containing layer and / or the amlodipine-containing layer contains a binder.
7). The bilayer tablet according to 6 above, wherein the binder is selected from the group consisting of hydroxypropylcellulose, hypromellose, povidone, polyvinyl alcohol, and polyethylene glycol 6000.
8). The bilayer tablet according to any one of 1 to 7 above, wherein the azilsartan-containing layer and / or the amlodipine-containing layer further contains a disintegrant.
9. The disintegrant is selected from the group consisting of croscarmellose sodium, carmellose, carmellose calcium, crospovidone, sodium starch glycolate, light anhydrous silicic acid, crystalline cellulose, and low-substituted hydroxypropylcellulose, 8 double-layer tablets.
10. The bilayer tablet according to any one of 1 to 9 above, comprising 18 to 22 mg of azilsartan and 3 to 7.5 mg of amlodipine besylate.
11. The bilayer tablet according to any one of 1 to 10 above, having a weight of 200 to 310 mg.
12 The bilayer tablet according to any one of 1 to 11 above, having a weight of 250 to 310 mg.
13. Furthermore, the bilayer tablet in any one of said 1-12 which contains a film coating layer.

  According to the present invention having the above-described configuration, it is possible to increase the stability of amlodipine in a bilayer tablet of amlodipine with azilsartan, and to suppress the formation of N-formyl body of amlodipine over time.

FIG. 1 is a graph showing the relationship between the weight ratio (horizontal axis) of the amlodipine-containing layer and the amount of N-formyl produced in the bilayer tablet produced in the example.

  The bilayer tablet of the present invention contains azilsartan in one of the two layers (Azilsartan-containing layer) and contains amlodipine besylate in the other (Amlodipine-containing layer). The bilayer tablet may be in the form of a bare tablet, or may be coated with a conventional coating material such as film coating or sugar coating as desired. When referring to the weight of the bilayer tablet of the present invention, it means the weight of the uncoated tablet. The same applies to the ratio (% by weight) of any layer in the tablet and the content ratio (% by weight) of each component.

  In the bilayer tablet of the present invention, the ratio of the amlodipine-containing layer is preferably 35% by weight or more, more preferably 40% by weight or more, still more preferably 45% by weight or more, still more preferably 50% by weight or more. Is 90% by weight or less, more preferably 85% by weight or less. The proportion of the azilsartan-containing layer corresponds to the remainder from 100% by weight in each case.

  In the bilayer tablet of the present invention, the azilsartan content is preferably 11% by weight or more of the azilsartan-containing layer, more preferably 12% by weight or more, still more preferably 12.5% by weight or more, and preferably 60% by weight or less, more preferably 55% by weight or less, and still more preferably 50% by weight or less.

  In the bilayer tablet of the present invention, the content of amlodipine besylate is preferably 8% by weight or less, more preferably 6.5% by weight or less, still more preferably 6% by weight or less, particularly preferably 5% by weight of the amlodipine-containing layer. 0.5 wt% or less, and preferably 1.4 wt% or more, more preferably 2.8 wt% or more.

  The bilayer tablet of the present invention may contain an excipient, and the excipient preferably accounts for 75 to 95% by weight, more preferably 80 to 90% by weight of the bilayer tablet.

;
Further, at least 35%, preferably 35 to 95%, more preferably 40 to 95%, and still more preferably 45 to 95% of the excipient is contained in the amlodipine-containing layer.

  Examples of preferred excipients include D-mannitol, sucrose, erythritol, lactose hydrate, crystalline cellulose, corn starch, partially pregelatinized starch, and ethylcellulose, and one or more of these should be used. Can do. Among these, D-mannitol is a particularly preferable example.

  The bilayer tablet of the present invention can contain a binder. Preferred binders include, but are not limited to, hydroxypropylcellulose, hypromellose, povidone, polyvinyl alcohol, and polyethylene glycol 6000. 1 type (s) or 2 or more types can be used for a binder.

  Furthermore, the bilayer tablet of the present invention can contain a disintegrant. Preferred disintegrants include, but are not limited to, croscarmellose sodium, carmellose, carmellose calcium, crospovidone, sodium starch glycolate, light anhydrous silicic acid, crystalline cellulose, and low substituted hydroxypropylcellulose. 1 type (s) or 2 or more types can be used for a disintegrating agent.

In the bilayer tablet of the present invention, the content of azilsartan per tablet is preferably 18 mg or more, more preferably 19 mg or more, and preferably 22 mg or less, more preferably 21 mg or less, for example 20 mg. .

  In the bilayer tablet of the present invention, the content of amlodipine besylate per tablet is preferably 3 mg or more, more preferably 3.3 g or more, and preferably 7.5 mg or less, more preferably 7 mg or less. , For example, 2.5 mg or 5 mg in terms of amlodipine.

  The weight of the bilayer tablet of the present invention can be, for example, 250 to 310 mg, 260 to 300 mg, 280 mg, etc., but is not limited thereto. Therefore, for example, it may be 200 to 310 mg.

  The bilayer tablet of the present invention can contain a lubricant and a colorant as needed. Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, talc, colloidal silica, sodium stearyl fumarate and the like.

  The bilayer tablet of the present invention may include a film coating layer. The film coating layer may be formed by a conventional method using conventional components as appropriate. Examples of such conventional components include colorants such as yellow ferric oxide and titanium oxide, bases such as talc and hypromellose. Solvents such as triacetin can be used, but are not limited thereto.

  The bilayer tablet of the present invention can be manufactured according to a conventional method by using the additives such as azilsartan, amlodipine besylate, and excipients, blending the components as described above, and the like.

  Hereinafter, the present invention will be described in more detail with reference to examples. However, it is not intended that the present invention be limited to the examples.

1. Manufacture of tablets Using azilsartan, amlodipine besylate, and D-mannitol as an excipient, according to the composition per tablet described in Table 1, 1-4 tablets are manufactured as follows. did. In the table, the “% / layer” column indicates the content ratio of each layer.

  A mixed powder of azilsartan, D-mannitol, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose and polyethylene glycol 6000 is put into a stirring granulator and sprayed with an aqueous dispersion of a colorant (yellow ferric oxide) to granulate And dried and sized to obtain azilsartan granules. Separately, a mixed powder of amlodipine besylate and D-mannitol was put into a fluidized bed granulator, sprayed with an aqueous solution of hydroxypropylcellulose, granulated, dried and sized to obtain amlodipine granules. Azilsartan granules and D-mannitol were mixed, and magnesium stearate was added thereto and mixed to obtain amlodipine tablet powder. Further, amlodipine granules and D-mannitol were mixed, and magnesium stearate was added and mixed to obtain amlodipine tablet powder. Azilsartan tableting powder and amlodipine tableting powder were tableted with a vertical double pressure molding three-layer machine to obtain a two-layer tablet.

2. Stability test For each of the bilayer tablets of Formulations 1 to 4, the N-formyl content was measured as follows immediately after production and after storage in a bottle (open) at 40 ° C. and a relative humidity of 75%. did.

  That is, for each of Formulations 1 to 4, 2 tablets were shaken in 8 mL of water to disintegrate, then 32 mL of acetonitrile / methanol mixture (1: 1) was added to the solution, shaken for 20 minutes, and further ultrasonicated for 10 minutes. The sample was processed and filtered through a 0.2 μm syringe filter (Whatman PVDF), and the remainder except 3 mL of the initial flow was used as a sample solution.

The N-formyl content in the sample solution was measured and compared by HPLC under the following conditions. The content of the N-formyl body was recorded as the ratio (%) of the peak area of the N-formyl body in the sample solution to the sum of all peak areas on the HPLC chart.
Detector: UV detector (measurement wavelength: 250 nm)
Column: Stainless steel tube with an inner diameter of 2.1 mm and a length of 10 cm packed with 1.7 μm octadecylsilylated silica gel for liquid chromatography (ACQUITY UPLC BEH C18 1.7 μm, 2.1 × 100 mm)
Column temperature: constant temperature around 40 ° C. Mobile phase A: Dissolve 2.64 g of diammonium hydrogen phosphate and 5.1 g of tetrabutylammonium hydrogen sulfate in 1000 mL of water, add 7 mL of triethylamine, and dilute phosphoric acid (1 → 10) A solution prepared by adjusting pH to 9.0 and adding 100 mL of acetonitrile to 900 mL of this solution.
Mobile phase B: acetonitrile
Transfer of mobile phase: Concentration control by changing the mixing ratio of mobile phase A and mobile phase B over time as shown in Table 2.
Flow rate: 0.5 mL per minute
Amlodipine retention time: about 9 minutes N-formyl body relative retention time (RRT vs. amlodipine): 1.23

  The results are shown in Table 3 and FIG.

  As can be seen from Table 3, in any of the preparations 1 to 4, the formation of N-formyl was not observed immediately after production. After storage for 1 month in an accelerated test at 40 ° C. and a relative humidity of 75%, formation of 0.158% of N-formyl was observed in Formulation 1. On the other hand, in the preparations 2 to 3, the formation of N-formyl body is remarkably small, and particularly as shown in FIG. 1, the proportion of excipients distributed to the amlodipine-containing layer is increased (thus, containing amlodipine). With the increase in the weight ratio of the layer and the increase in the ratio of the amount of excipient in the layer relative to amlodipine besylate), the formation of N-formyl body was extremely remarkably suppressed. The amount of N-formyl produced in Formulation 1 was ½ or less.

4). Manufacture of tablets (formulation 5)
Azilsartan, partially pregelatinized starch and low-substituted hydroxypropylcellulose are charged into a fluidized bed granulator and sprayed with an aqueous solution of hydroxypropylcellulose and macrogol 6000 in which a colorant (yellow ferric oxide) is dispersed. Granulated, dried and sized to give azilsartan granules. Separately, amlodipine besylate, D-mannitol and low-substituted hydroxypropylcellulose were added, sprayed with an aqueous solution of hydroxypropylcellulose, granulated, dried and sized to obtain amlodipine granules. Azilsartan granules and crystalline cellulose were mixed, and magnesium stearate was added and mixed with it to obtain azilsartan tableting powder. In addition, amlodipine granules and crystalline cellulose were mixed, and magnesium stearate was added and mixed to obtain amlodipine tablet powder. The azilsartan tableting powder and amlodipine tableting powder were tableted with a rotary tableting machine to obtain a bilayer tablet. The bilayer tablet was put into a film coating machine, and an aqueous solution of hypromellose and triacetin in which yellow iron sesquioxide, titanium oxide and talc were dispersed was spray-coated, and dried to obtain a film-coated tablet as Formulation 5.

5. Stability test Formulation 5 was measured for the content of N-formyl form immediately after production and after storage in a bottle (open) at 40 ° C. and a relative humidity of 75% as follows.

  Specifically, after disintegrating 2 tablets of Formulation 5 in 8 mL of water, 32 mL of acetonitrile / methanol mixture (1: 1) was added to the solution, shaken for 20 minutes, and further sonicated for 10 minutes. The solution was filtered through a 2 μm syringe filter (Whatman PVDF), and the remainder except 3 mL of the initial flow was used as a sample solution.

The content of N-formyl body in the sample solution was measured and compared by UPLC under the following conditions. The content of the N-formyl body was recorded as a ratio (%) of the peak area of the N-formyl body in the sample solution to the sum of all peak areas on the UPLC chart.
Detector: UV detector (measurement wavelength: 237 nm)
Column: Stainless steel tube (ACQUITY UPLC HSS C18 1.8 μm, 2.1 mm × 100 mm) with an inner diameter of 2.1 mm and a length of 10 cm packed with 1.8 μm octadecylsilylated silica gel for liquid chromatography
Column temperature: Constant temperature around 40 ° C. Mobile phase A: A solution prepared by dissolving 3.1 g of sodium dihydrogen phosphate dihydrate in 1000 mL of water and adjusting the pH to 2.3 with phosphoric acid.
Mobile phase B: Acetonitrile Mobile phase feeding: Concentration control by changing the mixing ratio of mobile phase A and mobile phase B over time as shown in Table 3.
Flow rate: 0.5 mL per minute
Amlodipine retention time: about 7.5 minutes N-formyl body relative retention time (RRT vs. amlodipine): 1.6

  As a result, the initial N-formyl content of Formulation 5 was 0.00%, and 0.039% after 1 month storage.

INDUSTRIAL APPLICABILITY The present invention is useful in providing a product in which the stability of amlodipine besylate is enhanced and the formation of N-formyl body is suppressed in a bilayer tablet containing azilsartan and amlodipine besylate in each layer It is.

Claims (13)

  A bilayer tablet comprising an azilsartan-containing layer and an amlodipine-containing layer, wherein the weight of the amlodipine-containing layer accounts for 35 to 85% of the weight of the bilayer tablet.   The bilayer tablet according to claim 1, wherein the azilsartan content in the azilsartan-containing layer is 11 to 60 wt%, and the amlodipine besylate content in the amlodipine-containing layer is 1.4 to 8 wt%.   The bilayer tablet according to claim 1 or 2, comprising an excipient, wherein the excipient comprises 75 to 95% by weight of the bilayer tablet.   The bilayer tablet according to claim 3, wherein 35 to 95% by weight of the excipient is contained in the amlodipine-containing layer.   The bilayer of claim 3 or 4, wherein the excipient is selected from the group consisting of D-mannitol, sucrose, erythritol, lactose hydrate, crystalline cellulose, corn starch, partially pregelatinized starch, and ethylcellulose. Tablets.   The bilayer tablet according to any one of claims 1 to 7, wherein the azilsartan-containing layer and / or the amlodipine-containing layer contains a binder.   The double-layer tablet according to claim 6, wherein the binder is selected from the group consisting of hydroxypropylcellulose, hypromellose, povidone, polyvinyl alcohol, and polyethylene glycol 6000.   The bilayer tablet according to any one of claims 1 to 7, wherein the azilsartan-containing layer and / or the amlodipine-containing layer further contains a disintegrant.   The disintegrant is selected from the group consisting of croscarmellose sodium, carmellose, carmellose calcium, crospovidone, sodium starch glycolate, light anhydrous silicic acid, crystalline cellulose, and low-substituted hydroxypropylcellulose. Item 8. Double-layer tablet according to item 8.   The bilayer tablet according to any one of claims 1 to 9, comprising 18 to 22 mg of azilsartan and 3 to 7.5 mg of amlodipine besylate.   The bilayer tablet according to any one of claims 1 to 10, having a weight of 200 to 310 mg.   The bilayer tablet according to any one of claims 1 to 11, which has a weight of 250 to 310 mg. The bilayer tablet according to any one of claims 1 to 12, further comprising a film coating layer.

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