A pharmaceutical composition containing irbesartan and amlodipine and a preparation method thereof

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing irbesartan and amlodipine besylate and a preparation method thereof. The pharmaceutical composition comprises an irbesartan layer, an amlodipine besylate layer and a coating layer; the raw materials of the irbesartan layer include irbesartan, croscarmellose sodium and hydroxypropyl cellulose; the raw materials of the amlodipine besylate layer include amlodipine besylate, croscarmellose sodium and hydroxypropyl cellulose; the model of the hydroxypropyl cellulose is HPC-M. The present invention granulates irbesartan with suitable excipients by wet granulation to solve the problems of small bulk density and poor fluidity of irbesartan itself. Granulates amlodipine besylate with suitable excipients by fluidized bed granulation to solve the problems of poor mixing uniformity and low content and improve the stability of the product, and has good application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing irbesartan and amlodipine and a preparation method thereof. Background Art

[0002] Irbesartan has a relatively low bulk density and tapped density, is prone to electrostatic agglomeration, has strong adhesiveness, shows extremely poor fluidity, and its specification in the preparation is large, making it difficult to prepare its effective dose into small-sized tablets with uniform weight and hardness.

[0003] Amlodipine besylate has relatively poor stability, its specification in the preparation is small, and due to its adsorptivity, problems such as poor mixing uniformity and low content are likely to occur during the process of processing it into a preparation.

[0004] Japanese Patent Application JP2011207873A discloses a pharmaceutical composition containing irbesartan and amlodipine or its salt. It is obtained by the following method: First, irbesartan and some pharmaceutical excipients are separately wet granulated and dried by the wet granulation process, and then the granulated irbesartan is blended with amlodipine and made into tablets.

[0005] Chinese Patent Application CN102573804A discloses a fixed-dose solid pharmaceutical composition containing irbesartan and amlodipine besylate, which is obtained by the following three methods: ① Irbesartan is embedded in the outer matrix of particles containing amlodipine besylate in the form of coated particles. Among them, irbesartan is granulated with an adhesive such as HPMC, and amlodipine is added to the outer part of the particles before the tableting step; ② Irbesartan and amlodipine are separately granulated with their respective suitable adhesives, and then blended with a lubricant and tabletted; ③ The irbesartan particles and amlodipine particles each containing excipients are separated by an inert layer, and the solid composition takes the form of a three-layer tablet.

[0006] Chinese Patent Application CN103860511A discloses a pharmaceutical composition containing irbesartan and amlodipine besylate and a preparation method thereof. By the dry granulation and tableting process, the sieved and crushed irbesartan and amlodipine besylate are mixed with microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and a part of magnesium stearate and then dry granulated, so that the product has good disintegration performance and improves the dissolution rate of the drug, overcoming the disadvantages of the wet granulation process. However, from its preparation method, it can be seen that effective physical isolation conditions cannot be created for irbesartan and amlodipine, and poor stability may occur due to compatibility problems.

[0007] Chinese invention patent application CN108578404A discloses a pharmaceutical composition containing irbesartan and amlodipine and a preparation method thereof, wherein irbesartan and amlodipine are mixed, granulated, and dried in a fluidized bed in one step. However, the process requires the preparation of a blend of irbesartan and micropowdered silica gel and a blend of amlodipine and microcrystalline cellulose, and then fluidized bed granulation with sieved mannitol and half the amount of disintegrant, which is a relatively complicated process and is not conducive to industrial production. Moreover, the process cannot create effective physical isolation conditions, and poor stability may occur due to compatibility issues.

[0008] In summary, due to the low bulk density and strong adhesion of irbesartan raw materials, its fluidity is extremely poor, and its specifications in the preparation are large, so it is necessary to improve the fluidity by granulation. Due to its adsorption and small specifications in the preparation, amlodipine besylate is prone to problems such as low content and poor mixing uniformity. In addition, since irbesartan and amlodipine besylate have compatibility issues, how to improve the stability of the compound preparation composed of the two is a problem that needs to be solved urgently in this field. Summary of the invention

[0009] In view of the deficiencies in the prior art, the present invention provides a pharmaceutical composition containing irbesartan and amlodipine and a preparation method thereof.

[0010] In order to achieve the purpose of the present invention, the technical solution adopted is as follows:

[0011] A pharmaceutical composition containing irbesartan and amlodipine, comprising an irbesartan layer, an amlodipine besylate layer and a coating layer; the raw materials of the irbesartan layer comprise irbesartan, croscarmellose sodium and hydroxypropyl cellulose; the raw materials of the amlodipine besylate layer comprise amlodipine besylate, croscarmellose sodium and hydroxypropyl cellulose; the model of the hydroxypropyl cellulose is HPC-M.

[0012] Preferably, the irbesartan layer further comprises a first diluent selected from mannitol and microcrystalline cellulose in a mass ratio of 1.5-3:1.

[0013] Preferably, the amlodipine besylate layer further comprises a second diluent selected from mannitol and microcrystalline cellulose in a mass ratio of 4.3-7:1.

[0014] Preferably, the model of the cross-linked sodium carboxymethyl cellulose is SD711.

[0015] Preferably, the mass ratio of croscarmellose sodium to hydroxypropyl cellulose in the amlodipine besylate layer is 5:1.5-5:5.

[0016] Preferably, the raw materials of the irbesartan layer and / or the amlodipine besylate layer further include a glidant.

[0017] Preferably, by weight, the irbesartan layer includes 60-70 parts of irbesartan, 20-30 parts of a first diluent, 5-10 parts of croscarmellose sodium, 1-5 parts of hydroxypropyl cellulose, and 0.2-1 part of a glidant.

[0018] Preferably, the amlodipine besylate layer includes 1-10 parts of amlodipine besylate, 80-90 parts of a second diluent, 2-10 parts of croscarmellose sodium, 1-5 parts of hydroxypropyl cellulose, and 0.2-1 part of a glidant.

[0019] The second object of the present invention is to provide a preparation method of a pharmaceutical composition, comprising the following steps:

[0020] (1) Mix irbesartan, a first diluent, and croscarmellose sodium, add an aqueous solution of hydroxypropyl cellulose for wet granulation, and add a glidant to obtain an irbesartan total mixed granule;

[0021] (2) Perform fluidized bed granulation on amlodipine besylate, a second diluent, and an aqueous solution of hydroxypropyl cellulose, then add cross-linked carboxymethyl cellulose sodium and a glidant for mixing to obtain an amlodipine besylate total mixed granule;

[0022] (3) First press the irbesartan total mixed granule into an irbesartan layer, then add the amlodipine besylate total mixed granule and press the amlodipine besylate layer to obtain a double-layer tablet;

[0023] (4) Coating the double-layer tablet to obtain the product.

[0024] Preferably, in step (2), using amlodipine besylate and a second diluent as the base material, spray the aqueous solution of hydroxypropyl cellulose from the top for fluidized bed granulation.

[0025] Preferably, the concentration of the aqueous solution of hydroxypropyl cellulose is 3-7 wt%.

[0026] Preferably, in step (1), the mixing time is 2-10 min, and the wet granules obtained by wet granulation are sieved through a 4×4 mm sieve for granulation, dried, and then sieved through a 1.5 mm sieve for granulation.

[0027] Preferably, the hardness of the tablet in step (3) is 80-120 N.

[0028] Preferably, in step (4), the coating includes preparing a coating solution with a solid content of 10% by mixing a gastric-soluble film coating premix with water, and then coating, controlling the coating weight gain to be 3%-5%.

[0029] Compared with the prior art, the beneficial effects of the present invention:

[0030] In the present invention, irbesartan and suitable excipients are wet granulated to solve the problems of small bulk density and poor fluidity of irbesartan itself. Amlodipine besylate and suitable excipients are fluidized bed granulated to solve the problems of poor mixing uniformity and low content, and improve the stability of the product.

[0031] Compared with the prior art, the present invention does not need to evaluate the mixing uniformity problem of added amlodipine besylate as in Japanese Patent Application JP2011207873A; the present invention is simpler than the process that requires pressing three-layer tablets, and can create more effective physical isolation conditions in terms of process design to ensure the stability of the product. Detailed Embodiments

[0032] The present invention will be further described below in conjunction with the detailed embodiments. The following raw materials are all commercially available conventional raw materials.

[0033] Examples 1 - 3

[0034] The irbesartan layer and the amlodipine layer are respectively prepared, and a double-layer tablet is pressed. Among them, the water addition amount for wet granulation of the irbesartan layer (33%, 37%, 41%) is investigated, and its prescription is as shown in Table 1 below.

[0035] Table 1

[0036]

[0037] The preparation methods of the tablets in Examples 1 - 3 are as follows:

[0038] (1) Preparation of the total mixed granules of the irbesartan layer: According to the prescription in Table 1, 4000 tablets are fed. Irbesartan, mannitol, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium are placed in a wet granulator and mixed for 5 min, and an aqueous solution of hydroxypropyl cellulose is added for granulation. The wet granules are screened through a 4×4 mm sieve for sizing, and then dried in a fluidized bed, controlling the moisture content < 2.0%; the dried granules are screened through a 1.5 mm sieve for sizing, and the sized granules are placed in a hopper mixer, and magnesium stearate is added and mixed for 5 min to obtain the total mixed granules of the irbesartan layer.

[0039] (2) Preparation of the total mixed granules of the amlodipine layer: According to the above prescription, 4000 tablets are fed. Amlodipine besylate, mannitol, and microcrystalline cellulose are placed in a fluidized bed and fluidized and mixed for 5 min, and an aqueous solution of hydroxypropyl cellulose is added for granulation by top spraying. After the spraying is completed, drying is carried out, controlling the moisture content < 2.0%; the dried granules are screened through a 1.5 mm sieve for sizing, and the sized granules are placed in a hopper mixer, and magnesium stearate is added and mixed for 5 min to obtain the total mixed granules of the amlodipine layer.

[0040] (3) Tabletting: Use a rotary tabletting machine to press double-layer tablets. Install an 8 mm diameter punch die and control the hardness at 110 N and the weight variation at ±5% in the order of first pressing the irbesartan layer and then the amlodipine layer.

[0041] (4) Coating: Prepare a coating solution with a solid content of 10% by mixing a film coating premix (gastric-soluble type) with purified water. Use a high-efficiency coating machine to coat the plain tablets and control the coating weight gain at 4%.

[0042] Examples 4 - 5

[0043] Its formulation is shown in Table 2.

[0044] Table 2

[0045]

[0046] The preparation methods of Examples 4 - 5 are as follows:

[0047] (1) Preparation of the total mixed granules of the irbesartan layer: According to the formulation in Table 2, charge for 4000 tablets. Put irbesartan, mannitol, microcrystalline cellulose, and cross-linked carboxymethylcellulose sodium into a wet granulator and mix for 5 min. Add a 6 wt% aqueous solution of hydroxypropyl cellulose for granulation. Screen the wet granules through a 4×4 mm sieve for sizing, and then dry them using a fluidized bed, controlling the moisture content < 2.0%; Screen the dried granules through a 1.5 mm sieve for sizing. Put the sized granules into a hopper mixer and add magnesium stearate and mix for 5 min to obtain the total mixed granules of the irbesartan layer.

[0048] (2) Preparation of the total mixed granules of the amlodipine layer: According to the above formulation, charge for 4000 tablets. Put amlodipine besylate, mannitol, and microcrystalline cellulose into a fluidized bed and fluidize and mix for 5 min. Spray a 5.4 wt% aqueous solution of hydroxypropyl cellulose from the top for granulation. After spraying, dry the granules, controlling the moisture content < 2.0%; Screen the dried granules through a 1.5 mm sieve for sizing. Put the sized granules into a hopper mixer and add magnesium stearate and mix for 5 min to obtain the total mixed granules of the amlodipine layer.

[0049] (3) Tabletting: Use a rotary tabletting machine to press double-layer tablets. Install an 8 mm diameter punch die and control the hardness at 90 N and the weight variation at ±5% in the order of first pressing the irbesartan layer and then the amlodipine layer.

[0050] (4) Coating: Prepare a coating solution with a solid content of 10% by mixing a film coating premix (gastric-soluble type) with purified water. Use a high-efficiency coating machine to coat the plain tablets and control the coating weight gain at 4%.

[0051] Comparative Example 1 (single-layer tablet, wet granulation of two active ingredients together)

[0052] Irbesartan and amlodipine besylate are wet granulated together with excipients; prepared into single-layer tablets, and the stability is investigated after coating.

[0053] Table 3

[0054]

[0055] The preparation method of Comparative Example 1 is as follows:

[0056] According to the prescription in Table 3, 4000 tablets are fed. Irbesartan, amlodipine besylate, mannitol, microcrystalline cellulose, and croscarmellose sodium are mixed and placed in a wet granulator for mixing for 5 min. An aqueous solution of hydroxypropyl cellulose is added for granulation. The wet granules are screened through a 4×4 mm sieve for sizing, and then dried in a fluidized bed, controlling the moisture content <2.0%; the dried granules are screened through a 1.5 mm sieve for sizing. The sized granules are placed in a hopper mixer, and magnesium stearate is added for mixing for 5 min to obtain the total mixed granules. A single-layer tablet is pressed using a rotary tablet press, an 8 mm diameter punch die is installed, the hardness is controlled at 110 N, and the weight variation is ±5%. The film coating premix (gastric-soluble type) is prepared into a coating solution with a solid content of 10% using purified water, and the plain tablets are coated using a high-efficiency coating machine, controlling the coating weight gain at 4%.

[0057] Comparative Example 2 (single-layer tablet, irbesartan wet granulated, amlodipine besylate added externally)

[0058] Irbesartan is wet granulated together with excipients. After drying, the powder properties of the granules prepared with different sizing sieve apertures (1.0 mm, 1.2 mm, and 1.5 mm), the mixing uniformity after mixing with externally added amlodipine besylate, and the material fluidity during the process of pressing into single-layer tablets are investigated; the stability is investigated after coating the single-layer tablets.

[0059] Table 4

[0060]

[0061] The preparation method of Comparative Example 2 is as follows:

[0062] According to the prescription in Table 4, the feeding amount is equivalent to 12,000 tablets. Place irbesartan, mannitol, microcrystalline cellulose, and croscarmellose sodium in a wet granulator and mix for 5 minutes. Add an aqueous solution of hydroxypropyl cellulose to granulate. Screen the wet granules through a 4×4 mm sieve for granule sizing, and then dry them in a fluidized bed, controlling the moisture content to be <2.0%. After drying, divide the granules into three equal parts, and screen them through 1.0 mm, 1.2 mm, and 1.5 mm sieves respectively for granule sizing. According to the yield of the sized granules, weigh and take amlodipine besylate and magnesium stearate, and place them in a hopper mixer to mix for 5 minutes to obtain the total mixed granules. Use a rotary tablet press to press the three kinds of total mixed granules into single-layer tablets respectively. Install an 8 mm diameter punch die, control the hardness to be 110 N, and the weight variation to be ±5%. Prepare a coating solution with a solid content of 10% by mixing the film coating premix (gastric-soluble type) with purified water, and use a high-efficiency coating machine to coat the plain tablets, controlling the coating weight gain to be 4%.

[0063] Comparative Example 3

[0064] The difference from Example 1 is that the hydroxypropyl cellulose in the irbesartan layer is hydroxypropyl cellulose HPMC 6CPS, and the rest is the same as the formulation and process of Example 1.

[0065] Comparative Example 4

[0066] The difference from Example 1 is that the hydroxypropyl cellulose in the irbesartan layer and the amlodipine besylate layer is replaced with the auxiliary material polyvinyl alcohol. The binder in step (1) is a 6 wt% polyvinyl alcohol p-88 solution, and the binder in step (2) is a 5.4 wt% polyvinyl alcohol p-88 solution. The rest is the same as the formulation and process of Example 1.

[0067] Comparative Example 5

[0068] The difference from Example 1 is that the hydroxypropyl cellulose in the irbesartan layer and the amlodipine besylate layer is replaced with the auxiliary material polyvinylpyrrolidone k30, and the rest is the same as the formulation and process of Example 1.

[0069] Comparative Example 6

[0070] The difference from Example 1 is that the hydroxypropyl cellulose in the irbesartan layer and the amlodipine besylate layer is replaced with the auxiliary material hydroxypropyl methylcellulose, and the rest is the same as the formulation and process of Example 1.

[0071] Comparative Example 7

[0072] The difference from Example 1 is that the diluent ratios in the irbesartan layer and the amlodipine besylate layer are different. Specifically, see Table 5 below.

[0073] Table 5

[0074]

[0075] Experiment 1: Evaluation of Flowability and Feasibility of Tablet Pressing Production

[0076] The total mixed granules containing irbesartan component prepared in the above examples were evaluated for flowability, with the angle of repose as the evaluation index; and the influence of the total mixed granules containing irbesartan component on the feasibility of tablet pressing production was observed during the tablet pressing process. The results are shown in Table 6.

[0077] Table 6

[0078]

[0079] Conclusion: According to the results in Table 6, it can be seen that after irbesartan was granulated by wet granulation and sized with a 1.5 mm sieving screen, the angle of repose of the obtained total mixed granules was all < 30°, with good flowability and a smooth tablet pressing process. However, when the water addition amount for wet granulation of irbesartan was fixed and sized with 1.0 mm and 1.2 mm sieving screens, or other binders were used instead of hydroxypropyl cellulose, the flowability of the obtained total mixed granules was poor, bridging occurred during the tablet pressing process, the material could not freely fall into the feeder, resulting in unstable tablet weight and hardness, and it was shown that the smaller the aperture of the sieving screen for sizing, the worse the feasibility of tablet pressing production.

[0080] Experiment 2: Evaluation of Mixing Uniformity and Content Uniformity

[0081] Since the proportion of amlodipine besylate component in the formulation is relatively small, samples of the total mixed granules containing amlodipine besylate component in the above examples were taken, and the sampling positions referred to the "Technical Guidelines for the Study of Mixing Uniformity and In-Process Dosage Unit Uniformity of Chemical Oral Solid Preparations (Trial)", and the mixing uniformity was detected. At the same time, the content uniformity of the plain tablets after tablet pressing was measured. The results are shown in Table 7.

[0082] Table 7

[0083]

[0084] Conclusion: According to the results in Table 7, it can be seen that when amlodipine besylate was granulated by fluidized bed with excipients, or granulated by wet granulation with irbesartan and excipients, the content of amlodipine in the obtained total mixed granules was normal (close to the labeled amount of 100%) and the uniformity was good; however, when amlodipine besylate was added externally to the irbesartan granules, the results of the mixing uniformity of the total mixed granules and the content uniformity of the plain tablets were significantly affected by the aperture of the sieving screen for sizing the irbesartan granules, showing that the larger the aperture of the sieving screen for sizing, the worse the uniformity result, and even did not meet the requirements of the current guidelines (mixing uniformity RSD ≤ 5.0%) and the Chinese Pharmacopoeia (content uniformity A + 2.2S < 15.0). For the tablets of Comparative Example 2, 7, and Comparative Examples 3, 5 - 6 prepared with other excipients, the uniformity results were poor.

[0085] Experiment 3: Stability Evaluation

[0086] The coated tablets in the above examples were packaged in high-density polyethylene bottles and subjected to an accelerated test at 40°C / 75% RH for 6 months to examine the content of amlodipine degradation impurities. The results are shown in Table 8 below.

[0087] Table 8

[0088]

[0089] Conclusion: According to the results in Table 8, the samples of Examples 1-5 and the sample of Comparative Example 3 all created physical isolation conditions for irbesartan and amlodipine to a certain extent, effectively improving the stability of amlodipine. However, for the sample of Comparative Example 1 obtained by wet granulation of irbesartan and amlodipine together, since irbesartan and amlodipine were directly exposed, significant degradation of amlodipine occurred, resulting in poor stability of the sample. For the tablets of Comparative Examples 4-7 prepared with other excipients, the stability of their samples was not as good as that of Comparative Example 3 and Examples 1-5 to a certain extent.

[0090] In summary, the pharmaceutical composition of the present invention is selected in the form of a bilayer tablet, which not only ensures excellent mixing uniformity and stability of amlodipine besylate, but also solves the problem of poor fluidity of irbesartan during the tableting process.

[0091] The above detailed description is a specific description of one feasible embodiment of the present invention, and this embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification without departing from the present invention shall be included within the scope of the technical solution of the present invention.

Claims

1. A pharmaceutical composition containing irbesartan and amlodipine, characterized in that, The pharmaceutical composition comprises an irbesartan layer, an amlodipine besylate layer and a coating layer; the raw materials of the irbesartan layer include irbesartan, croscarmellose sodium and hydroxypropyl cellulose; the raw materials of the amlodipine besylate layer include amlodipine besylate, croscarmellose sodium and hydroxypropyl cellulose; the model of the hydroxypropyl cellulose is HPC-M, and the model of the croscarmellose sodium is SD711; the irbesartan layer further includes a first diluent, the amlodipine besylate layer further includes a second diluent, and the raw materials of both the irbesartan layer and the amlodipine besylate layer further include a glidant. The preparation method of the pharmaceutical composition comprises the following steps: (1) Mix irbesartan, the first diluent and croscarmellose sodium, add an aqueous solution of hydroxypropyl cellulose for wet granulation, and add a glidant to obtain the total mixed granules of irbesartan; (2) Perform fluidized bed granulation on amlodipine besylate, the second diluent and an aqueous solution of hydroxypropyl cellulose, then add croscarmellose sodium and a glidant for mixing to obtain the total mixed granules of amlodipine besylate; (3) First press the total mixed granules of irbesartan into an irbesartan layer, then add the total mixed granules of amlodipine besylate and press the amlodipine besylate layer to obtain a double-layer tablet; (4) Coating the double-layer tablet to obtain the product.

2. The pharmaceutical composition according to claim 1, wherein The first diluent is selected from mannitol and microcrystalline cellulose with a mass ratio of 1.5 - 3:

1.

3. The pharmaceutical composition according to claim 1, wherein The second diluent is selected from mannitol and microcrystalline cellulose with a mass ratio of 4.3 - 7:

1.

4. The pharmaceutical composition according to claim 1, wherein In the amlodipine besylate layer, the mass ratio of croscarmellose sodium to hydroxypropyl cellulose is 5:1.5 - 5.

5. The pharmaceutical composition according to claim 4, wherein By weight, the irbesartan layer comprises 60 - 70 parts of irbesartan, 20 - 30 parts of the first diluent, 5 - 10 parts of croscarmellose sodium, 1 - 5 parts of hydroxypropyl cellulose and 0.2 - 1 part of glidant; the amlodipine besylate layer comprises 1 - 10 parts of amlodipine besylate, 80 - 90 parts of the second diluent, 2 - 10 parts of croscarmellose sodium agent, 1 - 5 parts of hydroxypropyl cellulose and 0.2 - 1 part of glidant.

6. A method for preparing the pharmaceutical composition according to claim 5, characterized in that, Comprises the following steps: (1) Mix irbesartan, the first diluent and croscarmellose sodium, add an aqueous solution of hydroxypropyl cellulose for wet granulation, and add a glidant to obtain the total mixed granules of irbesartan; (2) Perform fluidized bed granulation on amlodipine besylate, the second diluent and an aqueous solution of hydroxypropyl cellulose, then add croscarmellose sodium and a glidant for mixing to obtain the total mixed granules of amlodipine besylate; (3) First press the total mixed granules of irbesartan into an irbesartan layer, then add the total mixed granules of amlodipine besylate and press the amlodipine besylate layer to obtain a double-layer tablet; (4) Coating the double-layer tablet to obtain the product.

7. The preparation method according to claim 6, wherein In step (2), using amlodipine besylate and the second diluent as the base material, top-spray the aqueous solution of hydroxypropyl cellulose for fluidized bed granulation, and the concentration of the aqueous solution of hydroxypropyl cellulose is 3 - 7wt%.

8. The preparation method according to claim 6, characterized in that, The mixing time described in step (1) is 2 - 10 min. The wet granules obtained by wet granulation are sized through a 4×4 mm sieve, dried, and then sized through a 1.5 mm sieve. The hardness of the tablets in step (3) is 80 - 120 N. The coating in step (4) includes preparing an enteric film coating premix into a coating solution with a solids content of 10% using water, and then coating, with the coating weight gain controlled at 3 - 5%.

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