Pharmaceutical composition containing irbesartan and amlodipine and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing irbesartan and amlodipine and a preparation method of the pharmaceutical composition. The pharmaceutical composition comprises an irbesartan layer, an amlodipine besylate layer and a coating layer, the irbesartan layer is prepared from the following raw materials: irbesartan, croscarmellose sodium and hydroxypropyl cellulose; the amlodipine besylate layer is prepared from the following raw materials: amlodipine besylate, croscarmellose sodium and hydroxypropyl cellulose; the model number of the hydroxypropyl cellulose is HPC-M. According to the invention, irbesartan and proper auxiliary materials are subjected to wet granulation, so that the problems of low bulk density and poor fluidity of irbesartan are solved. The amlodipine p-besylate and suitable auxiliary materials are subjected to fluidized bed granulation, so that the problems of poor mixing uniformity and low content are solved, the stability of the product is improved, and the amlodipine p-besylate has a good application prospect.

Description

Technical Field

[0001] The 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 relatively low bulk density and tap density, is prone to electrostatic agglomeration, has strong adhesion, and exhibits extremely poor fluidity. In addition, its specifications in the preparation are 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 specifications in the preparation are small, and due to its adsorption, it is prone to problems such as poor mixing uniformity and low content during its processing into preparations.

[0004] Japanese patent application JP2011207873A discloses a pharmaceutical composition containing irbesartan and amlodipine or a salt thereof, which is obtained by the following method: firstly irbesartan and part of the pharmaceutical excipients are separately wet-granulated and dried by a wet granulation process, and then the granulated irbesartan and amlodipine are blended to form tablets.

[0005] Chinese invention patent application CN102573804A discloses a fixed-dose solid pharmaceutical composition comprising irbesartan and amlodipine besylate, which is obtained by the following three methods: ① embedding irbesartan in the form of coated particles in an extragranular matrix comprising amlodipine besylate, wherein irbesartan is granulated with a binder such as HPMC, and amlodipine is added to the extragranular part before the tableting step; ② granulating irbesartan and amlodipine using their own suitable binders, and then tableting after blending with a lubricant; ③ separating the irbesartan particles and amlodipine particles each containing an excipient by an inert layer, and the solid composition takes the form of a three-layer tablet.

[0006] Chinese invention patent application CN103860511A discloses a pharmaceutical composition containing irbesartan and amlodipine besylate and a preparation method thereof, wherein the crushed and sieved irbesartan and amlodipine besylate are mixed with microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, micro-powdered silica gel and a portion of magnesium stearate and then dry granulated through a dry granulation tableting process, so that the product has good disintegration performance, improves the solubility of the drug, and overcomes the shortcomings of the wet granulation process. However, it can be seen from the preparation method that effective physical isolation conditions cannot be created for irbesartan and amlodipine, and poor stability may occur due to compatibility issues.

[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: 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.

[0011] Preferably, the irbesartan layer further comprises a first diluent selected from mannitol and microcrystalline cellulose in a mass ratio of 1.5-3:1.

[0012] 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.

[0013] Preferably, the model of the cross-linked sodium carboxymethyl cellulose is SD711.

[0014] Preferably, the mass ratio of croscarmellose sodium to hydroxypropyl cellulose in the amlodipine besylate layer is 5:1.5-5:5.

[0015] Preferably, the raw materials of the irbesartan layer and / or the amlodipine besylate layer further include a glidant.

[0016] Preferably, the irbesartan layer comprises 60-70 parts of irbesartan, 20-30 parts of the first diluent, 5-10 parts of cross-linked carboxymethyl cellulose sodium, 1-5 parts of hydroxypropyl cellulose and 0.2-1 parts of a glidant, in parts by weight.

[0017] Preferably, the amlodipine besylate layer comprises 1-10 parts of amlodipine besylate, 80-90 parts of a second diluent, 2-10 parts of cross-linked carboxymethyl cellulose sodium, 1-5 parts of hydroxypropyl cellulose and 0.2-1 part of a glidant.

[0018] The second object of the present invention is to provide a method for preparing a pharmaceutical composition, comprising the following steps: (1) mixing irbesartan, a first diluent, and croscarmellose sodium, adding an aqueous solution of hydroxypropyl cellulose for wet granulation, and adding a glidant to obtain irbesartan total mixed granules; (2) fluidizing the amlodipine besylate, the second diluent, and the aqueous solution of hydroxypropyl cellulose, and then adding the second cross-linked carboxymethyl cellulose sodium and the flow aid to mix, thereby obtaining the amlodipine besylate total mixed granules; (3) first compressing the irbesartan total mixed granules into an irbesartan layer, then adding the amlodipine besylate total mixed granules, and compressing the amlodipine besylate layer to obtain a double-layer tablet; (4) The double-layer tablets are coated.

[0019] Preferably, in step (2), amlodipine besylate and the second diluent are used as the base material, and the hydroxypropyl cellulose aqueous solution is top-sprayed to perform fluidized bed granulation.

[0020] Preferably, the concentration of the hydroxypropylcellulose aqueous solution is 3-7wt%.

[0021] Preferably, the mixing time in step (1) is 2-10 min, and the wet granules obtained by wet granulation are sieved through a 4×4 mm sieve for granulation, dried, and sieved through a 1.5 mm sieve for granulation.

[0022] Preferably, the hardness of the tablet in step (3) is 80-120N.

[0023] Preferably, the coating in step (4) comprises preparing a gastric soluble film coating premix with water into a coating solution with a solid content of 10%, and then coating, and controlling the coating weight gain to be 3%-5%.

[0024] Compared with the prior art, the present invention has the following beneficial effects: The invention performs wet granulation on irbesartan and suitable auxiliary materials, thereby solving the problem of low bulk density and poor fluidity of irbesartan itself. Amlodipine besylate and suitable auxiliary materials are subjected to fluidized bed granulation, thereby solving the problem of poor mixing uniformity and low content, and improving the stability of the product.

[0025] Compared with the prior art, the present invention does not need to evaluate the mixing uniformity problem of the added amlodipine besylate as in Japanese patent application JP2011207873A; compared with the process requiring pressing three-layer tablets, the present invention is simpler and can create more effective physical isolation conditions from the process design to ensure the stability of the product. DETAILED DESCRIPTION

[0026] The present invention is further described below in conjunction with specific embodiments. The following raw materials are all commercially available conventional raw materials.

[0027] Example 1-Example 3 The irbesartan layer and the amlodipine layer were prepared separately and pressed into double-layer tablets. The amount of water added by wet granulation (33%, 37%, and 41%) was investigated for the irbesartan layer. The prescription is shown in Table 1.

[0028] Table 1

[0029] The preparation method of the tablets of Example 1-Example 3 is as follows: (1) Preparation of irbesartan layered total mixed granules: According to the prescription in Table 1, 4000 tablets were added. Irbesartan, mannitol, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium were mixed in a wet granulator for 5 minutes, and hydroxypropyl cellulose aqueous solution was added for granulation. The wet granules were sieved through a 4×4 mm mesh and then dried in a fluidized bed to control the moisture content to <2.0%. The dried granules were sieved through a 1.5 mm mesh and granulated. The granules were placed in a hopper mixer and magnesium stearate was added and mixed for 5 minutes to obtain irbesartan layered total mixed granules.

[0030] (2) Preparation of amlodipine layered total mixed granules: According to the above prescription, 4000 tablets were added. Amlodipine besylate, mannitol and microcrystalline cellulose were placed in a fluidized bed for fluidized mixing for 5 minutes, and hydroxypropyl cellulose aqueous solution was added by top spraying for granulation. After the spraying, the granules were dried to control the moisture content to <2.0%. The dried granules were sieved through a 1.5 mm sieve, and the granules were placed in a hopper mixer. Magnesium stearate was added and mixed for 5 minutes to obtain the amlodipine layered total mixed granules.

[0031] (3) Tablet pressing: Use a rotary tablet press to press double-layer tablets. Install a die with a diameter of 8 mm. Press the irbesartan layer first and then the amlodipine layer. Control the hardness to 110 N and the weight difference to ±5%.

[0032] (4) Coating: Prepare the film coating premix (gastric soluble type) with purified water into a coating solution with a solid content of 10%. Use a high-efficiency coating machine to coat the plain tablets, and control the coating weight gain to 4%.

[0033] Example 4-Example 5 The prescription is shown in Table 2.

[0034] Table 2

[0035] The preparation methods of Example 4-Example 5 are as follows: (1) Preparation of irbesartan layered total mixed granules: According to the prescription in Table 2, 4000 tablets were added. Irbesartan, mannitol, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium were mixed in a wet granulator for 5 minutes, and a 6wt% hydroxypropyl cellulose aqueous solution was added for granulation. The wet granules were sieved through a 4×4mm mesh and then dried in a fluidized bed to control the moisture content to <2.0%. The dried granules were sieved through a 1.5mm mesh and granulated. The granules were placed in a hopper mixer and magnesium stearate was added and mixed for 5 minutes to obtain irbesartan layered total mixed granules.

[0036] (2) Preparation of amlodipine layered total mixed granules: According to the above prescription, 4000 tablets were added. Amlodipine besylate, mannitol and microcrystalline cellulose were placed in a fluidized bed for fluidized mixing for 5 minutes, and a 5.4wt% hydroxypropyl cellulose aqueous solution was added by top spraying for granulation. After the spraying, the granules were dried to control the moisture content to <2.0%. The dried granules were sieved through a 1.5mm mesh, and the granules were placed in a hopper mixer. Magnesium stearate was added and mixed for 5 minutes to obtain the amlodipine layered total mixed granules.

[0037] (3) Tablet pressing: Use a rotary tablet press to press double-layer tablets. Install a die with a diameter of 8 mm. Press the irbesartan layer first and then the amlodipine layer. Control the hardness to 90N and the weight difference to ±5%.

[0038] (4) Coating: Prepare the film coating premix (gastric soluble type) with purified water into a coating solution with a solid content of 10%. Use a high-efficiency coating machine to coat the plain tablets, and control the coating weight gain to 4%.

[0039] Comparative Example 1 (monolayer tablet, two active ingredients wet granulated together) Irbesartan and amlodipine besylate were wet granulated with excipients; single-layer tablets were prepared and the stability was examined after coating.

[0040] Table 3

[0041] Comparative Example 1 The preparation method is as follows: According to the prescription in Table 3, 4000 tablets were added. Irbesartan, amlodipine besylate, mannitol, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium were mixed and placed in a wet granulator for 5 minutes. Hydroxypropyl cellulose aqueous solution was added for granulation. The wet granules were passed through a 4×4mm sieve for granulation, and then dried in a fluidized bed to control the moisture content <2.0%; the dried granules were passed through a 1.5mm sieve for granulation, and the granulated granules were placed in a hopper mixer, and magnesium stearate was added and mixed for 5 minutes to obtain the total mixed granules. A rotary tablet press was used to compress a single-layer tablet, and a die with a diameter of 8mm was installed. The hardness was controlled to be 110N, and the weight difference was ±5%. The film coating premix (gastric soluble type) was prepared into a coating solution with a solid content of 10% with purified water, and the plain tablets were coated with a high-efficiency coating machine to control the coating weight gain to 4%.

[0042] Comparative Example 2 (single-layer tablet, irbesartan wet granulation, amlodipine besylate added) Irbesartan was wet granulated with excipients. After drying, the powder properties of granules obtained with different sieve apertures (1.0mm, 1.2mm and 1.5mm), the mixing uniformity after mixing with added amlodipine besylate, and the material flowability during compression into single-layer tablets were investigated; the stability of the single-layer tablets was investigated after coating.

[0043] Table 4

[0044] Comparative Example 2 The preparation method is as follows: According to the prescription in Table 4, 12,000 tablets were added. Irbesartan, mannitol, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose were mixed in a wet granulator for 5 minutes, and hydroxypropyl cellulose aqueous solution was added for granulation. The wet granules were sieved through a 4×4mm mesh for granulation, and then dried in a fluidized bed to control the moisture content <2.0%; after drying, the granules were divided into three equal parts, sieved through 1.0mm, 1.2mm and 1.5mm meshes respectively for granulation. According to the granulation yield, amlodipine besylate and magnesium stearate were weighed and weighed, and mixed in a hopper mixer for 5 minutes to obtain the total mixed granules. The three kinds of total mixed granules were pressed into single-layer tablets using a rotary tablet press, and a die with a diameter of 8mm was installed. The hardness was controlled to be 110N, and the weight difference was ±5%. The film coating premix (gastric soluble type) was prepared into a coating solution with a solid content of 10% with purified water, and the plain tablets were coated with a high-efficiency coating machine to control the coating weight gain to 4%.

[0045] Comparative Example 3 The difference from Example 1 is that the hydroxypropyl cellulose in the irbesartan layer is hydroxypropyl cellulose HPMC 6CPS, and the rest of the formula and process are consistent with those in Example 1.

[0046] Comparative Example 4 The difference from Example 1 is that the hydroxypropyl cellulose in the irbesartan layer and the amlodipine besylate layer is replaced by the auxiliary material polyvinyl alcohol, the adhesive in step (1) is a 6wt% polyvinyl alcohol P-88 solution, and the adhesive in step (2) is a 5.4wt% polyvinyl alcohol P-88 solution. The rest of the formula and process are consistent with Example 1.

[0047] Comparative Example 5 The difference from Example 1 is that the hydroxypropylcellulose in the irbesartan layer and the amlodipine besylate layer is replaced by the auxiliary material polyvinyl pyrrolidone k30, and the rest of the formula and process are consistent with Example 1.

[0048] Comparative Example 6 The difference from Example 1 is that the hydroxypropylcellulose in the irbesartan layer and the amlodipine besylate layer is replaced by the auxiliary material hydroxypropyl methylcellulose, and the rest of the formula and process are consistent with Example 1.

[0049] Comparative Example 7 The difference from Example 1 is that the diluent ratios in the irbesartan layer and the amlodipine besylate layer are different. The details are shown in Table 5 below.

[0050] Table 5

[0051] Experiment 1: Evaluation of flowability and tableting feasibility The fluidity of the total mixed granules containing the irbesartan component prepared in the above examples was evaluated, with the angle of repose as the evaluation index; and the effect of the total mixed granules containing the irbesartan component on the feasibility of tableting production during the tableting process was observed. The results are shown in Table 6.

[0052] Table 6

[0053] Conclusion: According to the results in Table 6, the angle of repose of the total mixed granules obtained by wet granulation of irbesartan and granulation with a 1.5mm granulation screen is <30°, the fluidity is good, and the tableting process is smooth. However, when the amount of water added in the wet granulation of irbesartan is fixed, granulation is performed with 1.0mm and 1.2mm granulation screens, or other adhesives are used instead of hydroxypropyl cellulose, the total mixed granules obtained have poor fluidity, bridging occurs during the tableting process, and the material cannot be freely fed into the feeder, resulting in unstable tablet weight and hardness. It also shows that the smaller the aperture of the granulation screen, the worse the feasibility of tableting production.

[0054] Experiment 2: Evaluation of mixing uniformity and content uniformity Since the proportion of amlodipine besylate in the prescription is relatively small, the total mixed granules containing the amlodipine component in the above embodiment were sampled, and the sampling position was referred to the "Technical Guidance for the Study of Mixing Uniformity and Central Control Dose Unit Uniformity of Chemical Oral Solid Preparations (Trial)" to detect the mixing uniformity. At the same time, the content uniformity of the plain tablets after tableting was measured, and the results are shown in Table 7.

[0055] Table 7

[0056] Conclusion: According to the results in Table 7, the amlodipine content in the total mixed granules prepared by fluidized bed granulation with amlodipine besylate and excipients, or wet granulation with irbesartan and excipients is normal (close to 100% of the labeled amount) and has good uniformity; however, when amlodipine besylate is added to irbesartan granules by external addition, the mixing uniformity of the total mixed granules and the content uniformity of the plain tablets are significantly affected by the aperture of the sieve for granulation of irbesartan granules, which is manifested as the larger the aperture of the sieve for granulation, the worse the uniformity result, and even does not meet the requirements of the current guidelines (mixing uniformity RSD ≤ 5.0%) and the Chinese Pharmacopoeia (content uniformity A + 2.2S < 15.0). The tablets of Comparative Examples 2 and 7, as well as Comparative Examples 3, 5-6 prepared with other excipients, have poor uniformity results.

[0057] Experiment 3: Stability Evaluation The coated tablets in the above examples were packaged in high-density polyethylene bottles and subjected to accelerated testing at 40°C / 75%RH for 6 months to detect the content of degraded impurities in amlodipine. The results are shown in Table 8 below.

[0058] Table 8

[0059] Conclusion: According to the results in Table 8, the samples of Examples 1-5 and Comparative Example 3 all created physical isolation conditions between irbesartan and amlodipine to a certain extent, effectively improving the stability of amlodipine. However, the sample of Comparative Example 1 obtained by wet granulating irbesartan and amlodipine together caused significant degradation of amlodipine due to direct exposure of irbesartan and amlodipine, resulting in poor sample stability. The tablets of Comparative Examples 4-7 prepared with other excipients were not as stable as those of Comparative Examples 3 and Examples 1-5 to a certain extent.

[0060] In summary, the pharmaceutical composition of the present invention is in the form of a double-layer tablet, which not only ensures that amlodipine besylate has excellent mixing uniformity and stability, but also solves the problem of poor fluidity of irbesartan during tableting.

[0061] The above detailed description is a specific description of one feasible embodiment of the present invention. The embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the present invention should be included in 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 comprise irbesartan, cross-linked sodium carboxymethyl cellulose and hydroxypropyl cellulose; the raw materials of the amlodipine besylate layer comprise amlodipine besylate, cross-linked sodium carboxymethyl cellulose and hydroxypropyl cellulose; the model of the hydroxypropyl cellulose is HPC-M.

2. The pharmaceutical composition according to claim 1, characterized in that The irbesartan layer further comprises a first diluent selected from mannitol and microcrystalline cellulose in a mass ratio of 1.5-3:

1.

3. The pharmaceutical composition according to claim 2, characterized in that The amlodipine besylate layer further comprises a second diluent selected from mannitol and microcrystalline cellulose in a mass ratio of 4.3-7:

1.

4. The pharmaceutical composition according to claim 1, characterized in that The model of the cross-linked sodium carboxymethyl cellulose is SD711.

5. The pharmaceutical composition according to claim 4, characterized in that The mass ratio of cross-linked carboxymethyl cellulose sodium to hydroxypropyl cellulose in the amlodipine besylate layer is 5:1.5-5.

6. The pharmaceutical composition according to claim 3, characterized in that The raw materials of the irbesartan layer and the amlodipine besylate layer both further include a glidant.

7. The pharmaceutical composition according to claim 6, characterized in that In terms of weight, the irbesartan layer comprises 60-70 parts of irbesartan, 20-30 parts of a first diluent, 5-10 parts of cross-linked sodium carboxymethyl cellulose, 1-5 parts of hydroxypropyl cellulose and 0.2-1 parts of a flow aid; the amlodipine besylate layer comprises 1-10 parts of amlodipine besylate, 80-90 parts of a second diluent, 2-10 parts of cross-linked sodium carboxymethyl cellulose, 1-5 parts of hydroxypropyl cellulose and 0.2-1 parts of a flow aid.

8. A method for preparing the pharmaceutical composition according to claim 7, characterized in that: The steps include: (1) mixing irbesartan, a first diluent, and croscarmellose sodium, adding an aqueous solution of hydroxypropyl cellulose for wet granulation, and adding a glidant to obtain irbesartan total mixed granules; (2) subjecting the amlodipine besylate, the second diluent, and the aqueous solution of hydroxypropyl cellulose to fluidized bed granulation, and then adding croscarmellose sodium and a flow aid to mix, thereby obtaining the amlodipine besylate total mixed granules; (3) first compressing the irbesartan total mixed granules into an irbesartan layer, then adding the amlodipine besylate total mixed granules, and compressing the amlodipine besylate layer to obtain a double-layer tablet; (4) The double-layer tablets are coated.

9. The preparation method according to claim 8, characterized in that: In step (2), amlodipine besylate and the second diluent are used as base materials, and a hydroxypropyl cellulose aqueous solution is top-sprayed for fluidized bed granulation, wherein the concentration of the hydroxypropyl cellulose aqueous solution is 3-7 wt %.

10. The preparation method according to claim 8, characterized in that: The mixing time in step (1) is 2-10 minutes, the wet granules prepared by the wet granulation are sieved through a 4×4 mm sieve for granulation, dried, and sieved through a 1.5 mm sieve for granulation; the hardness of the tablets in step (3) is 80-120 N, and the coating in step (4) includes preparing a gastric soluble film coating premix with water into a coating solution with a solid content of 10%, and then coating, and controlling the coating weight gain to be 3-5%.

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