Olmesartan medoxomil amlodipine tablet and preparation method thereof

Abstract

The invention discloses an olmesartan medoxomil amlodipine tablet and a preparation method thereof. The preparation method comprises the following steps: weighing, mixing and sieving, mixing for the first time, mixing for the second time, mixing for the third time, totally mixing, tabletting, coating and packaging. According to the invention, by selecting proper auxiliary materials, the requirements of a preparation process are met; according to the invention, colloidal silicon dioxide is used as a flow aid, so that the adhesiveness between materials is reduced, the flowability of the materials is improved, the flowability of the obtained materials can meet the requirements of commercial production, the content uniformity result of the prepared tablets meets the requirements, and the paddle method 75rpm dissolution curve in a SDS medium with the pH value of 4.5 + 0.1% is consistent with that of a reference preparation.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical manufacturing, and in particular to an Olmesartan Medoxomil Amlodipine tablet and a preparation method thereof. Background Art

[0002] As the latest generation of ARB drugs, Olmesartan has a stronger, longer-acting and more stable antihypertensive effect due to its unique "2046" structure. Its combination with CCB amlodipine is a model of a strong combination of antihypertensive treatment. It is a clinically preferred treatment option that can achieve strong antihypertensive effect, high target achievement rate and good tolerability. When Olmesartan medoxomil and amlodipine were co-administered, the pharmacokinetics of both did not change. The pharmacokinetics were consistent with the pharmacokinetics of the two when used alone. The bioavailability of both was less than 100%, but neither was affected by food. The effective half-life of amlodipine is 45±11 hours, and the effective half-life of olmesartan is 7±1 hours. Therefore, after once-daily administration, amlodipine has 2 to 3 times the accumulation, and the accumulation of olmesartan is negligible. Olmesartan medoxomil is absorbed through the gastrointestinal tract after oral administration, and is rapidly and completely deesterified and hydrolyzed into Olmesartan, with an absolute bioavailability of about 26%. The peak blood concentration is reached 1 to 2 hours after oral administration, and eating does not affect the bioavailability of Olmesartan medoxomil. After oral therapeutic doses of amlodipine, the blood concentration reaches the peak 6 to 12 hours later, and the absolute bioavailability is about 64% to 90%.

[0003] The original preparation process of Olmesartan Medoxomil Amlodipine Tablets was direct tablet compression, in which the prescription had the following problems:

[0004] (1) The particle size of the olmesartan medoxomil raw material in the prescription is relatively fine, and the fluidity is poor, so the material feeding is not smooth, and the outer wall of the mixer needs to be manually knocked to assist the material feeding;

[0005] (2) The materials in the prescription have strong adhesion and poor fluidity, which can easily lead to problems such as tablet sticking, large fluctuations in tablet pressure, and poor tablet content uniformity;

[0006] (3) The tablets produced have low hardness, and the tablet surface is worn during the coating process, resulting in uneven coating surface. Summary of the invention

[0007] The technical problem to be solved by the present invention is to overcome the technical defects of the background technology and provide an Olmesartan Medoxomil Amlodipine Tablet and a preparation method thereof. The present invention meets the requirements of the preparation process by selecting suitable auxiliary materials; the present invention uses colloidal silicon dioxide as a glidant to reduce the adhesion between materials and increase the fluidity of the materials. The fluidity of the obtained materials can meet the needs of commercial production, and the content uniformity results of the prepared plain tablets meet the requirements. The paddle method 75rpm dissolution curve in pH4.5+0.1% SDS medium is consistent with the reference preparation.

[0008] The technical solution adopted by the present invention to solve the above technical problems is as follows:

[0009] A method for preparing Olmesartan Medoxomil Amlodipine Tablets, comprising the following steps: weighing → mixing and sieving → mixing 1 → mixing 2 → mixing 3 → total mixing → tableting → coating → packaging:

[0010] (1) Weighing: Weigh the raw materials and excipients according to the prescription amount of each Olmesartan Medoxomil Amlodipine Tablet, namely, 20 mg of Olmesartan Medoxomil, 6.94 mg of Amlodipine Besylate, 19.7-39.7 mg of silicified microcrystalline cellulose, 30.0-50.0 mg of pregelatinized starch, 1.0-5.0 mg of croscarmellose sodium, 0.5-2.0 mg of colloidal silicon dioxide, 0.7-2.0 mg of magnesium stearate, and 2.0-5.0 mg of film coating premix (gastric soluble) for use;

[0011] (2) Mixing and sieving: Olmesartan medoxomil and an appropriate amount of silicified microcrystalline cellulose are mixed and sieved to obtain material a for later use; colloidal silicon dioxide and an appropriate amount of pregelatinized starch are mixed and sieved to obtain material b for later use;

[0012] (3) Mixing 1: Add the material a and the remaining silicified microcrystalline cellulose in step (2) into a hopper mixer and mix to obtain material c for later use;

[0013] (4) Mixing 2: Mixing the material c described in step (3) with the remaining pregelatinized starch and amlodipine besylate to obtain material d for later use;

[0014] (5) Mixing 3: Mixing the material b of step (2), the material d of step (4), and cross-linked sodium carboxymethyl cellulose to obtain material e for later use;

[0015] (6) Total mixing: uniformly mixing the material e and magnesium stearate in step (5) in a mixer to obtain material f for later use;

[0016] (7) tableting: tableting the material f described in step (6) to obtain a plain tablet g for later use;

[0017] (8) Coating: coating the plain tablet g described in step (7) to obtain coated tablet h for later use;

[0018] (9) Packaging: Packaging the coated tablets h described in step (8) to obtain.

[0019] Preferably, in step (1), the model of the pregelatinized starch is PC-10.

[0020] Preferably, in step (1), the colloidal silica is of the type AEROSIL 200.

[0021] Preferably, in step (2), the amount of the silicified microcrystalline cellulose added is 0.5 to 2 times the amount of the olmesartan medoxomil.

[0022] Preferably, in step (2), the amount of the pregelatinized starch added is 5 to 20 times the amount of the colloidal silicon dioxide.

[0023] Preferably, in step (2), the mesh size of the sieving is 20 to 60 meshes.

[0024] Preferably, in step (3), the rotation speed during mixing is 5 to 25 rpm, and the mixing time is 1 to 10 min.

[0025] Preferably, in step (4), the rotation speed during mixing is 5 to 25 rpm, and the mixing time is 1 to 10 min.

[0026] Preferably, in step (5), the rotation speed during mixing is 5 to 25 rpm, and the mixing time is 5 to 30 min.

[0027] More preferably, in step (5), the mixing time is 10 to 20 minutes.

[0028] Preferably, in step (6), the rotation speed during mixing is 5 to 25 rpm, and the mixing time is 1 to 10 min.

[0029] More preferably, in step (6), the mixing time is 3 to 7 minutes.

[0030] Preferably, in step (7), the average hardness of the plain tablet is 30-70N.

[0031] More preferably, in step (7), the average hardness of the plain tablet is 40 to 60N.

[0032] Preferably, in step (8), the weight gain of the coated tablet is 2% to 5%.

[0033] Preferably, in step (9), the packaging is aluminum-plastic packaging with an additional desiccant and an aluminum foil bag.

[0034] The invention discloses an Olmesartan medoxomil amlodipine tablet. According to the prescription amount, the formula of each Olmesartan medoxomil amlodipine tablet comprises 20 mg of Olmesartan medoxomil, 6.94 mg of amlodipine besylate, 19.7-39.7 mg of silicified microcrystalline cellulose, 30.0-50.0 mg of pregelatinized starch, 1.0-5.0 mg of cross-linked sodium carboxymethyl cellulose, 0.5-2.0 mg of colloidal silicon dioxide, 0.7-2.0 mg of magnesium stearate, and 2.0-5.0 mg of film coating premix (gastric soluble type); according to the prescription amount, the total weight of each plain tablet of the Olmesartan medoxomil amlodipine tablet is 78.84-125.64 mg, and the weight of the coated tablet is 80.84-130.64 mg.

[0035] In the above technical solution, the silicified microcrystalline cellulose and pregelatinized starch are fillers.

[0036] In the above technical solution, the cross-linked carboxymethyl cellulose sodium is a disintegrant.

[0037] In the above technical solution, the colloidal silicon dioxide is a glidant.

[0038] In the above technical solution, the magnesium stearate is a lubricant.

[0039] Basic principles of the present invention:

[0040] The technical solution provided by the present invention is to improve the fluidity of materials, reduce the risk of tabletting and sticking, and improve the content uniformity of tablets. The present invention uses a powder direct tableting process, screens the types and models of auxiliary materials, and uses colloidal silicon dioxide as a glidant, which will be adsorbed on the surface of the olmesartan medoxomil raw material with strong viscosity, so that the spacing between the raw material powders is increased, thereby reducing the force between the particles and improving the fluidity of the material; at the same time, it can reduce the binding force between the material and the punch surface, reduce the risk of sticking, and the obtained material fluidity can meet the needs of commercial production. The content uniformity result of the prepared plain tablet is better than that of the reference preparation, and the paddle method 75rpm dissolution curve in pH4.5+0.1% SDS medium is consistent with the reference preparation.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] (1) The present invention reduces the interaction force between viscous materials and the bonding force between the materials and the metal surface of the punch by adding the flow aid colloidal silicon dioxide, thereby increasing the fluidity of the materials and greatly reducing the risk of sticking.

[0043] (2) The present invention uses colloidal silicon dioxide as a glidant to improve material fluidity, reduce the trouble caused by manual tapping operations, and greatly reduce tableting pressure fluctuations;

[0044] (3) The present invention reduces the interaction between materials and improves the content uniformity of tablets by adding colloidal silicon dioxide. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The dissolution curves of the Olmesartan Medoxomil Amlodipine Tablets prepared in Examples 1 to 8 of the present invention and Comparative Example 1 are compared with those of the reference preparation. DETAILED DESCRIPTION

[0046] In order to better understand the content of the present invention, further description is given below in conjunction with specific embodiments and accompanying drawings. It should be understood that these embodiments are only used to further illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content described in the present invention, those skilled in the art may make some non-essential changes or adjustments to the present invention, which still belong to the protection scope of the present invention.

[0047] Example 1

[0048] A preparation method of Olmesartan Medoxomil Amlodipine Tablets, comprising the following steps:

[0049] (1) Weighing: weigh the raw materials and excipients according to the prescription amount of 5000 Olmesartan Medoxomil Amlodipine Tablets, namely, 100 g of Olmesartan Medoxomil, 34.7 g of Amlodipine Besylate, 148.5 g of silicified microcrystalline cellulose, 200.0 g of pregelatinized starch, 15.0 g of croscarmellose sodium, 4.0 g of colloidal silicon dioxide, 5.0 g of magnesium stearate, and 20.0 g of film coating premix (gastric soluble) for use; the model of the pregelatinized starch is PC-10, and the model of the colloidal silicon dioxide is AEROSIL 200;

[0050] (2) Mixing and sieving: Olmesartan medoxomil and 100 g of silicified microcrystalline cellulose were mixed and passed through a 40-mesh sieve to obtain material a, which was set aside; colloidal silicon dioxide and 40 g of pregelatinized starch were mixed and passed through a 40-mesh sieve to obtain material b, which was set aside;

[0051] (3) Mixing 1: Add the material a and the remaining silicified microcrystalline cellulose in step (2) into a hopper mixer and mix for 3 minutes at a speed of 20 rpm to obtain material c for later use;

[0052] (4) Mixing 2: Mix the material c described in step (3) with the remaining pregelatinized starch and amlodipine besylate for 3 min at a speed of 20 rpm to obtain material d for standby use;

[0053] (5) Mixing 3: Mix material b from step (2), material d from step (4), and cross-linked sodium carboxymethyl cellulose for 10 min at a speed of 20 rpm to obtain material e for later use;

[0054] (6) Total mixing: The material e described in step (5) and magnesium stearate are uniformly mixed in a mixer for 5 min at a speed of 20 rpm to obtain material f for later use;

[0055] (7) tableting: the material f described in step (6) is tableted to obtain a plain tablet g having a hardness of 30 to 70 N for later use;

[0056] (8) Coating: coating the plain tablet g described in step (7) to obtain coated tablet h, with a coating weight gain of 4%, for later use;

[0057] (9) Packaging: The coated tablets h prepared in step (8) are packaged in an aluminum-plastic package, and then sealed in an aluminum foil bag after adding a desiccant.

[0058] Example 2

[0059] This embodiment is substantially the same as embodiment 1, except that 148.5 g of silicified microcrystalline cellulose and 200.0 g of pregelatinized starch in step (1) of embodiment 1 are replaced with 123.5 g of silicified microcrystalline cellulose and 225.0 g of pregelatinized starch, respectively.

[0060] Example 3

[0061] This embodiment is substantially the same as embodiment 1, except that 148.5 g of silicified microcrystalline cellulose and 200.0 g of pregelatinized starch in step (1) of embodiment 1 are replaced with 173.5 g of silicified microcrystalline cellulose and 175.0 g of pregelatinized starch, respectively.

[0062] Example 4

[0063] This example is substantially the same as Example 1, except that 148.5 g of silicified microcrystalline cellulose and 15.0 g of croscarmellose sodium in step (1) of Example 1 are replaced with 153.5 g of silicified microcrystalline cellulose and 10.0 g of croscarmellose sodium, respectively.

[0064] Example 5

[0065] This example is substantially the same as Example 1, except that 148.5 g of silicified microcrystalline cellulose and 15.0 g of croscarmellose sodium in step (1) of Example 1 are replaced with 138.5 g of silicified microcrystalline cellulose and 25.0 g of croscarmellose sodium, respectively.

[0066] Example 6

[0067] This example is basically the same as Example 1, except that 4.0 g of colloidal silicon dioxide in step (1) of Example 1 is replaced with 2.5 g of colloidal silicon dioxide.

[0068] Example 7

[0069] This embodiment is substantially the same as embodiment 1, except that 148.5 g of silicified microcrystalline cellulose, 4.0 g of colloidal silicon dioxide and 5.0 g of magnesium stearate in step (1) of embodiment 1 are replaced with 137.5 g of silicified microcrystalline cellulose, 10.0 g of colloidal silicon dioxide and 10.0 g of magnesium stearate, respectively.

[0070] Example 8

[0071] This embodiment is substantially the same as embodiment 1, except that the mixing time in step (5) of embodiment 1 is changed from 10 min to 30 min, and the mixing time in step (6) is changed from 5 min to 10 min.

[0072] Comparative Example 1

[0073] A preparation method of Olmesartan Medoxomil Amlodipine Tablets, comprising the following steps:

[0074] (1) Weighing: weigh the raw materials and excipients according to the prescription amount of 5000 Olmesartan Medoxomil Amlodipine Tablets, namely, 100 g of Olmesartan Medoxomil, 34.7 g of Amlodipine Besylate, 148.5 g of silicified microcrystalline cellulose, 200.0 g of pregelatinized starch, 15.0 g of croscarmellose sodium, 5.0 g of magnesium stearate, and 20.0 g of film coating premix (gastric soluble type), and set aside; the model of the above-mentioned pregelatinized starch is PC-10;

[0075] (2) Mixing and sieving: Olmesartan medoxomil and 100 g of silicified microcrystalline cellulose were mixed and passed through a 40-mesh sieve to obtain material a for later use; pregelatinized starch was passed through a 40-mesh sieve to obtain material b for later use;

[0076] (3) Mixing 1: Add the material a and the remaining silicified microcrystalline cellulose in step (2) into a hopper mixer and mix for 3 minutes at a speed of 20 rpm to obtain material c for later use;

[0077] (4) Mixing 2: Mix the material b described in step (2) and the material c described in step (3) and amlodipine besylate for 3 min at a rotation speed of 20 rpm to obtain material d for standby use;

[0078] (5) Mixing 3: Mix the material d and cross-linked sodium carboxymethyl cellulose described in step (4) for 10 minutes at a speed of 20 rpm to obtain material e for later use;

[0079] (6) Total mixing: The material e described in step (5) and magnesium stearate are uniformly mixed in a mixer for 5 min at a speed of 20 rpm to obtain material f for later use;

[0080] (7) tableting: the material f described in step (6) is tableted to obtain a plain tablet g having a hardness of 30 to 70 N for later use;

[0081] (8) Coating: coating the plain tablet g described in step (7) to obtain coated tablet h, with a coating weight gain of 4%, for later use;

[0082] (9) Packaging: The coated tablets h prepared in step (8) are packaged in an aluminum-plastic package, and then sealed in an aluminum foil bag after adding a desiccant.

[0083] Effect evaluation experiment

[0084] 1. Dissolution Determination

[0085] The coated tablets obtained in Examples 1 to 8 and Comparative Example 1 were compared in vitro with the reference preparation (batch number: SY079YD, manufacturer: Daiichi Sankyo Pharmaceutical (Shanghai) Co., Ltd.). Dissolution curve method: paddle method; dissolution medium: pH 4.0 + 0.1% SDS medium; dissolution volume: 900 ml; rotation speed: 75 rpm; absorption wavelength: 254 nm; sampling time: 5 min, 10 min, 15 min, 30 min, 45 min, 60 min.

[0086] The comparison table and graph of the dissolution curve effects of the Olmesartan Medoxomil Amlodipine Tablets prepared in Examples 1 to 8 of the present invention and Comparative Example 1 and the reference preparation are shown in Tables 1 and Figure 1 .

[0087] Table 1 Comparison of dissolution curves of Olmesartan Medoxomil Amlodipine Tablets prepared in Examples 1 to 8 of the present invention and Comparative Example 1 and the reference preparation

[0088]

[0089] Note: f2 represents the similarity factor with the reference preparation, which is calculated at time points of 5min, 10min, 15min, 30min, 45min, and 60min. If f2 is greater than 50, it indicates that the dissolution condition is similar to that of the reference preparation in vitro.

[0090] From Table 1 and Figure 1 It can be seen that compared with Comparative Example 1, the compositions prepared in Examples 1 to 8 have better dissolution performance, and f2 is greater than 50, which is similar to the reference preparation; among them, the composition prepared in Example 1 has the highest similarity to the reference preparation, while Comparative Example 1 is not similar to the reference preparation in dissolution in the medium, and f2 is less than 50.

[0091] 2. Determination of tablet content uniformity

[0092] According to the general rules of Part IV of the 2020 edition of the Chinese Pharmacopoeia <0941 Content Uniformity Test Method>, three batches of small-scale tests were reproduced using the prescription process of Example 1, the plain tablets obtained in Comparative Example 1, and three batches of reference preparations (batch numbers: SY054YD, SY079YD, SY901YD, manufacturer: Daiichi Sankyo Pharmaceutical (Shanghai) Co., Ltd.) for content uniformity testing and comparison. The results are shown in Table 2.

[0093] Table 2 Comparison of the effects of content uniformity of three batches of reference preparations, three batches of small-scale trials of Example 1 of the present invention, and tablets of Comparative Example 1

[0094]

[0095] The content uniformity test results in Table 2 show that compared with the original technology of Olmesartan Medoxomil Amlodipine Tablets preparation prescription process, the Olmesartan Medoxomil Amlodipine Tablets prepared in this application show excellent product quality, which is a significant improvement over the original prescription and is better than the reference preparation quality.

[0096] The technical solution provided by the present invention is to improve the fluidity of materials, reduce the risk of tabletting and sticking, and improve the content uniformity of tablets. The present invention uses a powder direct tableting process, screens the types and models of auxiliary materials, and uses colloidal silicon dioxide as a glidant, which will be adsorbed on the surface of the olmesartan medoxomil raw material with strong viscosity, so that the spacing between the raw material powders is increased, thereby reducing the force between the particles and improving the fluidity of the material; at the same time, it can reduce the binding force between the material and the punch surface, reduce the risk of sticking, and the obtained material fluidity can meet the needs of commercial production. The content uniformity result of the prepared plain tablet is better than that of the reference preparation, and the paddle method 75rpm dissolution curve in pH4.5+0.1% SDS medium is consistent with the reference preparation.

[0097] The above description is not intended to limit the present invention, and the present invention is not limited to the above examples. Any changes, modifications, additions or substitutions made by a person skilled in the art within the spirit and scope of the present invention shall also fall within the protection scope of the present invention.

Claims

1. A method for preparing Olmesartan Medoxomil Amlodipine Tablets, characterized in that: The steps include: (1) Weighing: Weigh the raw materials and excipients according to the prescription amount of each Olmesartan Medoxomil Amlodipine Tablet, namely, 20 mg of Olmesartan Medoxomil, 6.94 mg of Amlodipine Besylate, 19.7-39.7 mg of silicified microcrystalline cellulose, 30.0-50.0 mg of pregelatinized starch, 1.0-5.0 mg of croscarmellose sodium, 0.5-2.0 mg of colloidal silicon dioxide, 0.7-2.0 mg of magnesium stearate, and 2.0-5.0 mg of film coating premix, and set aside; (2) Mixing and sieving: Olmesartan medoxomil and an appropriate amount of silicified microcrystalline cellulose are mixed and sieved to obtain material a, which is set aside; colloidal silicon dioxide and an appropriate amount of pregelatinized starch are mixed and sieved to obtain material b, which is set aside; (3) Mixing 1: Add the material a and the remaining silicified microcrystalline cellulose in step (2) into a hopper mixer and mix to obtain material c for later use; (4) Mixing 2: Mixing the material c described in step (3) with the remaining pregelatinized starch and amlodipine besylate to obtain material d for later use; (5) Mixing 3: Mixing the material b of step (2), the material d of step (4), and cross-linked sodium carboxymethyl cellulose to obtain material e for later use; (6) Total mixing: uniformly mixing the material e and magnesium stearate in step (5) in a mixer to obtain material f for later use; (7) tableting: tableting the material f described in step (6) to obtain a plain tablet g for later use; (8) Coating: coating the plain tablet g described in step (7) to obtain coated tablet h for later use; (9) Packaging: Packaging the coated tablets h described in step (8) to obtain.

2. The method for preparing Olmesartan Medoxomil Amlodipine Tablets according to claim 1, wherein: In step (1), the model of the pregelatinized starch is PC-10; the model of the colloidal silicon dioxide is AEROSIL 200.

3. The method for preparing Olmesartan Medoxomil Amlodipine Tablets according to claim 1, characterized in that: In step (2), the amount of the silicified microcrystalline cellulose added is 0.5 to 2 times the amount of the olmesartan medoxomil; the amount of the pregelatinized starch added is 5 to 20 times the amount of the colloidal silicon dioxide.

4. The method for preparing Olmesartan Medoxomil Amlodipine Tablets according to claim 1, characterized in that: In step (3), the rotation speed during mixing is 5 to 25 rpm, and the mixing time is 1 to 10 min.

5. The method for preparing Olmesartan Medoxomil Amlodipine Tablets according to claim 1, characterized in that: In step (4), the rotation speed during mixing is 5 to 25 rpm, and the mixing time is 1 to 10 min.

6. The method for preparing Olmesartan Medoxomil Amlodipine Tablets according to claim 1, characterized in that: In step (5), the rotation speed during mixing is 5 to 25 rpm, and the mixing time is 5 to 30 min.

7. The method for preparing Olmesartan Medoxomil Amlodipine Tablets according to claim 1, characterized in that: In step (6), the rotation speed during mixing is 5 to 25 rpm, and the mixing time is 1 to 10 min.

8. The method for preparing Olmesartan Medoxomil Amlodipine Tablets according to claim 1, characterized in that: In step (7), the average hardness of the plain tablet is 30 to 70N.

9. The method for preparing Olmesartan Medoxomil Amlodipine Tablets according to claim 1, characterized in that: In step (8), the weight gain of the coated tablet is 2% to 5%.

10. An Olmesartan Medoxomil Amlodipine Tablet, characterized in that: According to the prescription quantity, the formula of each Olmesartan medoxomil amlodipine tablet includes 20 mg of Olmesartan medoxomil, 6.94 mg of amlodipine besylate, 19.7-39.7 mg of silicified microcrystalline cellulose, 30.0-50.0 mg of pregelatinized starch, 1.0-5.0 mg of cross-linked sodium carboxymethyl cellulose, 0.5-2.0 mg of colloidal silicon dioxide, 0.7-2.0 mg of magnesium stearate, and 2.0-5.0 mg of film coating premix; according to the prescription quantity, the total weight of each plain tablet of Olmesartan medoxomil amlodipine tablet is 78.84-125.64 mg, and the weight of the coated tablet is 80.74-130.64 mg.

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