Oral solid medicinal composition containing irbesartan and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and relates to an oral solid pharmaceutical composition containing irbesartan and a preparation method thereof. Irbesartan particles are prepared by adopting a wet granulation process, levamlodipine besylate particles are prepared by adopting a dry granulation process, the irbesartan particles and the levamlodipine besylate particles are mixed, a filling agent adopted in the dry granulation process is microcrystalline cellulose, and the mass ratio of irbesartan to levamlodipine besylate is (150-300): (2-4). The content uniformity of the levamlodipine besylate can meet the standard, and the stability of the composition can be improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to an oral solid pharmaceutical composition containing irbesartan and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] The antihypertensive strategy for hypertension includes lifestyle intervention and antihypertensive drug treatment based on this. A healthy lifestyle is the cornerstone of hypertension prevention and treatment, and the rational use of antihypertensive drugs is the key to achieving blood pressure targets. Studies on antihypertensive drugs have shown that the combined use of different types of antihypertensive drugs in small doses has a better antihypertensive effect and fewer adverse reactions than the use of a single drug in larger doses; combined therapy can improve the antihypertensive effect, neutralize the adverse reactions caused by different drugs, prevent the compensatory reaction triggered by the decrease in blood pressure during monotherapy, increase patient tolerance, and improve compliance.

[0004] Irbesartan is one of the five commonly used antihypertensive drugs. Its molecular formula is C 25 H 28 N6O, molecular weight is 428.54, chemical structure is as follows:

[0005]

[0006] Levoamlodipine besylate was developed by the Changchun Institute of Applied Chemistry, Chinese Academy of Sciences. Its efficacy is twice that of racemic amlodipine. Its molecular formula is C 20 H 25 N2O5Cl·C6H6O3S, molecular weight is 567.1, chemical structure is as follows:

[0007]

[0008] The inventors found in the process of developing a compound preparation with irbesartan and levamlodipine besylate as main ingredients that the common specification of levamlodipine besylate is 2.5 mg, and the conventional dosage of irbesartan is 150 mg and 300 mg, and the difference in the dosage of the active ingredients between the two is large, resulting in uneven mixing of the raw materials of the levamlodipine besylate during the preparation process, resulting in a low content of levamlodipine besylate, which affects the antihypertensive effect of the compound preparation; in addition, although levamlodipine besylate is the levorotatory isomer of amlodipine, the melting points of the two are quite different, and the melting point of the levorotatory isomer is only about 60° C., which is much lower than 200° C. of the racemate, and its stability is lower than that of the racemate, and it is more easily oxidized. The levamlodipine besylate raw material is directly exposed to the mixed material of the compound preparation. During the stability placement process, the levamlodipine besylate is degraded, and the impurities of the levamlodipine are increased, which seriously affects the stability, efficacy and safety of the drug. Summary of the invention

[0009] In order to overcome the deficiencies of the prior art, the object of the present invention is to provide an oral solid pharmaceutical composition containing irbesartan and a preparation method thereof, which can not only make the content uniformity of levamlodipine besylate meet the standard, but also improve the stability of the composition.

[0010] In order to achieve the above object, the present invention provides the following technical solutions:

[0011] In a first aspect, a method for preparing an oral solid pharmaceutical composition containing irbesartan comprises the following steps:

[0012] The irbesartan, the first filler, the first disintegrant and the binder are prepared into irbesartan granules by a wet granulation process;

[0013] The levoamlodipine besylate is prepared into levoamlodipine besylate granules by using a dry granulation process with a second filler, a second disintegrant and a first lubricant;

[0014] The irbesartan granules, levamlodipine besylate granules and a second lubricant are uniformly mixed to obtain;

[0015] The mass ratio of irbesartan to levamlodipine besylate is 150-300:2-4, and the second filler is microcrystalline cellulose.

[0016] In order to improve the uniformity of levamlodipine besylate during the preparation process, the present invention prepares irbesartan and levamlodipine besylate into granules respectively, and then mixes them. In the preparation of irbesartan granules, because irbesartan accounts for a large proportion of the preparation, about 60%; and the fluidity of the irbesartan raw material is poor, dry granulation cannot improve its fluidity, and finally wet granulation is used to improve its fluidity, so that the efficacy is easier to express. In the preparation of levamlodipine besylate granules, because levamlodipine besylate has a low melting point and is sensitive to moisture and heat, wet granulation cannot be performed, so levamlodipine besylate granules need to be prepared by direct powder mixing or dry granulation. However, studies have shown that when a powder mixture of levoamlodipine besylate is obtained by direct powder mixing and then mixed with irbesartan dry granules, the differences in powder properties and raw material ratios lead to uneven mixing, resulting in poor uniformity of levoamlodipine besylate content, affecting product quality. At the same time, the levoamlodipine besylate raw material has strong hygroscopicity and is unstable to light, moisture and heat. The powdered levoamlodipine besylate is directly exposed to the mixed materials of the compound preparation, causing the levoamlodipine besylate to degrade and increase the impurities of levoamlodipine besylate, seriously affecting the stability, efficacy and safety of the drug.

[0017] Therefore, when preparing the levoamlodipine besylate granules, the present invention adopts the method of mixing levoamlodipine besylate with the second filler for dry granulation, which can not only ensure the mixing uniformity of the levoamlodipine besylate, but also in the prepared granules, since the amount of the second filler is higher than the amount of the levoamlodipine besylate, and the levoamlodipine besylate and the second filler can be mixed uniformly, the levoamlodipine besylate is uniformly dispersed in the second filler, and the packing density is increased by dry granulation, so that the second filler tightly covers the levoamlodipine besylate to form a protective layer, thereby ensuring the stability of the levoamlodipine besylate.

[0018] In the study of dry granulation of levamlodipine besylate, it was found that the type of the second filler directly affects the stability of levamlodipine besylate. When the second filler is lactose, the primary amino group in levamlodipine besylate will undergo a Maillard reaction with lactose, resulting in an increase in related substances in the composition and a decrease in efficacy; when the second filler is mannitol, due to the hygroscopicity of levamlodipine besylate and the high water content of mannitol, the fluidity is poor during the preparation process, resulting in slightly poor content uniformity and a relatively high content of related impurities, which is not conducive to the efficacy and safety of the preparation; when the second filler is microcrystalline cellulose, it can not only ensure the content uniformity of levamlodipine besylate, but also significantly improve the stability of levamlodipine besylate, thereby ensuring the efficacy and safety of the prepared oral solid composition.

[0019] In some embodiments, the mass ratio of levamlodipine besylate to the second filler is 1:3 to 8. Studies have shown that in the dry granulation process, excessive addition of the second filler will result in less first filler in the irbesartan layer, resulting in poor irbesartan granular feel and sticky and astringent tableting. The above ratio can avoid the sticky and astringent phenomenon.

[0020] In some embodiments, the process of preparing irbesartan granules by wet granulation is: first, irbesartan is uniformly mixed with a first filler and a first disintegrant to form an irbesartan mixed material, and then the irbesartan mixed material is wet granulated with a solution of a binder, and then wet granulated, dried, and dry granulated to obtain irbesartan granules. Specifically, the concentration of the binder solution is 5.0-7.0%. Specifically, a wetting agent is added after granulation for wet granulation. More specifically, the wetting agent is purified water. Specifically, the drying is fluidized drying.

[0021] In some embodiments, the first filler is mannitol and / or microcrystalline cellulose. The fillers of the original drug of irbesartan tablets are lactose and microcrystalline cellulose; since the primary amino group in levamlodipine besylate will undergo a Maillard reaction with lactose, lactose is no longer used as a filler in the formulation; secondly, since irbesartan accounts for 60% of the preparation, the raw material itself is sticky and abrasive, and the selection of mannitol is easy to wet granulate the raw material irbesartan, and mannitol affects the permeability in the body. The filler is indispensable and the dosage cannot be adjusted too much; therefore, the first filler of irbesartan granules is mannitol and microcrystalline cellulose for wet granulation. Specifically, the first filler is mannitol and microcrystalline cellulose. More specifically, in the first filler, the mass ratio of mannitol to microcrystalline cellulose is 2.00-2.50:1. Specifically, the mass ratio of irbesartan to the first filler is 150:40-70.

[0022] In some embodiments, the first disintegrant is croscarmellose sodium.

[0023] In some embodiments, the added amount of the first disintegrant is 3.0-4.0% of the mass of irbesartan.

[0024] In some embodiments, the binder is polyvinyl alcohol.

[0025] In some embodiments, the added amount of the binder is 2.0-3.0% of the mass of irbesartan.

[0026] In some embodiments, the second disintegrant is croscarmellose sodium.

[0027] In some embodiments, the added amount of the second disintegrant is 1.25 to 2.50 times the mass of levamlodipine besylate.

[0028] In some embodiments, the first lubricant is magnesium stearate.

[0029] In some embodiments, the amount of the first lubricant added is 6-12% of the mass of levamlodipine besylate.

[0030] In some embodiments, the second lubricant is magnesium stearate.

[0031] In some embodiments, the mass ratio of the second lubricant to the first lubricant is 8 to 10:1.

[0032] On the other hand, an oral solid pharmaceutical composition containing irbesartan is obtained by the above preparation method.

[0033] The beneficial effects of the present invention are:

[0034] The present invention adopts a method of granulating irbesartan and levamlodipine besylate separately and then mixing them together when preparing an oral solid pharmaceutical composition containing irbesartan, so as to solve the problem of uneven mixing of levamlodipine besylate caused by the large difference in the content of irbesartan and levamlodipine besylate. In the granulation process of levamlodipine besylate, dry granulation is adopted, so that granules can be prepared under the premise of ensuring the stability of levamlodipine besylate, and by selecting microcrystalline cellulose as a filler in the dry granulation process, not only can the levamlodipine besylate be mixed evenly in the granules, but also the stability of levamlodipine besylate is further ensured by coating the microcrystalline cellulose.

[0035] Experimental studies have shown that the oral solid pharmaceutical composition containing irbesartan prepared by the present invention has the advantages of higher content uniformity and stability, thereby greatly improving its efficacy and safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0037] Figure 1 The dissolution curve of irbesartan from the irbesartan-amlodipine coated tablets prepared in an embodiment of the present invention when the pH value is 2.0;

[0038] Figure 2 The dissolution curve of irbesartan from the irbesartan-amlodipine coated tablets prepared in an embodiment of the present invention at a pH value of 4.5;

[0039] Figure 3The dissolution curve of levoamlodipine of the irbesartan levoamlodipine coated tablets prepared in an embodiment of the present invention at a pH value of 2.0;

[0040] Figure 4 This is the dissolution curve of levoamlodipine from the irbesartan levoamlodipine coated tablets prepared in an embodiment of the present invention at a pH value of 4.5. DETAILED DESCRIPTION

[0041] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in combination with specific embodiments and comparative examples.

[0042] Embodiment 1:

[0043] The invention discloses an irbesartan levoamlodipine tablet, wherein the irbesartan portion is prepared by a wet granulation process, and the levoamlodipine besylate portion is prepared by a dry granulation process, wherein the filler used in the dry granulation portion is microcrystalline cellulose, and the ratio of levoamlodipine besylate to microcrystalline cellulose is 1:3. The prescription is shown in Table 1 below.

[0044] Table 1 Dry granulation process recipe

[0045]

[0046] Preparation process

[0047] 1. Preparation

[0048] Irbesartan granules:

[0049] (1) Prepare 6% polyvinyl alcohol adhesive solution

[0050] Weigh the prescribed amount of polyvinyl alcohol, add it into a beaker of cold water to disperse it, then heat it to dissolve it. When it is completely dissolved, place it at room temperature for later use.

[0051] (2) Raw material and auxiliary material processing

[0052] Mannitol is passed through a 60-mesh sieve and set aside.

[0053] (3) Weighing

[0054] Weigh the prescribed amount of raw and auxiliary materials for later use.

[0055] (4) Wet granulation

[0056] Take irbesartan, mannitol, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose, mix well, and then add 6.0% polyvinyl alcohol solution to granulate; add all the binders, add appropriate amount of wetting agent purified water, and the soft material should be moderate (according to the standard for soft material operation in the tablet preparation process of "Pharmaceutics": lightly squeeze into a ball, and lightly press to disperse).

[0057] (5) Drying

[0058] After drying at 50-70°C, the granules are granulated to obtain irbesartan dry granules.

[0059] Levoamlodipine granules:

[0060] (1) Pretreatment of raw materials and auxiliary materials

[0061] Levaline besylate was passed through a 40-mesh sieve for later use.

[0062] (2) Weighing

[0063] Weigh microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, 1% magnesium stearate and levamlodipine besylate according to the prescription amount.

[0064] (3) Mixing

[0065] Microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, 1% magnesium stearate and levamlodipine besylate were put into a three-dimensional mixer, the mixing speed was set to 10 rpm, the mixing time was 10 min, and the mixture was mixed to obtain a levamlodipine mixture.

[0066] (4) Dry granulation

[0067] The dry granulation machine was used for granulation, the tableting speed was set at 10.00 rpm, the granulation speed was set at 100.00 rpm, and the sieves with apertures of 5.0 mm and 1.0 mm were selected to obtain dry granulation granules.

[0068] (5) Total mixing

[0069] The converted amount of irbesartan granules was mixed with the dry granulated granules prepared in step (4), the mixer speed was set to 15 rpm, the mixture was mixed for 15 min, and then 2 mg of magnesium stearate was added, and the mixture was mixed for another 5 min.

[0070] 2. Tablet pressing.

[0071] 3. Coating.

[0072] Embodiment 2:

[0073] A kind of irbesartan levoamlodipine tablets, wherein the irbesartan part adopts a wet granulation process, and the levoamlodipine besylate part adopts a dry granulation process, wherein the filler used in the dry granulation part is microcrystalline cellulose, and the ratio of levoamlodipine besylate to microcrystalline cellulose is 1:5. The prescription is shown in Table 2 below.

[0074] Table 2 Dry granulation process recipe

[0075]

[0076] Preparation process

[0077] 1. Preparation

[0078] Irbesartan granules:

[0079] (1) Prepare 6% polyvinyl alcohol adhesive solution

[0080] Weigh the prescribed amount of polyvinyl alcohol, add it into a beaker of cold water to disperse it, then heat it to dissolve it. When it is completely dissolved, place it at room temperature for later use.

[0081] (2) Raw material and auxiliary material processing

[0082] Mannitol is passed through a 60-mesh sieve and set aside.

[0083] (3) Weighing

[0084] Weigh the prescribed amount of raw and auxiliary materials for later use.

[0085] (4) Wet granulation

[0086] Take irbesartan, mannitol, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose, mix well, and then add 6.0% polyvinyl alcohol solution to granulate; add all the binder, add appropriate amount of wetting agent purified water, and moderate soft material.

[0087] (5) Drying

[0088] After drying at 50-70°C, the granules are granulated to obtain irbesartan dry granules.

[0089] Levoamlodipine granules:

[0090] (1) Pretreatment of raw materials and auxiliary materials

[0091] Levaline besylate was passed through a 40-mesh sieve for later use.

[0092] (2) Weighing

[0093] Weigh microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, 1% magnesium stearate and levamlodipine besylate according to the prescription amount.

[0094] (3) Mixing

[0095] Microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, 1% magnesium stearate and levamlodipine besylate were put into a three-dimensional mixer, the mixing speed was set to 10 rpm, the mixing time was 10 min, and the mixture was mixed to obtain a levamlodipine mixture.

[0096] (4) Dry granulation

[0097] The dry granulation machine was used for granulation, the tableting speed was set at 10.00 rpm, the granulation speed was set at 100.00 rpm, and the sieves with apertures of 5.0 mm and 1.0 mm were selected to obtain dry granulation granules.

[0098] (5) Total mixing

[0099] The converted amount of irbesartan granules was mixed with the dry granulated granules prepared in step (4), the mixer speed was set to 15 rpm, the mixture was mixed for 15 min, and then 2 mg of magnesium stearate was added, and the mixture was mixed for another 5 min.

[0100] 2. Tablet pressing.

[0101] 3. Coating.

[0102] Embodiment 3:

[0103] A kind of irbesartan levoamlodipine tablets, wherein the irbesartan part adopts a wet granulation process, and the levoamlodipine besylate part adopts a dry granulation process, wherein the filler used in the dry granulation part is microcrystalline cellulose, and the ratio of levoamlodipine besylate to microcrystalline cellulose is 1:8. The prescription is shown in Table 3 below.

[0104] Table 3 Dry granulation process recipe

[0105]

[0106] Preparation process

[0107] 1. Preparation

[0108] Irbesartan granules:

[0109] (1) Prepare 6% polyvinyl alcohol adhesive solution

[0110] Weigh the prescribed amount of polyvinyl alcohol, add it into a beaker of cold water to disperse it, then heat it to dissolve it. When it is completely dissolved, place it at room temperature for later use.

[0111] (2) Raw material and auxiliary material processing

[0112] Mannitol is passed through a 60-mesh sieve and set aside.

[0113] (3) Weighing

[0114] Weigh the prescribed amount of raw and auxiliary materials for later use.

[0115] (4) Wet granulation

[0116] Take irbesartan, mannitol, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose, mix well, and then add 6.0% polyvinyl alcohol solution to granulate; add all the binder, add appropriate amount of wetting agent purified water, and moderate soft material.

[0117] (5) Drying

[0118] After drying at 50-70°C, the granules are granulated to obtain irbesartan dry granules.

[0119] Levoamlodipine granules:

[0120] (1) Pretreatment of raw materials and auxiliary materials

[0121] Levaline besylate was passed through a 40-mesh sieve for later use.

[0122] (2) Weighing

[0123] Weigh microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, 1% magnesium stearate and levamlodipine besylate according to the prescription amount.

[0124] (3) Mixing

[0125] Microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, 1% magnesium stearate and levamlodipine besylate were put into a three-dimensional mixer, the mixing speed was set to 10 rpm, the mixing time was 10 min, and the mixture was mixed to obtain a levamlodipine mixture.

[0126] (4) Dry granulation

[0127] The dry granulation machine was used for granulation, the tableting speed was set at 10.00 rpm, the granulation speed was set at 100.00 rpm, and the sieves with apertures of 5.0 mm and 1.0 mm were selected to obtain dry granulation granules.

[0128] (5) Total mixing

[0129] The converted amount of irbesartan granules was mixed with the dry granulated granules prepared in step (4), the mixer speed was set to 15 rpm, the mixture was mixed for 15 min, and then 2 mg of magnesium stearate was added, and the mixture was mixed for another 5 min.

[0130] 2. Tablet pressing.

[0131] 3. Coating.

[0132] The irbesartan levamlodipine coated tablets of Examples 1 to 3 were respectively packaged in aluminum-plastic-aluminum packages and placed in an accelerated test chamber (40°C / RH75%). Samples were taken at 10 days and 30 days to examine related substances, and the content uniformity and dissolution curve at day 0 were compared.

[0133] When comparing the dissolution curves, since the compound preparation of irbesartan and amlodipine tablets has not been approved for marketing in any country, there is no reference preparation for this variety. The present invention selects the original imported drug of irbesartan tablets as the control drug (trade name: ), specification is 0.15g. NMPA has not yet announced the reference preparation of levamlodipine besylate tablets. The levamlodipine besylate tablets that have passed the consistency evaluation in China are all based on As the reference preparation, according to the serial number 11-1 in the "Catalogue of Reference Preparations for Generic Drugs" issued by NMPA, the original domestically produced amlodipine besylate tablets were selected as the control drug (trade name ), the specification is 5 mg. The results are shown in Tables 4 to 7. Figures 1 to 4 shown.

[0134] Table 4 Content uniformity data of irbesartan levamlodipine tablets in Examples 1 to 3

[0135]

[0136] Table 5 Data on related substances in Examples 1 to 3 Irbesartan Levoamlodipine Tablets

[0137]

[0138]

[0139] Table 6 Dissolution curve results of irbesartan levamlodipine tablets in Examples 1 to 3 - irbesartan

[0140]

[0141]

[0142] Table 7 Dissolution curve results of irbesartan levamlodipine tablets in Examples 1 to 3 - levamlodipine

[0143]

[0144]

[0145] By comparing Examples 1 to 3, Example 1 has the worst content uniformity, but the data are all qualified, and Example 2 has the best content uniformity data, indicating that the mixing is the most uniform.

[0146] During the stability investigation of Examples 1 to 3, there was little difference in the related substances.

[0147] Comparing the dissolution curves, for irbesartan, in pH 2.0 hydrochloric acid solution and pH 4.5 acetate buffer, the dissolution curve similarity factor f2 was greater than 50, indicating that the dissolution curves were similar. For levoamlodipine, the cumulative dissolution in pH 2.0 hydrochloric acid solution and pH 4.5 acetate buffer reached more than 85% in 15 minutes, which was a very rapid dissolution. There was no need to use the f2 method to compare their similarity, and the dissolution curves were considered similar.

[0148] Therefore, combined with the content uniformity, stability and dissolution curve results, it can be seen that in the embodiment, when levoamlodipine besylate is granulated by dry method, levoamlodipine besylate: microcrystalline cellulose = 1:3-8, the formulation process is feasible.

[0149] Comparative Example 1:

[0150] A kind of irbesartan levoamlodipine tablets, wherein the irbesartan part adopts a wet granulation process, and the levoamlodipine besylate part adopts a powder direct mixing process, wherein the filler used in the powder direct mixing is microcrystalline cellulose, and the ratio of levoamlodipine besylate to microcrystalline cellulose is 1:8. The prescription is shown in Table 8 below.

[0151] Table 8 Powder direct compression process prescription

[0152]

[0153]

[0154] Preparation process

[0155] 1. Preparation

[0156] Irbesartan granules:

[0157] (1) Prepare 6% polyvinyl alcohol adhesive solution

[0158] Weigh the prescribed amount of polyvinyl alcohol, add it into a beaker of cold water to disperse it, then heat it to dissolve it. When it is completely dissolved, place it at room temperature for later use.

[0159] (2) Raw material and auxiliary material processing

[0160] Mannitol is passed through a 60-mesh sieve and set aside.

[0161] (3) Weighing

[0162] Weigh the prescribed amount of raw and auxiliary materials for later use.

[0163] (4) Wet granulation

[0164] Take irbesartan, mannitol, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose, mix well, and add 6.0% polyvinyl alcohol solution to granulate; add all the binder and the soft material is moderate.

[0165] (5) Drying

[0166] After drying at 50-70°C, the granules are granulated to obtain irbesartan dry granules.

[0167] Levoamlodipine granules:

[0168] (1) Pretreatment of raw materials and auxiliary materials

[0169] Levaline besylate was passed through a 40-mesh sieve for later use.

[0170] (2) Weighing

[0171] Weigh microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and levamlodipine besylate according to the prescribed amount.

[0172] (3) Mixing

[0173] Microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and levamlodipine besylate were put into a three-dimensional mixer, and the mixing speed was set to 10 rpm and the mixing time was 10 min. The mixture was mixed to obtain a levamlodipine mixture.

[0174] (4) Total mixing

[0175] The converted amount of irbesartan granules was mixed with the levamlodipine besylate mixed material of step (3), the mixer speed was set to 15 rpm, the mixture was mixed for 15 min, and then magnesium stearate was added, and the mixture was continued for 5 min.

[0176] 2. Tablet pressing.

[0177] 3. Coating.

[0178] Comparative Example 2:

[0179] A kind of irbesartan levamlodipine tablets, wherein the irbesartan part adopts a wet granulation process, and the levamlodipine besylate part adopts a dry granulation process, wherein the filler used in the dry granulation process is lactose, and the prescription is shown in Table 9 below.

[0180] Table 9 Dry granulation process prescription

[0181]

[0182] Preparation process

[0183] 1. Preparation

[0184] Irbesartan granules:

[0185] (1) Prepare 6% polyvinyl alcohol adhesive solution

[0186] Weigh the prescribed amount of polyvinyl alcohol, add it into a beaker of cold water to disperse it, then heat it to dissolve it. When it is completely dissolved, place it at room temperature for later use.

[0187] (2) Raw material and auxiliary material processing

[0188] Mannitol is passed through a 60-mesh sieve and set aside.

[0189] (3) Weighing

[0190] Weigh the prescribed amount of raw and auxiliary materials for later use.

[0191] (4) Wet granulation

[0192] Take irbesartan, mannitol, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose, mix well, and then add 6.0% polyvinyl alcohol solution to granulate; add all the binder, add appropriate amount of wetting agent purified water, and moderate soft material.

[0193] (5) Drying

[0194] After drying at 50-70°C, the granules are granulated to obtain irbesartan dry granules.

[0195] Levoamlodipine granules:

[0196] (1) Pretreatment of raw materials and auxiliary materials

[0197] Levaline besylate was passed through a 40-mesh sieve for later use.

[0198] (2) Weighing

[0199] Weigh lactose, cross-linked sodium carboxymethyl cellulose, magnesium stearate and levamlodipine besylate according to the prescribed amount.

[0200] (3) Mixing

[0201] Put lactose, cross-linked sodium carboxymethyl cellulose, 1% magnesium stearate and levamlodipine besylate into a three-dimensional mixer, set the mixing speed to 10 rpm, and the mixing time to 10 min, and mix to obtain a levamlodipine besylate mixture.

[0202] (4) Dry granulation

[0203] The dry granulation machine was used for granulation, the tableting speed was set at 10.00 rpm, the granulation speed was set at 100.00 rpm, and the sieves with apertures of 5.0 mm and 1.0 mm were selected to obtain dry granulation granules.

[0204] (5) Total mixing

[0205] The converted amount of irbesartan granules was mixed with the dry granulated granules of levamlodipine prepared in step (4), the mixer speed was set to 15 rpm, the mixture was mixed for 15 min, and then 2 mg of magnesium stearate was added, and the mixture was mixed for another 5 min.

[0206] 2. Tablet pressing.

[0207] 3. Coating.

[0208] Comparative Example 3:

[0209] A kind of irbesartan levamlodipine tablets, wherein the irbesartan part adopts a wet granulation process, and the levamlodipine besylate part adopts a dry granulation process, wherein the filler used in the dry granulation process is mannitol, and the prescription is shown in Table 10 below.

[0210] Table 10 Dry granulation process recipe

[0211]

[0212] Preparation process

[0213] 1. Preparation

[0214] Irbesartan granules:

[0215] (1) Prepare 6% polyvinyl alcohol adhesive solution

[0216] Weigh the prescribed amount of polyvinyl alcohol, add it into a beaker of cold water to disperse it, then heat it to dissolve it. When it is completely dissolved, place it at room temperature for later use.

[0217] (2) Raw material and auxiliary material processing

[0218] Mannitol is passed through a 60-mesh sieve and set aside.

[0219] (3) Weighing

[0220] Weigh the prescribed amount of raw and auxiliary materials for later use.

[0221] (4) Wet granulation

[0222] Take irbesartan, mannitol, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose, mix well, and then add 6.0% polyvinyl alcohol solution to granulate; add all the binder, add appropriate amount of wetting agent purified water, and moderate soft material.

[0223] (5) Drying

[0224] After drying at 50-70°C, the granules are granulated to obtain irbesartan dry granules.

[0225] Levoamlodipine granules:

[0226] (1) Pretreatment of raw materials and auxiliary materials

[0227] Levaline besylate was passed through a 40-mesh sieve for later use.

[0228] (2) Weighing

[0229] Weigh mannitol, cross-linked sodium carboxymethyl cellulose, 1% magnesium stearate and levamlodipine besylate according to the prescription amount.

[0230] (3) Mixing

[0231] Mannitol, cross-linked sodium carboxymethyl cellulose, 1% magnesium stearate and levamlodipine besylate were put into a three-dimensional mixer, the mixing speed was set to 10 rpm, the mixing time was 10 min, and the mixture was mixed to obtain a levamlodipine mixture.

[0232] (4) Dry granulation

[0233] The dry granulation machine was used for granulation, the tableting speed was set at 10.00 rpm, the granulation speed was set at 100.00 rpm, and the sieves with apertures of 5.0 mm and 1.0 mm were selected to obtain dry granulation granules.

[0234] (5) Total mixing

[0235] The converted amount of irbesartan granules was mixed with the dry granulated granules prepared in step (4), the mixer speed was set to 15 rpm, the mixture was mixed for 15 min, and then 2 mg of magnesium stearate was added, and the mixture was mixed for another 5 min.

[0236] 2. Tablet pressing.

[0237] 3. Coating.

[0238] Comparative Example 4:

[0239] A kind of irbesartan levoamlodipine tablets, wherein the irbesartan part adopts a wet granulation process, and the levoamlodipine besylate part adopts a dry granulation process, wherein the filler adopted in the dry granulation process is microcrystalline cellulose, and the ratio of levoamlodipine besylate to microcrystalline cellulose is 1:10. The prescription is shown in Table 11 below.

[0240] Table 11 Dry granulation process recipe

[0241]

[0242] Preparation process

[0243] 1. Preparation

[0244] Irbesartan granules:

[0245] (1) Prepare 6% polyvinyl alcohol adhesive solution

[0246] Weigh the prescribed amount of polyvinyl alcohol, add it into a beaker of cold water to disperse it, then heat it to dissolve it. When it is completely dissolved, place it at room temperature for later use.

[0247] (2) Raw material and auxiliary material processing

[0248] Mannitol is passed through a 60-mesh sieve and set aside.

[0249] (3) Weighing

[0250] Weigh the prescribed amount of raw and auxiliary materials for later use.

[0251] (4) Wet granulation

[0252] Take irbesartan, mannitol, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose, mix well, and then add 6.0% polyvinyl alcohol solution to granulate; add all the binder, add appropriate amount of wetting agent purified water, and moderate soft material.

[0253] (5) Drying

[0254] After drying at 50-70°C, the granules are granulated to obtain irbesartan dry granules.

[0255] Levoamlodipine granules:

[0256] (1) Pretreatment of raw materials and auxiliary materials

[0257] Levaline besylate was passed through a 40-mesh sieve for later use.

[0258] (2) Weighing

[0259] Weigh microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, 1% magnesium stearate and levamlodipine besylate according to the prescription amount.

[0260] (3) Mixing

[0261] Microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, 1% magnesium stearate and levamlodipine besylate were put into a three-dimensional mixer, the mixing speed was set to 10 rpm, the mixing time was 10 min, and the mixture was mixed to obtain a levamlodipine mixture.

[0262] (4) Dry granulation

[0263] The dry granulation machine was used for granulation, the tableting speed was set at 10.00 rpm, the granulation speed was set at 100.00 rpm, and the sieves with apertures of 5.0 mm and 1.0 mm were selected to obtain dry granulation granules.

[0264] (5) Total mixing

[0265] The converted amount of irbesartan granules was mixed with the dry granulated granules prepared in step (4), the mixer speed was set to 15 rpm, the mixture was mixed for 15 min, and then 2 mg of magnesium stearate was added, and the mixture was mixed for another 5 min.

[0266] 2. Tablet pressing

[0267] Since the amount of mannitol and microcrystalline cellulose fillers in the irbesartan granules is relatively small, the irbesartan granules have a poor texture and the tablets are sticky and astringent.

[0268] Since the tableting process of Comparative Example 4 is not feasible, coating and subsequent stability testing are no longer carried out. The irbesartan levamlodipine coated tablets of Comparative Examples 1 to 3 are packaged in aluminum-plastic-aluminum packages and placed in an accelerated test chamber (40°C / RH75%). Samples are taken at 10 days and 30 days to investigate the changes in related substances and compare the content uniformity at 0 day. The results are shown in Tables 12 and 13.

[0269] Table 12 Content uniformity data of irbesartan levamlodipine tablets of Example 2 and Comparative Examples 1 to 4

[0270]

[0271] Table 13 Related substance data of Example 2 and Comparative Examples 1 to 4 Irbesartan Levoamlodipine Tablets

[0272]

[0273]

[0274]

[0275] By comparing Example 2 with Comparative Examples 1 to 4, the content uniformity of Comparative Example 1 is the worst, indicating that the mixing effect of the powder direct mixing process is not good; the growth of related substances in Comparative Example 2 is the most obvious, and the primary amino group in levamlodipine besylate will undergo Maillard reaction with lactose, resulting in an increase in related substances in the composition; followed by Comparative Example 3, when the filler is mannitol, due to the hygroscopicity of levamlodipine besylate, mannitol has high water content, resulting in poor fluidity during the preparation process, resulting in slightly poor content uniformity and a relatively high content of related impurities, which is not conducive to the efficacy and safety of the preparation; the raw materials of Comparative Examples 2 and 3 are all degraded, resulting in a faster growth of related substances; due to the sticky and astringent phenomenon during the tableting process of Comparative Example 4, the next step of the process is no longer investigated, and the stability and content uniformity are no longer tested; Comparative Examples 1 to 4, the prescription process is not feasible.

[0276] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing an oral solid pharmaceutical composition containing irbesartan, characterized in that: The steps include: The irbesartan, the first filler, the first disintegrant and the binder are prepared into irbesartan granules by a wet granulation process; The levoamlodipine besylate is prepared into levoamlodipine besylate granules by using a dry granulation process with a second filler, a second disintegrant and a first lubricant; The irbesartan granules, levamlodipine besylate granules and a second lubricant are uniformly mixed to obtain; The mass ratio of irbesartan to levamlodipine besylate is 150-300:2-4, and the second filler is microcrystalline cellulose.

2. The method for preparing the oral solid pharmaceutical composition containing irbesartan according to claim 1, characterized in that: The mass ratio of levamlodipine besylate to the second filler is 1:3-8.

3. The method for preparing the oral solid pharmaceutical composition containing irbesartan according to claim 1, characterized in that: The process of preparing irbesartan granules by wet granulation technology is as follows: first, irbesartan is uniformly mixed with a first filler and a first disintegrant to form an irbesartan mixed material, and then the irbesartan mixed material is wet granulated with a binder solution, and then wet granulated, dried, and dry granulated to obtain irbesartan granules; preferably, the concentration of the binder solution is 5.0-7.0% by mass; preferably, a wetting agent is added after granulation to perform wet granulation; preferably, the wetting agent is purified water; preferably, the drying is fluidized drying.

4. The method for preparing the oral solid pharmaceutical composition containing irbesartan according to claim 1, characterized in that: The first filler is mannitol and / or microcrystalline cellulose; preferably, the first filler is mannitol and microcrystalline cellulose; preferably, in the first filler, the mass ratio of mannitol to microcrystalline cellulose is 2.00-2.50:1; preferably, the mass ratio of irbesartan to the first filler is 150:40-70.

5. The method for preparing the oral solid pharmaceutical composition containing irbesartan according to claim 1, characterized in that: The first disintegrant is cross-linked carboxymethyl cellulose sodium; Alternatively, the added amount of the first disintegrant is 3.0-4.0% of the mass of irbesartan.

6. The method for preparing the oral solid pharmaceutical composition containing irbesartan according to claim 1, characterized in that: The adhesive is polyvinyl alcohol; Alternatively, the added amount of the binder is 2.0-3.0% of the mass of irbesartan.

7. The method for preparing the oral solid pharmaceutical composition containing irbesartan according to claim 1, characterized in that: The second disintegrant is cross-linked carboxymethyl cellulose sodium; Alternatively, the added amount of the second disintegrant is 1.25 to 2.50 times the mass of levamlodipine besylate.

8. The method for preparing the oral solid pharmaceutical composition containing irbesartan according to claim 1, characterized in that: The first lubricant is magnesium stearate; Alternatively, the first lubricant is added in an amount of 6 to 12% of the mass of levamlodipine besylate.

9. The method for preparing the oral solid pharmaceutical composition containing irbesartan according to claim 1, characterized in that: The second lubricant is magnesium stearate; Alternatively, the mass ratio of the second lubricant to the first lubricant is 8 to 10:

1.

10. An oral solid pharmaceutical composition containing irbesartan, obtained by the preparation method according to any one of claims 1 to 9.

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