Tablet containing arginine perindopril and levamlodipine besylate and preparation method thereof

Abstract

According to the tablet containing the arginine perindopril and the levamlodipine besylate and the preparation method of the tablet, the pregelatinized starch and microcrystalline cellulose colloidal silicon dioxide co-treated substance is used as a filling agent, and the proportion of the pregelatinized starch and the microcrystalline cellulose colloidal silicon dioxide co-treated substance is controlled, so that the tablet containing the arginine perindopril and the levamlodipine besylate is prepared. The problem that the fluidity of the tablet is poor in preparation is solved, the stability is remarkably improved, the tablet has the advantages of being simple in preparation method, low in cost, good in fluidity, good in compressibility and the like, meanwhile, the tablet shows rapid disintegration, dissolution and stability, and the tablet is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a tablet containing arginine perindopril and levamlodipine besylate and its preparation method. Background Technology

[0002] Hypertension is the most prevalent chronic cardiovascular disease worldwide. According to the "China Cardiovascular Health and Disease Report 2023," the prevalence of hypertension among adults in my country has reached 23.2%, with over 300 million patients. Long-term uncontrolled hypertension can lead to damage to target organs such as the heart, brain, and kidneys, causing serious complications such as stroke, myocardial infarction, and chronic renal failure. It is one of the leading causes of death and disability among residents.

[0003] Clinical treatment guidelines clearly state that for patients with initial blood pressure ≥160 / 100 mmHg or whose blood pressure remains uncontrolled after monotherapy, combination therapy with two or more antihypertensive drugs with different mechanisms of action should be used. Among them, the combination regimen of angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers (CCBs) is recommended as the first-line combination regimen because of its synergistic antihypertensive effect (ACEIs inhibit the production of angiotensin II, and CCBs block the influx of calcium ions, thus reducing peripheral vascular resistance through different pathways), clear target organ protection effect (it can improve vascular endothelial function and delay kidney damage), and complementary adverse reactions (lower extremity edema that may be caused by CCBs can be partially relieved by ACEIs).

[0004] Arginine perindopril, a representative ACE inhibitor, is characterized by its long half-life (approximately 9 hours) and stable blood pressure reduction with once-daily dosing. Furthermore, its arginine salt form is more water-soluble and less irritating to the gastrointestinal tract compared to perindopril tert-butylamine salt. Levoamlodipine besylate, a long-acting dihydropyridine CCB, has a blood pressure-lowering effect 1000 times that of the dextrorotatory isoform and twice that of the 1:1 racemic isoform, while the dextrorotatory isoform has almost no blood pressure-lowering effect. After taking racemic amlodipine, the levorotatory isoform has a significantly longer half-life than the dextrorotatory isoform, with the former at 50.6 hours and the latter at 35.5 hours. The levorotatory isoform is also absorbed better than the dextrorotatory isoform, resulting in smaller fluctuations in blood drug concentration and effectively avoiding cardiovascular risks caused by diurnal blood pressure fluctuations. Summary of the Invention

[0005] The purpose of this invention is to provide a tablet containing arginine perindopril and levamlodipine besylate, based on existing technology. It uses pregelatinized starch and microcrystalline cellulose colloidal silica co-treated material as fillers, and controls the ratio of pregelatinized starch to microcrystalline cellulose colloidal silica co-treated material. This solves the problem of poor flowability in the preparation of this tablet and significantly improves its stability. It has advantages such as simple preparation method, low cost, good flowability, and good compressibility. It also exhibits rapid disintegration, dissolution, and stability, making it suitable for large-scale industrial production.

[0006] A second objective of this invention is to provide a method for preparing the tablets containing arginine perindopril and levamlodipine besylate.

[0007] The technical solution of the present invention is as follows:

[0008] A tablet containing arginine perindopril and levamlodipine besylate, the tablet being made from the following components in parts by weight: 10 parts arginine perindopril, 2.5 parts levamlodipine besylate, 98.53-132.53 parts filler, and 0.5-2.5 parts lubricant; the filler is a microcrystalline cellulose colloidal silica co-treated material and pregelatinized starch, wherein the microcrystalline cellulose colloidal silica co-treated material is spray-dried and has a particle size D 50 90-150μm, D 90 The particle size is 190-300 μm. The weight ratio of the microcrystalline cellulose colloidal silica co-treated product to the pregelatinized starch is 0.5-4:1; the lubricant is sodium stearate fumarate.

[0009] The tablet of this invention comprises the active ingredients perindopril arginine, levamlodipine besylate, and excipients. The excipients include fillers and lubricants. The fillers are microcrystalline cellulose colloidal silica co-treated material and pregelatinized starch. The lubricant is sodium stearate fumarate.

[0010] The microcrystalline cellulose and colloidal silica co-treated product mentioned in this invention is prepared by spray drying of microcrystalline cellulose and colloidal silica, wherein the weight ratio of microcrystalline cellulose to colloidal silica is 98:2, and the particle size D is controlled during the preparation process. 50 90-150μm, D 90 The particle size is 190-300 μm. Compared to the simple physical mixing of existing microcrystalline cellulose and colloidal silica, the novel composite excipient prepared by spray drying offers significant advantages in terms of process and properties, such as higher drug loading and simpler processing. It not only possesses good flowability but also excellent compressibility, achieving a synergistic effect, and has a surface conducive to drug adsorption, high drug loading, and good mixing uniformity. In a preferred embodiment, the microcrystalline cellulose and colloidal silica co-processed material mentioned in this invention is spray-dried, which can be used as... SMCC 90, wherein the weight ratio of microcrystalline cellulose to colloidal silica is 98:2.

[0011] For the tablets of this invention, spray-dried microcrystalline cellulose colloidal silica co-treated material and pregelatinized starch are selected as fillers. The amount and particle size range of the microcrystalline cellulose colloidal silica co-treated material, as well as the ratio of the co-treated material to colloidal silica in the entire tablet core, are controlled. The resulting tablets exhibit good flowability, compressibility, brittleness, and a smooth surface during compression. For example, during tablet preparation, it is necessary to control the ratio of pregelatinized starch to microcrystalline cellulose colloidal silica co-treated material. When the ratio is inappropriate, sticking and poor particle flowability are likely to occur during compression. In the experiment, replacing the microcrystalline cellulose colloidal silica co-treated material with an equal proportion of microcrystalline cellulose colloidal silica resulted in significantly poorer tablet stability.

[0012] For the tablets of this invention, the lubricant is sodium stearate fumarate; using other similar lubricants affects the tablet's efficacy. The filler is a co-treated microcrystalline cellulose colloidal silica and pregelatinized starch; using other similar fillers also affects the tablet's efficacy. For example, in the tablet preparation process, replacing the pregelatinized starch with lactose monohydrate resulted in tablets with significantly poorer stability.

[0013] The present invention also provides a method for preparing the above-mentioned tablets containing arginine perindopril and levamlodipine besylate, comprising the following steps: mixing arginine perindopril, levamlodipine besylate, microcrystalline cellulose colloidal silica co-treated product, pregelatinized starch and sodium stearate evenly, and compressing the mixture into tablets to obtain tablets.

[0014] In a preferred embodiment, the present invention provides a tablet containing arginine perindopril and levamlodipine besylate, the tablet being made from the following components in parts by weight: 10 parts arginine perindopril, 2.5 parts levamlodipine besylate, 100.53-130.53 parts filler, and 0.8-1.5 parts sodium stearate fumarate; wherein the filler is a microcrystalline cellulose colloidal silica co-treated product and pregelatinized starch, and the weight ratio of the microcrystalline cellulose colloidal silica co-treated product to the pregelatinized starch is 0.4-3.5:1.

[0015] In a more preferred embodiment, the present invention provides a tablet containing arginine perindopril and levamlodipine besylate, the tablet being made from the following components in parts by weight: 10 parts arginine perindopril, 2.5 parts levamlodipine besylate, 105.53-125.53 parts filler, and 0.9-1.1 parts sodium stearate fumarate; wherein the filler is a microcrystalline cellulose colloidal silica co-treated product and pregelatinized starch, and the weight ratio of the microcrystalline cellulose colloidal silica co-treated product to the pregelatinized starch is 0.5-3:1.

[0016] For example, the present invention provides a tablet containing arginine perindopril and levamlodipine besylate, the tablet being made from the following components in parts by weight: 10 parts arginine perindopril, 2.5 parts levamlodipine besylate, 115.53 parts filler and 1.0 part sodium stearate fumarate; wherein, 38.51 parts microcrystalline cellulose colloidal silica co-treated product and 77.02 parts pregelatinized starch are present, and the weight ratio of microcrystalline cellulose colloidal silica co-treated product to pregelatinized starch is 0.5:1.

[0017] For example, the present invention provides a tablet containing arginine perindopril and levamlodipine besylate, the tablet being made from the following components in parts by weight: 10 parts arginine perindopril, 2.5 parts levamlodipine besylate, 115.53 parts filler and 1.0 part sodium stearate fumarate; wherein, 57.73 parts microcrystalline cellulose colloidal silica co-treated product and 57.80 parts pregelatinized starch are present, and the weight ratio of microcrystalline cellulose colloidal silica co-treated product to pregelatinized starch is 1:1.

[0018] For example, the present invention provides a tablet containing arginine perindopril and levamlodipine besylate, the tablet being made from the following components in parts by weight: 10 parts arginine perindopril, 2.5 parts levamlodipine besylate, 115.53 parts filler and 1.0 part sodium stearate fumarate; wherein, 77.02 parts microcrystalline cellulose colloidal silica co-treated product and 38.51 parts pregelatinized starch are present, and the weight ratio of microcrystalline cellulose colloidal silica co-treated product to pregelatinized starch is 2:1.

[0019] For example, the present invention provides a tablet containing arginine perindopril and levamlodipine besylate, the tablet being made from the following components in parts by weight: 10 parts arginine perindopril, 2.5 parts levamlodipine besylate, 115.53 parts filler and 1.0 part sodium stearate fumarate; wherein, 86.53 parts microcrystalline cellulose colloidal silica co-treated product and 29.0 parts pregelatinized starch are present, and the weight ratio of microcrystalline cellulose colloidal silica co-treated product to pregelatinized starch is 3:1.

[0020] For example, the present invention provides a tablet containing arginine perindopril and levamlodipine besylate, the tablet being made from the following components in parts by weight: 10 parts arginine perindopril, 2.5 parts levamlodipine besylate, 105.53 parts filler and 1.0 part sodium stearate fumarate; wherein, 52.73 parts microcrystalline cellulose colloidal silica co-treated product and 52.80 parts pregelatinized starch are present, and the weight ratio of microcrystalline cellulose colloidal silica co-treated product to pregelatinized starch is 1:1.

[0021] For example, the present invention provides a tablet containing arginine perindopril and levamlodipine besylate, the tablet being made from the following components in parts by weight: 10 parts arginine perindopril, 2.5 parts levamlodipine besylate, 125.53 parts filler and 1.0 part sodium stearate fumarate; wherein, 62.73 parts microcrystalline cellulose colloidal silica co-treated product and 62.80 parts pregelatinized starch are present, and the weight ratio of microcrystalline cellulose colloidal silica co-treated product to pregelatinized starch is 1:1.

[0022] The advantages of using the technical solution of this invention are as follows:

[0023] This invention provides a tablet containing arginine perindopril and levamlodipine besylate, and a method for preparing the same. It uses a pregelatinized starch and microcrystalline cellulose colloidal silica co-treated material as fillers, and controls the ratio of these materials. This solves the problem of poor flowability in the preparation of the tablet and significantly improves its stability. The method is simple, low-cost, has good flowability and compressibility, and exhibits rapid disintegration, dissolution, and stability, making it suitable for large-scale industrial production. Detailed Implementation

[0024] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0025] Examples 1-5

[0026] A tablet containing arginine perindopril and levamlodipine besylate is made from the following components in parts by weight, wherein the microcrystalline cellulose colloidal silica co-treated product is... SMCC 90, particle size D 50 90-150μm, D 90 The microcrystalline cellulose and colloidal silica have a particle size of 190-300 μm and a weight ratio of 98:2. The specific components and weights of Examples 1-6 are shown in Table 1.

[0027] Table 1. Components and Dosage

[0028]

[0029]

[0030] The tablet preparation method in Example 1 includes the following steps:

[0031] Arginine perindopril, levamlodipine besylate, microcrystalline cellulose colloidal silica co-treated product, pregelatinized starch and sodium stearate fumarate are mixed evenly, and the resulting mixture is compressed into tablets using a rotary tableting machine. The tableting speed is controlled at 30-50 tablets / minute, the tablet hardness is 3-5 kgf, and the tablet weight difference is controlled within ±4%.

[0032] In the preparation process, compared with Example 1, the difference between Examples 2-6 lies in the amount and ratio of the microcrystalline cellulose colloidal silica co-treated material and the pregelatinized starch.

[0033] Comparative Examples 1-6

[0034] A tablet containing arginine perindopril and levamlodipine besylate is made from the following components in parts by weight, and the components and weights of comparative examples 1-6 are shown in Table 2.

[0035] Table 2 Components and Dosage

[0036]

[0037] The preparation method of the tablets in Comparative Example 1 includes the following steps:

[0038] Arginine perindopril, levamlodipine besylate, microcrystalline cellulose colloidal silica co-treated product, pregelatinized starch and sodium stearate fumarate are mixed evenly, and the resulting mixture is compressed into tablets using a rotary tableting machine. The tableting speed is controlled at 30-50 tablets / minute, the tablet hardness is 3-5 kgf, and the tablet weight difference is controlled within ±4%.

[0039] In the preparation process, compared with Comparative Example 1, the difference between Comparative Examples 2-4 lies in the different amounts and ratios of the microcrystalline cellulose colloidal silica co-treated material and the pregelatinized starch; the difference in Comparative Example 5 lies in replacing the pregelatinized starch with lactose monohydrate; the difference in Comparative Example 6 lies in replacing the microcrystalline cellulose colloidal silica co-treated material with the same proportion of microcrystalline cellulose and colloidal silica.

[0040] The effect data of the examples and comparative examples are as follows:

[0041] 1. Particle Powder Properties

[0042] The angle of repose of the samples in the examples and comparative examples was measured, and the results are shown in Table 3 below.

[0043] Table 3. Angle of repose data

[0044] sample Angle of repose Tableting phenomenon Example 1 37.5 Smooth tablet compression Example 2 39.0 Smooth tablet compression Example 3 37.8 Smooth tablet compression Example 4 39.0 Smooth tablet compression Example 5 40.0 Smooth tablet compression Example 6 39.5 Smooth tablet compression Comparative Example 1 43.5 Poor fluidity, stickiness, and unstable tablet weight Comparative Example 2 44.0 Poor liquidity, one-sided and crude Comparative Example 3 45.3 The fluidity is too poor, resulting in incomplete tablet filling during compression. Comparative Example 4 30.1 Adhesive punching, rough surface Comparative Example 5 40.5 Smooth tablet compression Comparative Example 6 40.0 Smooth tablet compression

[0045] The smaller the angle of repose of the particles, the better the particle flowability. Generally, an angle of repose less than 42° is considered to indicate good powder flowability, which meets the flowability requirements during tableting. An angle of repose greater than 42° makes tableting difficult. As shown in Table 4, the tablets in Examples 1-6 had an angle of repose less than 42°, indicating good powder flowability, which met the flowability requirements during tableting. However, in Comparative Examples 1 and 2, due to excessively high or low proportions of microcrystalline cellulose colloidal silica co-treated material and pregelatinized starch in the filler, the particle angle of repose was greater than 42°, resulting in poor flowability, sticking, and uneven tableting, leading to unstable tablet weight. In Comparative Example 3, the total amount of filler was too low, resulting in poor flowability and incomplete tableting. In Comparative Example 4, the total amount of filler was too high, resulting in excessively good flowability, sticking, and rough tablet surfaces. Therefore, excessively high or low ratios of microcrystalline cellulose colloidal silica co-treated material and pregelatinized starch in the filler, as well as excessively high or low total filler content, will affect tableting and prevent successful tableting.

[0046] 2. Disintegration time limit

[0047] Referring to the 2025 edition of the Chinese Pharmacopoeia, Volume IV, 0921, the disintegration time limit of the sample in purified water was tested, and the results are shown in Table 4 below.

[0048] Table 4 Disintegration Time Limit

[0049] sample Disintegration time limit Example 1 1 minute 30 seconds Example 2 1 minute 52 seconds Example 3 2min09s Example 4 1 minute 25 seconds Example 5 1 minute 53 seconds Example 6 1 minute 58 seconds Comparative Example 1 20s Comparative Example 2 25s Comparative Example 3 30s Comparative Example 4 20s Comparative Example 5 2min02s Comparative Example 6 1 minute 35 seconds

[0050] The Chinese Pharmacopoeia requires that the disintegration time of unprocessed tablets be within 15 minutes. Table 5 shows that the disintegration time of the examples and comparative examples was within 15 minutes. However, in Comparative Examples 1 and 2, the disintegration time was too fast because the proportions of microcrystalline cellulose colloidal silica co-treated material and pregelatinized starch in the filler were either too high or too low. In Comparative Examples 3 and 4, the disintegration time was too fast when the total amount of filler was too high or too low.

[0051] 3. Stability of influencing factors

[0052] The samples from the examples and comparative examples were placed at a high temperature of 60°C for 30 days, and the relevant substances were tested. The results are shown in Table 6 below.

[0053] Table 6 Stability Data

[0054]

[0055] As shown in Table 6, the maximum single impurity of the tablets prepared in Comparative Examples 5 and 6 exceeded the limit, and the total impurities were close to the upper limit. This indicates that replacing the pregelatinized starch in the filler with lactose monohydrate in Comparative Example 5, and replacing the microcrystalline cellulose colloidal silica co-treated material with an equal proportion of microcrystalline cellulose colloidal silica in Comparative Example 6, significantly worsened the stability of the tablets. In contrast, the maximum single impurity and total impurities of Examples 1-6 were within the limit, and their growth trend was significantly better than that of Comparative Examples 5 and 6, indicating better stability.

[0056] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A tablet comprising perindopril arginine and levamlodipine besylate, characterized in that, The tablet is made from the following components by weight: 10 parts of arginine perindopril, 2.5 parts of levamlodipine besylate, 98.53-132.53 parts of a filler, and 0.5-2.5 parts of a lubricant; the filler is a microcrystalline cellulose colloidal silicon dioxide co-treatment and pregelatinized starch, wherein the microcrystalline cellulose colloidal silicon dioxide co-treatment is a spray-dried type; the weight ratio of the microcrystalline cellulose colloidal silicon dioxide co-treatment and the pregelatinized starch is 0.5-4:1; and the lubricant is sodium stearyl fumarate.

2. The tablet according to claim 1, characterized in that, The microcrystalline cellulose colloidal silica co-processed product is made by spray drying of microcrystalline cellulose and colloidal silica, having a particle size D 50 90-150 μm, D 90 190-300 μm; preferably, the microcrystalline cellulose colloidal silica co-processed product is SMCC 90, having a weight ratio of microcrystalline cellulose and colloidal silica of 98:

2.

3. The tablet according to claim 2, characterized in that, In the preparation of the tablet, the arginine perindopril, the levamlodipine besylate, the microcrystalline cellulose colloidal silicon dioxide co-treatment, the pregelatinized starch, and the sodium stearyl fumarate are uniformly mixed, and then tableting is performed to obtain the tablet.

4. The tablet according to claim 3, characterized in that, The tablet is made from the following components by weight: 10 parts of arginine perindopril, 2.5 parts of levamlodipine besylate, 100.53-130.53 parts of a filler, and 0.8-1.5 parts of sodium stearyl fumarate; wherein the filler is a microcrystalline cellulose colloidal silicon dioxide co-treatment and pregelatinized starch, and the weight ratio of the microcrystalline cellulose colloidal silicon dioxide co-treatment and the pregelatinized starch is 0.4-3.5:

1.

5. The tablet according to claim 4, characterized in that, The tablet is made from the following components by weight: 10 parts of arginine perindopril, 2.5 parts of levamlodipine besylate, 105.53-125.53 parts of a filler, and 0.9-1.1 parts of sodium stearyl fumarate; wherein the filler is a microcrystalline cellulose colloidal silicon dioxide co-treatment and pregelatinized starch, and the weight ratio of the microcrystalline cellulose colloidal silicon dioxide co-treatment and the pregelatinized starch is 0.5-3:

1.

6. The tablet according to claim 5, characterized in that, The tablet is made from the following components by weight: 10 parts of arginine perindopril, 2.5 parts of levamlodipine besylate, 115.53 parts of a filler, and 1.0 part of sodium stearyl fumarate; wherein the microcrystalline cellulose colloidal silicon dioxide co-treatment is 38.51 parts, the pregelatinized starch is 77.02 parts, and the weight ratio of the microcrystalline cellulose colloidal silicon dioxide co-treatment and the pregelatinized starch is 0.5:1; 10 parts of arginine perindopril, 2.5 parts of levamlodipine besylate, 115.53 parts of a filler, and 1.0 part of sodium stearyl fumarate; wherein the microcrystalline cellulose colloidal silicon dioxide co-treatment is 57.73 parts, the pregelatinized starch is 57.80 parts, and the weight ratio of the microcrystalline cellulose colloidal silicon dioxide co-treatment and the pregelatinized starch is 1:1; 10 parts of arginine perindopril, 2.5 parts of levamlodipine besylate, 115.53 parts of a filler, and 1.0 part of sodium stearyl fumarate; wherein the microcrystalline cellulose colloidal silicon dioxide co-treatment is 77.02 parts, the pregelatinized starch is 38.51 parts, and the weight ratio of the microcrystalline cellulose colloidal silicon dioxide co-treatment and the pregelatinized starch is 2:1; 10 parts of arginine perindopril, 2.5 parts of levamlodipine besylate, 115.53 parts of a filler, and 1.0 part of sodium stearyl fumarate; wherein the microcrystalline cellulose colloidal silicon dioxide co-treatment is 86.53 parts, the pregelatinized starch is 29.0 parts, and the weight ratio of the microcrystalline cellulose colloidal silicon dioxide co-treatment and the pregelatinized starch is 3:1; Arginineteprotide 10 parts, levamlodipine besylate 2.5 parts, filler 105.53 parts and sodium stearyl fumarate 1.0 part; wherein, microcrystalline cellulose colloidal silicon dioxide co-treatment 52.73 parts, pregelatinized starch 52.80 parts, the weight ratio of microcrystalline cellulose colloidal silicon dioxide co-treatment and pregelatinized starch is 1:1; Arginineteprotide 10 parts, levamlodipine besylate 2.5 parts, filler 125.53 parts and sodium stearyl fumarate 1.0 part; wherein, microcrystalline cellulose colloidal silicon dioxide co-treatment 62.73 parts, pregelatinized starch 62.80 parts, the weight ratio of microcrystalline cellulose colloidal silicon dioxide co-treatment and pregelatinized starch is 1:

1.

7. A process for the preparation of the tablet according to claim 1, characterized in that, It comprises the following steps: mixing arginineteprotide, levamlodipine besylate, microcrystalline cellulose colloidal silicon dioxide co-treatment, pregelatinized starch and sodium stearyl fumarate uniformly, and then compressing into tablets to obtain the tablets.

8. The method of claim 7, wherein the tablet is prepared by, The microcrystalline cellulose colloidal silica co-processed product is made by spray drying of microcrystalline cellulose and colloidal silica, the particle size D 50 is 90-150 μm, D 90 is 190-300 μm.

9. The method of claim 8, wherein the tablet is prepared by, Microcrystalline cellulose colloidal silicon dioxide co-processed substance was SMCC 90, the weight ratio of microcrystalline cellulose and colloidal silicon dioxide was 98:

2.

10. The method of claim 9, wherein the tablet is prepared by, The tablets are prepared from the following components in parts by weight: arginineteprotide 10 parts, levamlodipine besylate 2.5 parts, filler 105.53-125.53 parts and sodium stearyl fumarate 0.9-1.1 parts; wherein, the filler is microcrystalline cellulose colloidal silicon dioxide co-treatment and pregelatinized starch, and the weight ratio of microcrystalline cellulose colloidal silicon dioxide co-treatment and pregelatinized starch is 0.5-3:1.

Images