High-stability oseltamivir phosphate dry suspension and preparation method thereof

Abstract

The invention provides a high-stability oseltamivir phosphate dry suspension and a preparation method thereof, pharmaceutical raw materials are divided into three types and are subjected to dry granulation respectively, oseltamivir phosphate, sodium benzoate and sorbitol are used as medicine-containing particles for dry granulation, sorbitol, titanium dioxide and saccharin sodium non-medicine-containing particles are used for dry granulation, and the oseltamivir phosphate dry suspension is prepared. The sodium citrate, the sodium benzoate and the xanthan gum do not contain medicine particles and are subjected to dry granulation, so that contact between the oseltamivir phosphate raw materials and auxiliary materials and between the auxiliary materials is avoided, the negative reaction between the medicine components is remarkably reduced, and the medicine stability of the oseltamivir phosphate is improved. The preparation method is simple in process, low in power consumption and suitable for large-scale production and application of the oseltamivir phosphate dry suspension, the safety risk of solvent residues in wet granulation is avoided, the influence of mixing of whole raw materials in dry granulation on the property of oseltamivir phosphate is avoided, and the effectiveness of the medicine is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a high-stability oseltamivir phosphate dry suspension and a preparation method thereof. Background Art

[0002] Oseltamivir phosphate is a prodrug of its active metabolite (oseltamivir carboxylate), and is an inhibitor of influenza virus neuraminidase, wherein neuraminidase is a glycoproteinase on the surface of the virus, and the activity of glycoproteinase is of great significance for the release of newly formed viruses from infected cells, the further spread of infectious viruses in cells, and the regulation of virus entry into uninfected cells. After oral administration of oseltamivir phosphate, it can be rapidly absorbed by the gastrointestinal tract and rapidly converted into the active metabolite oseltamivir carboxylate by liver and / or intestinal wall esterase. The dry suspension of the drug is a dosage form developed on the basis of the suspension. The drug is mixed with a variety of excipients and made into a powdered or granular solid preparation by a suitable method. Water is added and shaken before use to disperse the drug particles in the liquid medium, which is conducive to solving the stability problem of the suspension during storage.

[0003] Dry suspensions are widely used in clinical practice, with definite efficacy, small dosage, easy storage and carrying, and have the advantages of accurate dosage, beautiful appearance, and easy use. After the drug is made into a dry suspension, the particles are evenly distributed, and after entering the gastrointestinal tract, they have high dispersion, rapid absorption, and rapid onset of action, which to a certain extent reduces the impact of individual differences on drug metabolism and also reduces the occurrence of adverse reactions. There are two methods for preparing dry suspensions. One is granulation, that is, the drug and suitable excipients are made into dry granular preparations with a certain particle size. According to their solubility properties, they can be roughly divided into two categories: soluble (water-soluble, alcohol-soluble) granules and suspension granules; the other is a dry suspension in the form of powder by direct mixing of dry powder.

[0004] At present, commercially available oseltamivir phosphate preparations include capsules, dry suspensions, granules, orally disintegrating tablets and tablet dosage forms, wherein granules or dry suspensions are convenient for the elderly, children or other people who are not suitable for taking solid preparations. However, the current commercially available oseltamivir phosphate dry suspension has the following problems: oseltamivir is easily compatible with the sugar substances in the auxiliary materials, there is a Maillard reaction, furfural compounds are produced, resulting in a reduction in the stability of the oseltamivir phosphate product, affecting the drug efficacy, and the auxiliary materials xanthan gum and sorbitol used in the prescription increase viscosity after moisture absorption, increasing the negative reaction between the auxiliary materials and between the auxiliary materials and oseltamivir phosphate. To solve this problem, the present invention provides a high-stability oseltamivir phosphate dry suspension and a preparation method thereof. Summary of the invention

[0005] In view of this, the present invention provides a high-stability oseltamivir phosphate dry suspension and a preparation method thereof.

[0006] The technical solution of the present invention is achieved in this way:

[0007] A method for preparing a high-stability oseltamivir phosphate dry suspension, the raw materials comprising: 35-45 parts of oseltamivir phosphate, 4-10 parts of monosodium citrate, 5-15 parts of titanium dioxide, 850-900 parts of sorbitol, 10-20 parts of xanthan gum, 4-8 parts of yogurt powder flavor, 2-6 parts of sodium saccharin, and 3-5 parts of sodium benzoate, comprising the following steps:

[0008] S1. sieving oseltamivir phosphate, sodium benzoate and sorbitol respectively, and the sieved sorbitol is divided into 3 parts, namely sorbitol ①, sorbitol ② and sorbitol ③;

[0009] S2, sorbitol ① and oseltamivir phosphate are mixed and stirred evenly to obtain a mixed material Ⅰ;

[0010] S3, sorbitol ②, the sieved titanium dioxide and saccharin sodium are uniformly mixed to obtain a mixed material Ⅱ;

[0011] S4, monosodium citrate, sodium benzoate, xanthan gum and sorbitol ③ are mixed to obtain a mixed material III;

[0012] S5, dry granulating the mixed material I, the mixed material II and the mixed material III respectively;

[0013] S6. Mixture I, mixture II and mixture III are dry granulated and then mixed with yogurt powder essence, and the finished product is vacuum packaged.

[0014] Furthermore, S1, the D90 particle size of oseltamivir phosphate is 50-400 μm, the D90 particle size of sodium benzoate is 50-400 μm, and the mass ratio of oseltamivir phosphate to sodium benzoate is (35-45):(3-5).

[0015] Further, S1, sorbitol is passed through a 40-mesh sieve and divided into three parts according to weight ratio, with a total weight of 50% being sorbitol ①, a total weight of 10% being sorbitol ②, and a total weight of 40% being sorbitol ③.

[0016] Furthermore, for S2, S3, and S4, the spindle speed during mixing is 5r / min-8r / min, and the power is 1.5kw-2.5kw.

[0017] Furthermore, S3, titanium dioxide is passed through a 60-mesh sieve, saccharin sodium is passed through a 60-mesh sieve, and the mass ratio of sorbitol②, titanium dioxide, and saccharin sodium is (85-90):(5-15):(2-6).

[0018] Furthermore, in S4, the mass ratio of monosodium citrate, sodium benzoate, xanthan gum and sorbitol ③ is (4-10):(3-5):(10-20):(340-360).

[0019] Further, S5, the mixed material I is dry granulated, the roller oil pressure: 10-20bar, the roller gap: 0.6-1.2mm, the roller speed: 15-20rpm, the crushing speed: 130-150rpm, the crushing screen: 2.0mm, the granulation speed: 130-150rpm, the granulation screen: 1.0mm; the mixed material II and the mixed material III are dry granulated, the roller oil pressure: 15-20bar, the roller gap: 0.5-1.0mm, the roller speed: 15-20rpm, the crushing speed: 130-150rpm, the crushing screen: 1.5mm, the granulation speed: 130-150rpm, the granulation screen: 1.0mm.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] The three-step dry granulation method of the present invention is adopted, sorbitol and oseltamivir phosphate are used as drug-containing particles for dry granulation, auxiliary materials sorbitol, titanium dioxide, and saccharin sodium are dry granulated, and auxiliary materials monosodium citrate, sodium benzoate, xanthan gum, and sorbitol are dry granulated, thereby avoiding contact between the oseltamivir phosphate raw material and the auxiliary materials, avoiding contact between the auxiliary materials, significantly reducing the reaction between the drug components, and improving the drug stability of oseltamivir phosphate. The method is simple to operate and improves the stability of oseltamivir phosphate. DETAILED DESCRIPTION

[0022] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0023] Unless otherwise specified, the experimental methods used in the examples of the present invention are all conventional methods, and the reagents used in the examples are all available from commercial sources.

[0024] Example 1

[0025] The raw materials of a high-stability oseltamivir phosphate dry suspension include: 35 parts of oseltamivir phosphate, 5 parts of monosodium citrate, 6 parts of titanium dioxide, 850 parts of sorbitol, 10 parts of xanthan gum, 5 parts of yogurt powder flavor, 2 parts of saccharin sodium, and 3 parts of sodium benzoate. The production steps include:

[0026] (1) Sieve oseltamivir phosphate, sodium benzoate and sorbitol, wherein the mass ratio of oseltamivir phosphate to sodium benzoate is 35:3. The D90 particle size of oseltamivir phosphate is 100 μm, and the D90 particle size of sodium benzoate is 50 μm. Pass sorbitol through a 40-mesh sieve, and the sieved sorbitol is divided into three parts, namely sorbitol ①, sorbitol ② and sorbitol ③, wherein sorbitol ① accounts for 50% of the total weight, sorbitol ② accounts for 10% of the total weight, and sorbitol ③ accounts for 40% of the total weight;

[0027] (2) placing sorbitol ① and oseltamivir phosphate into a three-dimensional mixing tank for mixing, with the main shaft speed of the three-dimensional mixing tank being 5 r / min and the power being 1.5 kW, and stirring evenly to obtain a mixed material Ⅰ;

[0028] (3) Titanium dioxide is passed through a 60-mesh sieve, and sodium saccharin is passed through a 60-mesh sieve. Sorbitol ② is evenly mixed with the sieved titanium dioxide and sodium saccharin in a mass ratio of 85:5:2 to obtain a mixed material II;

[0029] (4) Sodium citrate, sodium benzoate, xanthan gum and sorbitol ③ in a mass ratio of 4:3:10:340 are added together into a three-dimensional mixing tank and mixed. The main shaft speed of the three-dimensional mixing tank is 5 r / min and the power is 1.5 kW to obtain a mixed material III;

[0030] (5) Dry granulating the mixed material I, the mixed material II and the mixed material III respectively. The mixed material I was dry granulated, and the granulation parameters were as follows: roller oil pressure: 10 bar, roller gap: 0.6 mm, roller speed: 15 rpm, crushing speed: 130 rpm, crushing screen: 2.0 mm, granulation speed: 130 rpm, and granulation screen: 1.0 mm; the mixed materials II and the mixed materials III were dry granulated, and the granulation parameters were as follows: roller oil pressure: 15 bar, roller gap: 0.5 mm, roller speed: 15 rpm, crushing speed: 130 rpm, crushing screen: 1.5 mm, granulation speed: 130 rpm, and granulation screen: 1.0 mm;

[0031] (6) Mixed material I and mixed material II are dry-granulated separately and added into a three-dimensional mixing tank for mixing with yogurt powder essence, and the finished product is vacuum packaged.

[0032] Example 2

[0033] The raw materials of a high-stability oseltamivir phosphate dry suspension include: 45 parts of oseltamivir phosphate, 10 parts of monosodium citrate, 15 parts of titanium dioxide, 900 parts of sorbitol, 20 parts of xanthan gum, 8 parts of yogurt powder flavor, 6 parts of saccharin sodium, and 5 parts of sodium benzoate. The production steps include:

[0034] (1) sieving oseltamivir phosphate, sodium benzoate, and sorbitol, wherein the mass ratio of oseltamivir phosphate to sodium benzoate is 45:5. The D90 particle size of oseltamivir phosphate is 300 μm, and the D90 particle size of sodium benzoate is 300 μm; sieving sorbitol through a 40-mesh sieve, and the sieved sorbitol is divided into three parts, namely, sorbitol ①, sorbitol ②, and sorbitol ③, wherein sorbitol ① accounts for 50% of the total weight, sorbitol ② accounts for 10% of the total weight, and sorbitol ③ accounts for 40% of the total weight;

[0035] (2) placing sorbitol ① and oseltamivir phosphate into a three-dimensional mixing tank for mixing, with the main shaft speed of the three-dimensional mixing tank being 8 r / min and the power being 2.5 kW, and stirring evenly to obtain a mixed material Ⅰ;

[0036] (3) Titanium dioxide is passed through a 60-mesh sieve, and sodium saccharin is passed through a 60-mesh sieve. Sorbitol ② is evenly mixed with the sieved titanium dioxide and sodium saccharin in a mass ratio of 85:10:3 to obtain a mixed material II;

[0037] (4) Sodium citrate, sodium benzoate, xanthan gum and sorbitol ③ in a mass ratio of 5:5:15:360 are added together into a three-dimensional mixing tank and mixed. The main shaft speed of the three-dimensional mixing tank is 5 r / min and the power is 1.5 kW to obtain a mixed material III;

[0038] (5) Dry granulating the mixed material I, the mixed material II and the mixed material III respectively. The mixed material I was dry granulated, and the granulation parameters were as follows: roller oil pressure: 20 bar, roller gap: 1.2 mm, roller speed: 20 rpm, crushing speed: 150 rpm, crushing screen: 2.0 mm, granulation speed: 150 rpm, and granulation screen: 1.0 mm; the mixed materials II and the mixed materials III were dry granulated, and the granulation parameters were as follows: roller oil pressure: 20 bar, roller gap: 1.0 mm, roller speed: 20 rpm, crushing speed: 150 rpm, crushing screen: 1.5 mm, granulation speed: 150 rpm, and granulation screen: 1.0 mm;

[0039] (6) Mixed materials I, II and III are dry-granulated separately and then added into a three-dimensional mixing tank for mixing with yogurt powder essence, and the finished products are vacuum packaged.

[0040] Example 3

[0041] The raw materials of a high-stability oseltamivir phosphate dry suspension include: 40 parts of oseltamivir phosphate, 8 parts of monosodium citrate, 12 parts of titanium dioxide, 860 parts of sorbitol, 15 parts of xanthan gum, 6 parts of yogurt powder flavor, 4 parts of saccharin sodium, and 4 parts of sodium benzoate. The production steps include:

[0042] (1) Sieve oseltamivir phosphate, sodium benzoate and sorbitol, wherein the mass ratio of oseltamivir phosphate to sodium benzoate is 40:4. The D90 particle size of oseltamivir phosphate is 200 μm, and the D90 particle size of sodium benzoate is 200 μm. Pass sorbitol through a 40-mesh sieve, and the sieved sorbitol is divided into three parts, namely sorbitol ①, sorbitol ② and sorbitol ③, wherein sorbitol ① accounts for 50% of the total weight, sorbitol ② accounts for 10% of the total weight, and sorbitol ③ accounts for 40% of the total weight;

[0043] (2) placing sorbitol ① and oseltamivir phosphate into a three-dimensional mixing tank for mixing, with the main shaft speed of the three-dimensional mixing tank being 6 r / min and the power being 2 kW, and stirring evenly to obtain a mixed material Ⅰ;

[0044] (3) Titanium dioxide is passed through a 60-mesh sieve, and sodium saccharin is passed through a 60-mesh sieve. Sorbitol ② is evenly mixed with the sieved titanium dioxide and sodium saccharin in a mass ratio of 85:10:4 to obtain a mixed material II;

[0045] (4) adding monosodium citrate, sodium benzoate, xanthan gum and sorbitol ③ in a mass ratio of 5:3:16:350 into a three-dimensional mixing tank for mixing, the main shaft speed of the three-dimensional mixing tank is 5 r / min, and the power is 1.5 kW to obtain a mixed material III;

[0046] (5) Dry granulating the mixed material I, the mixed material II and the mixed material III respectively. The mixed material I was dry granulated, and the granulation parameters were as follows: roller oil pressure: 15 bar, roller gap: 1.0 mm, roller speed: 16 rpm, crushing speed: 140 rpm, crushing screen: 2.0 mm, granulation speed: 140 rpm, and granulation screen: 1.0 mm; the mixed materials II and the mixed materials III were dry granulated, and the granulation parameters were as follows: roller oil pressure: 18 bar, roller gap: 0.8 mm, roller speed: 18 rpm, crushing speed: 140 rpm, crushing screen: 1.5 mm, granulation speed: 130 rpm, and granulation screen: 1.0 mm;

[0047] (6) Mixed material I, mixed material II and mixed material III are dry-granulated separately, added into a three-dimensional mixing tank and mixed with yogurt powder essence, and the finished product is vacuum packaged.

[0048] Comparative Example 1

[0049] The main difference between Comparative Example 1 and Example 3 is that the dry granulation of mixed material I and mixed material II is replaced by a single dry granulation, and the drug raw materials, proportions and other steps are not changed.

[0050] Comparative Example 2

[0051] The main difference between Comparative Example 2 and Example 3 is that the dry granulation of mixed material I and mixed material III is replaced by a single dry granulation, and the drug raw materials, proportions and other steps are not changed.

[0052] Comparative Example 3

[0053] The main difference between Comparative Example 3 and Example 3 is that the dry granulation of mixed material II and mixed material III is replaced by a single dry granulation, and the drug raw materials, proportions and other steps are not changed.

[0054] Comparative Example 4

[0055] The main difference between Comparative Example 4 and Example 3 is that dry granulation is replaced by wet granulation, and the drug raw materials and proportions are not changed.

[0056] Positive Control

[0057] An equal amount of commercially available oseltamivir phosphate dry suspension was used, and the manufacturer was Jiangsu Wangao Pharmaceutical Co., Ltd.

[0058] Hygroscopicity test

[0059] The hygroscopicity of a drug refers to the ability and degree of the substance to absorb water under certain temperature and humidity conditions. The oseltamivir phosphate dry suspension prepared by the methods of Examples 1-3 and Comparative Examples 1-4 and the positive control oseltamivir phosphate dry suspension were subjected to a hygroscopicity test. According to the Chinese Pharmacopoeia 2020 Edition Four General Rules 9103 Drug Hygroscopicity Test Guidelines, ① Select a flat glass weighing bottle with a lid of the same specification (OD = 50mm, Height = 15mm), place it in a closed vacuum oven for 24h in advance, (select a saturated solution of ammonium chloride with a humidity condition of 75%, and store it at room temperature) and weigh it accurately; ② Weigh the sample in appropriate amount, spread it flat in the above-mentioned weighing bottle (thickness 1mm), weigh it accurately, and also place it in a closed drying oven under the same humidity and temperature conditions; ③ Open the lid of the weighing bottle, open it, and place the bottle cap together under the above-mentioned constant temperature and humidity conditions for 24h; ④ Cover the lid, accurately weigh the weight, and calculate the weight gain. The test results are shown in Table 1.

[0060] Table 1 Humidity change observation table

[0061]

[0062] The weight change of the oseltamivir phosphate dry suspension before and after moisture absorption is quite different. The results in Table 1 show that the weight increase of the oseltamivir phosphate dry suspension prepared by the methods of Examples 1-3 after moisture absorption is small, ranging from 0.0002 to 0.0003 g, and the weight after moisture absorption of the comparative example and the positive control is higher than that of the example.

[0063] Stability test

[0064] The oseltamivir phosphate dry suspension prepared by the methods of Examples 1-3 and Comparative Examples 1-4 and the positive control oseltamivir phosphate dry suspension were respectively placed under the experimental conditions of high temperature (60°C), high humidity (RH75%), and strong light (4500LX+500LX), and samples were taken on the 0th day (initial time) and the 5th day, and the appearance properties were observed and recorded and the changes in the content of oseltamivir phosphate were measured. The color change was measured using a powder spectrophotometer. First, the measurement angle was selected to be 0°, and the instrument was placed on a stable workbench, the measuring head was kept perpendicular to the sample surface, the machine was preheated, a standard white plate was used for calibration, the sample was placed, and the measurement temperature was kept at 25-28°C and the humidity was 40-45%. The observation results are shown in Table 2. The content of oseltamivir phosphate was determined using a SHISEIDO Capcell PAKC18MGII (4.6mm×150mm, 5μm) chromatographic column, with 0.05mol / L potassium dihydrogen phosphate solution (adjusted to pH 5.8 with 1mol / L potassium hydroxide solution) as mobile phase A, and acetonitrile-methanol (volume ratio 245:135) as mobile phase B; gradient elution, flow rate 1.0mL / min, column temperature 40°C. The content of impurities was calculated using the main component self-control method with correction factors, and the established method was methodologically verified. The results of the determination of oseltamivir phosphate are shown in Table 3.

[0065] Table 2 Appearance characteristics observation table

[0066] Group Day 0 (day) Day 5 (High Humidity) Day 5 (High Temperature) Day 5 (strong light) Example 1 White powder White powder White powder White powder Example 2 White powder White powder White powder White powder Example 3 White powder White powder White powder White powder Comparative Example 1 White powder Yellowish powder Yellowish powder White powder Comparative Example 2 White powder Yellowish powder White powder Yellowish powder Comparative Example 3 White powder Yellowish powder White powder White powder Comparative Example 4 White powder Yellowish powder Yellowish powder Yellowish powder Positive Control White powder Yellowish powder Yellowish powder White powder

[0067] Table 3 Changes in mass percentage of oseltamivir phosphate

[0068] Group Day 0 (day) Day 5 (High Humidity) Day 5 (High Temperature) Day 5 (strong light) Example 1 100.0％ 99.0％ 99.5％ 99.6％ Example 2 100.0％ 99.1％ 99.4％ 99.5％ Example 3 100.0％ 99.0％ 99.4％ 99.7％ Comparative Example 1 100.0％ 93.2％ 95.0％ 96.1％ Comparative Example 2 100.0％ 92.6％ 94.2％ 95.2％ Comparative Example 3 100.0％ 93.8％ 93.1％ 95.3％ Comparative Example 4 100.0％ 92.0％ 92.2％ 93.2％ Positive Control 100.0％ 94.7％ 94.2％ 95.5％

[0069] The oseltamivir phosphate dry suspension prepared by the methods of Examples 1-3 and Comparative Examples 1-4 and the positive control oseltamivir phosphate dry suspension were tested for 5 days at 60°C, RH75% high humidity, and 4500LX+500LX strong light. The data are shown in Table 3. The oseltamivir phosphate dry suspension prepared by the methods of Examples 1-3 has higher resistance to high temperature, high humidity and strong light than Comparative Examples 1-5 and the positive control, indicating that the oseltamivir phosphate dry suspension prepared by the method of the embodiment has higher stability.

[0070] In summary, the preparation method of the present invention is divided into three times and then mixed, sorbitol and oseltamivir phosphate are used as drug-containing particles for dry granulation, the auxiliary materials sorbitol, titanium dioxide, and saccharin sodium are dry granulated, and the auxiliary materials monosodium citrate, sodium benzoate, xanthan gum, and sorbitol are dry granulated, and then mixed. The granulation method of dry granulation avoids contact between the oseltamivir phosphate raw material and the auxiliary materials, avoids contact between the auxiliary materials, significantly reduces the negative reaction between the drug components and the auxiliary materials, and reduces the loss of the oseltamivir phosphate drug. The method is simple to operate and improves the stability of the main component of the drug, oseltamivir phosphate.

[0071] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a high-stability oseltamivir phosphate dry suspension, characterized in that: The method comprises the following raw materials in parts by weight: 35-45 parts of oseltamivir phosphate, 4-10 parts of monosodium citrate, 5-15 parts of titanium dioxide, 850-900 parts of sorbitol, 10-20 parts of xanthan gum, 4-8 parts of yogurt powder flavor, 2-6 parts of sodium saccharin, and 3-5 parts of sodium benzoate, and comprises the following steps: S1. sieving oseltamivir phosphate, sodium benzoate and sorbitol respectively, and the sieved sorbitol is divided into 3 parts, namely sorbitol ①, sorbitol ② and sorbitol ③; S2, sorbitol ① and oseltamivir phosphate are mixed and stirred evenly to obtain a mixed material Ⅰ; S3, sorbitol ②, the sieved titanium dioxide and saccharin sodium are uniformly mixed to obtain a mixed material Ⅱ; S4, monosodium citrate, sodium benzoate, xanthan gum and sorbitol ③ are mixed to obtain a mixed material III; S5, dry granulating the mixed material I, the mixed material II and the mixed material III respectively; S6. Mixture I, mixture II and mixture III are dry granulated and then mixed with yogurt powder essence, and the finished product is vacuum packaged.

2. The method for preparing a highly stable oseltamivir phosphate dry suspension according to claim 1, characterized in that: S1, the D90 particle size of oseltamivir phosphate is 50-400 μm, the D90 particle size of sodium benzoate is 50-400 μm, and the mass ratio of oseltamivir phosphate and sodium benzoate is (35-45):(3-5).

3. The method for preparing a highly stable oseltamivir phosphate dry suspension according to claim 1, characterized in that: S1, pass sorbitol through a 40-mesh sieve and divide it into three parts according to weight ratio, 50% of the total weight is sorbitol ①, 10% of the total weight is sorbitol ②, and 40% of the total weight is sorbitol ③.

4. The method for preparing a highly stable oseltamivir phosphate dry suspension according to claim 1, characterized in that: S2, S3, S4, the spindle speed during mixing is 5r / min-8r / min, and the power is 1.5kw-2.5kw.

5. The method for preparing a highly stable oseltamivir phosphate dry suspension according to claim 1, characterized in that: S3, titanium dioxide passed through a 60-mesh sieve, saccharin sodium passed through a 60-mesh sieve, the mass ratio of sorbitol②, titanium dioxide, and saccharin sodium is (85-90):(5-15):(2-6).

6. The method for preparing a highly stable oseltamivir phosphate dry suspension according to claim 1, characterized in that: S4, the mass ratio of monosodium citrate, sodium benzoate, xanthan gum and sorbitol ③ is (4-10):(3-5):(10-20):(340-360).

7. The method for preparing a highly stable oseltamivir phosphate dry suspension according to claim 1, characterized in that: S5, dry granulation of mixed material I, roller oil pressure: 10-20bar, roller gap: 0.6-1.2mm, roller speed: 15-20rpm, crushing speed: 130-150rpm, crushing screen: 2.0mm, granulation speed: 130-150rpm, granulation screen: 1.0mm; dry granulation of mixed material II and mixed material III, roller oil pressure: 15-20bar, roller gap: 0.5-1.0mm, roller speed: 15-20rpm, crushing speed: 130-150rpm, crushing screen: 1.5mm, granulation speed: 130-150rpm, granulation screen: 1.0mm.

8. A high-stability oseltamivir phosphate dry suspension prepared by the preparation method according to claims 1-7.

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