Oseltamivir phosphate capsule based on fluidized bed one-step granulation and anti-adhesion process

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and discloses an oseltamivir phosphate capsule based on fluidized bed one-step granulation and an anti-adhesion process. The content of the capsule comprises oseltamivir phosphate, a filler, a disintegrating agent, an adhesive, a lubricant, an internally added flow aid and an externally added flow aid, the mass ratio of oseltamivir phosphate in the content is 60%, the mass ratio of the filler in the content is 25%-30%, the mass ratio of the disintegrating agent in the content is 3%-5%, the mass ratio of the adhesive in the content is 1%-2%, and the mass ratio of the lubricant in the externally added flow aid is 1%-2%. The mass ratio of the lubricant in the content is 0.5%-2%, the mass ratio of the internally added glidant in the content is 1%-2%, and the mass ratio of the externally added glidant in the content is 1%-2%. The oseltamivir phosphate capsule filling machine effectively solves the problem of adhesion of oseltamivir phosphate capsules on a metering rod type filling machine, reduces the filling quantity difference, ensures continuous filling, improves the uniformity of particles and dissolution, and is suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a one-step granulation based on a fluidized bed and an anti-adhesion process for oseltamivir phosphate capsules. BACKGROUND

[0002] Oseltamivir phosphate is a neuraminidase inhibitor (NAI) that inhibits the replication and spread of influenza viruses in host cells by inhibiting the activity of neuraminidase. Its chemical name is: (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate. Oseltamivir phosphate is a prodrug of oseltamivir, which is rapidly converted into the active metabolite oseltamivir carboxylate in the liver and intestinal tract after oral administration, and exerts an antiviral effect. Oseltamivir phosphate has a significant inhibitory effect on both type A and type B influenza viruses, and exhibits high antiviral activity against type A H1N1, H3N2 and type B influenza virus strains. Its mechanism of action is to inhibit the activity of viral neuraminidase, thereby preventing the release of viruses from infected cells and reducing the spread and replication of viruses in the body.

[0003] However, in oseltamivir phosphate capsules, the proportion of raw material oseltamivir phosphate is relatively large (about 60%), and the raw material has poor flowability and high viscosity, so it cannot be directly filled into capsules by mixing the raw and auxiliary materials into powder. The conventional process for oseltamivir phosphate capsule preparation is the traditional wet granulation process, which is complex and has problems such as large filling weight variation, poor dissolution uniformity due to adhesion of equipment components during filling, etc.

[0004] Oseltamivir phosphate has high viscosity, and when filled using an ordinary metering rod filling machine, it easily adheres to the metering rod and film hole components, resulting in large filling weight variation and affecting dissolution uniformity. This is more pronounced in small size capsules (30mg / 45mg, with a filling weight of 66mg / 99mg). In addition, the filling process cannot be continuously operated during large batch production because the equipment components need to be frequently cleaned to remove adhesion, which hinders large batch production. Modifying the metering rod, such as siliconizing the metering rod or coating it with an anti-adhesion film, can improve the filling of materials with viscosity, but it is not ideal for improving the filling of oseltamivir phosphate capsules. A plug tube type capsule filling machine can better solve the adhesion problem during filling of oseltamivir phosphate capsules, but compared to the traditional metering rod type capsule filling machine, the plug tube type capsule filling machine is expensive and has a high cost, and the production batch size is small.

[0005] The prior art scheme (CN118141787A) adopts a traditional wet granulation process, and by adjusting the adding mode and amount of the flow aid and lubricant, the drug dissolution speed can be improved, but the uniformity of the drug dissolution behavior is not concerned, and the adhesion of the capsule filling process in continuous production is also not concerned. The traditional wet granulation process is complex, and the prepared granules have poor uniformity. If the fine powder rate is high, the material flowability is poor, and the electrostatic effect is strong, the adhesion is serious during capsule filling. If the fine powder rate is low, and there are more large particles, the dissolution speed will be slow.

[0006] The prior art scheme (CN111297823A) adopts a traditional wet granulation process, and by adjusting the adding mode and amount of the flow aid and lubricant, the uniformity of the dissolution behavior is improved to a certain extent, but the adhesion of the capsule filling process in continuous production is not concerned, and the problems of the traditional wet granulation process still exist.

[0007] The prior art scheme (CN111544413A) adopts a fluidized bed one-step granulation process, which can improve the drug dissolution speed to a certain extent and simplify the preparation process, but the lubricant and flow aid are added in a single external mode, which cannot well solve the adhesion problem during capsule filling.

[0008] At present, there is no solution to the problems of the loading difference caused by the adhesion of the material to the equipment accessories of the metering rod filling machine during filling of the oseltamivir phosphate capsules and the filling process obstacles. SUMMARY

[0009] Therefore, the purpose of the present application is to provide an oseltamivir phosphate capsule based on fluidized bed one-step granulation and an anti-adhesion process, which solves the problem of loading difference caused by the adhesion of the material to the equipment accessories during the filling of the oseltamivir phosphate capsules.

[0010] In order to achieve the above-mentioned purpose, the technical scheme adopted is as follows: The oseltamivir phosphate capsule comprises oseltamivir phosphate, a filler, a disintegrant, a binder, a lubricant and a flow aid, the flow aid is divided into an internal flow aid and an external flow aid, wherein the mass ratio of oseltamivir phosphate in the content is 60%, the mass ratio of the filler in the content is 25%-30%, the mass ratio of the disintegrant in the content is 3%-5%, the mass ratio of the binder in the content is 1%-2%, the mass ratio of the lubricant in the content is 0.5%-2%, the mass ratio of the internal flow aid in the content is 1%-2%, and the mass ratio of the external flow aid in the content is 1%-2%.

[0011] As a further improvement of the present application, the filler is compounded by lactose and pre-gelatinized starch in a mass ratio of 3:1 to 4:1, the disintegrant is low-substituted hydroxypropyl cellulose or cross-linked polyvinylpyrrolidone, the binder is hydroxypropyl methyl cellulose or polyvinylpyrrolidone, the lubricant is sodium stearyl fumarate, and the internal and external glidants are both hydrophilic colloidal silicon dioxide.

[0012] As a further improvement of the present application, the sodium stearyl fumarate is added in the form of external addition.

[0013] The anti-adhesion process for preparing the oseltamivir phosphate capsule of any of the above according to the one-step granulation of fluidized bed comprises the following steps: S1, weighing the oseltamivir phosphate, the filler, the disintegrant, the binder, the lubricant, the internal and external glidants according to the mass ratio of claim 1; S2, dissolving the binder in purified water to prepare a binder solution; S3, placing the oseltamivir phosphate, the filler, the disintegrant, and the internal hydrophilic colloidal silicon dioxide in a fluidized bed for mixing and preheating, wherein the preheating temperature is controlled at 30-40℃, the mixing speed is 8-12 rpm, and the mixing time is 5-15 min; after the mixing and preheating, the binder solution in step S2 is sprayed for granulation, the control parameters are as follows: the air inlet temperature is 50-80℃, the air inlet frequency is 20-40 Hz, the atomization pressure is 1500-2500 mbar, the material temperature is controlled at 30-40℃, and the liquid feeding speed is 150-300 g / min, and the granulation is completed; after the granulation is completed, the liquid spraying is stopped, and the granules are dried until the water content is ≤2.5%; S4, filling the capsules after mixing the prepared granules with the lubricant sodium stearyl fumarate and the external hydrophilic colloidal silicon dioxide to obtain the oseltamivir phosphate capsule.

[0014] The present application has the following beneficial effects: the one-step granulation process of fluidized bed is adopted in the present application, the composite anti-adhesion system of sodium stearyl fumarate and hydrophilic colloidal silicon dioxide is used, the adhesion rate is reduced through the synergistic effect of hydrophobic lubrication and hydrophilic glidant, the effect of anti-adhesion of capsule filling is achieved, the rapid dissolution of the drug is ensured, the flowability and anti-adhesion of the oseltamivir phosphate granules are significantly improved, the problem of material adhesion to the equipment parts during the filling on the metering rod filling machine is effectively solved, the loading difference is reduced, and the uniformity of the product quality is ensured.

[0015] The hydrophilic colloidal silicon dioxide added in the application can improve the fluidity of the material in the granulation process, prevent the material from caking and adhering to the wall of the fluidized bed; the hydrophilic colloidal silicon dioxide added outside and the sodium stearyl fumarate added outside synergistically further improve the fluidity and lubricity of the final granules, and ensure the smoothness of the capsule filling. In addition, by using the fluidized bed one-step granulation process, the mixing, granulation, drying and other steps are integrated, the production process is simplified, the production cycle is shortened, and at the same time, the prepared granules have uniform particle size distribution and good fluidity, reducing the situation of too high fine powder rate or too many large particles, which is beneficial to filling and lays a foundation for good dissolution performance. The application not only solves the problems of filling adhesion and filling amount difference in the prior art, but also simplifies the process, improves the production efficiency and product quality, and has significant economic and social benefits. DETAILED DESCRIPTION

[0016] It should be noted that the embodiments in the present application and the features in the embodiments can be combined with each other without conflict. The technical solutions in the embodiments of the present application will be described in detail below.

[0017] In order to enable the persons skilled in the art to better understand the present application, the technical solutions in the embodiments of the present application will be described clearly and completely below in combination with the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by the persons skilled in the art without creative labor should belong to the protection scope of the present application.

[0018] In the following embodiments of the present application, the oseltamivir phosphate capsule content comprises: about 60% of oseltamivir phosphate, 32.5-89% of a filler, 3-15% of a disintegrant, 2-8% of a binder, 0.5-2% of a lubricant, 1-2% of an internal flow aid, and 1-2% of an external flow aid.

[0019] Embodiment 1 The formula of the oseltamivir phosphate capsule content is shown in Table 1: Table 1 Formula of oseltamivir phosphate capsule content in embodiment 1 The anti-adhesion process for preparing oseltamivir phosphate capsules based on fluidized bed one-step granulation includes the following steps: S1, the binder is added to water and stirred until completely dissolved as a binder solution with a mass concentration of 6%. S2, the oseltamivir phosphate, lactose, low-substituted hydroxypropyl cellulose, polyvinyl pyrrolidone and hydrophilic colloidal silicon dioxide are placed in a fluidized bed for mixing and preheating, and when the material temperature is preheated to 32-35°C, the binder solution in step S1 is sprayed for granulation, the inlet air temperature is 60-70°C, the inlet air frequency is 25-35Hz, the atomization pressure is 1500-1800 mbar, the liquid addition speed is 150-200 g / min, and the material temperature is 30-35°C. After the binder solution is completely added, the liquid pump and the atomization switch are closed, and the granules are dried to a moisture content of ≤2.5%.

[0020] S3, the dry granules prepared in step S2 are placed in a three-dimensional mixer with additional glidants and lubricants for mixing, the mixing speed is 10 rpm, and the mixing time is 10 min.

[0021] S4, the capsule filling is performed using a conventional metering rod filler, and the capsule shell is type 2.

[0022] The intermediate powder properties after mixing in step S3 are detected, the time for smooth and continuous filling in the capsule filling process is investigated, the adhesion of the material to the equipment parts, the appearance and filling difference of the capsules are detected, the capsule dissolution curve is detected, and the dissolution curve is compared with the original research product Dafeng, 75 mg specification capsule (the dissolution determination method is the paddle method, 50 rpm, medium: hydrochloric acid 9→1000, medium volume: 900 ml, test sample number: 12, and the detection results are shown in Table 2.

[0023] Table 2 Detection results of intermediate powder properties in Example 1 Example 2 The formulation of the oseltamivir phosphate capsule content is shown in Table 3: Table 3 Formulation of oseltamivir phosphate capsule content in Example 2 The anti-adhesion process for preparing oseltamivir phosphate capsules based on fluidized bed one-step granulation includes the following steps: S1, the binder is added to water and stirred until completely dissolved as a binder solution with a concentration of 6%. S2, the oseltamivir phosphate, lactose, cross-linked povidone, polyvinyl pyrrolidone and hydrophilic colloidal silicon dioxide are placed in a fluidized bed for mixing and preheating, and when the material temperature is preheated to 30-35°C, the binder solution in step S1 is sprayed for granulation, the inlet air temperature is 60-65°C, the inlet air frequency is 25-35Hz, the atomization pressure is 1500-1800 mbar, the liquid addition speed is 150-200 g / min, and the material temperature is 30-35°C. After the binder solution is completely added, the liquid pump and the atomization switch are closed, and the granules are dried to a moisture content of ≤2.5%.

[0024] S3, the dry granules prepared in step S2 were mixed with additional glidants and lubricants in a three-dimensional mixer at a mixing speed of 12 rpm for 8 minutes.

[0025] S4, the capsules were filled using a conventional metering rod filler, and the capsule shell was type No. 4.

[0026] The properties of the intermediate powder after mixing in step S3 were detected, the time for smooth and continuous filling in the capsule filling process was investigated, and the adhesion of the material to the equipment parts, the appearance and filling amount of the capsules, and the dissolution curve of the capsules were detected. The dissolution curve was compared with that of the original research product, Tamiflu, 45 mg capsule (dissolution determination method: paddle method, 50 rpm, medium: hydrochloric acid 9→1000, medium volume: 900 ml, test sample number: 12, and the detection results are shown in Table 4.

[0027] Table 4. Detection results of the properties of the intermediate powder in Example 2 Example 3 The formulation of the oseltamivir phosphate capsule content is shown in Table 5: Table 5. Formulation of the oseltamivir phosphate capsule content in Example 3 The anti-adhesion process for preparing oseltamivir phosphate capsules based on fluidized bed one-step granulation includes the following steps: S1, the binder was added to water and stirred until completely dissolved as a binder solution with a concentration of 5%. S2, oseltamivir phosphate, lactose, cross-linked povidone, hydroxypropyl methyl cellulose, and hydrophilic colloidal silicon dioxide were placed in a fluidized bed for mixing and preheating. When the material temperature reached 35-40°C, the binder solution in S1 was sprayed to granulate. The inlet air temperature was 65-70°C, the inlet air frequency was 20-30 Hz, the atomization pressure was 1800-2300 mbar, the liquid addition speed was 180-230 g / min, and the material temperature was 32-38°C. After the binder solution was completely added, the liquid pump and the atomization switch were turned off, and the granules were dried to a moisture content of ≤2.5%.

[0028] S3, the dry granules prepared in step S2 were mixed with additional glidants and lubricants in a three-dimensional mixer at a mixing speed of 12 rpm for 8 minutes.

[0029] S4, the capsules were filled using a conventional metering rod filler, and the capsule shell was type No. 4.

[0030] The intermediate powder after mixing in step S3 was detected for its physical properties, the time for continuous filling in the capsule filling process was investigated, the adhesion of the material to the equipment parts, the appearance and weight difference of the capsules were detected, the dissolution curve of the capsules was detected, and the dissolution curve was compared with that of the original product Tamiflu, 30 mg capsule (the dissolution determination method was paddle method, 50 rpm, medium: hydrochloric acid 9→1000, medium volume: 900 ml, test sample number: 12, and the detection results are shown in Table 6.

[0031] Table 6 Detection results of the physical properties of the intermediate powder in Example 3 Example 4 The formulation of the oseltamivir phosphate capsule content is shown in Table 7: Table 7 Formulation of the oseltamivir phosphate capsule content in Example 4 The anti-adhesion process for preparing the oseltamivir phosphate capsule based on the fluidized bed one-step granulation includes the following steps: S1, the binder was added to water and stirred until completely dissolved as a binder solution with a concentration of 7%. S2, oseltamivir phosphate, lactose, cross-linked povidone, hydroxypropyl methyl cellulose and hydrophilic colloidal silicon dioxide were placed in a fluidized bed for mixing and preheating, and when the material temperature reached 33-38℃, the binder solution in S1 was sprayed for granulation, the inlet air temperature was 70-75℃, the inlet air frequency was 20-25 Hz, the atomization pressure was 1500-2000 mbar, the liquid addition speed was 200-250 g / min, and the material temperature was 33-38℃. After the binder solution was completely added, the liquid pump and the atomization switch were turned off, and the granules were dried to a water content of ≤2.5%.

[0032] S3, the dry granules prepared in S2 were mixed with additional flow aids and lubricants in a three-dimensional mixer at a mixing speed of 10 rpm for 12 min.

[0033] S4, a conventional metering rod filling machine was used for capsule filling, and the capsule shell type was No. 4.

[0034] The intermediate powder after mixing in step S3 was detected for its physical properties, the time for continuous filling in the capsule filling process was investigated, the adhesion of the material to the equipment parts, the appearance and weight difference of the capsules were detected, the dissolution curve of the capsules was detected, and the dissolution curve was compared with that of the original product Tamiflu, 30 mg capsule (the dissolution determination method was paddle method, 50 rpm, medium: hydrochloric acid 9→1000, medium volume: 900 ml, test sample number: 12, and the detection results are shown in Table 6.

[0035] Table 8. Results of detection of the intermediate powder properties in Example 4 The data of the "filling process" in Table 2, Table 4, Table 6 and Table 8 show that the material in Examples 1-4 of the present application does not adhere to the metering rod and the capsule film hole, and the continuous filling time is ≥2 hours. This shows that by using the composite anti-adhesion system of "internal addition of hydrophilic colloidal silica + external addition of hydrophilic colloidal silica + external addition of sodium stearyl fumarate" combined with the fluidized bed one-step granulation process, the problem of equipment adhesion caused by high stickiness and poor flowability of oseltamivir phosphate is significantly improved, frequent shutdown for cleaning is avoided, the continuity of the filling process is ensured, and it is suitable for large-scale production.

[0036] The data of "dose difference" in Examples 1-4 show that the dose fluctuation range is small, which shows that the present application effectively controls the dose difference by optimizing the particle flowability and anti-adhesion, ensures the uniformity of the capsule content dose, and meets the quality requirements of pharmaceutical products.

[0037] In the detection of the intermediate powder properties, the loose bulk density is between 0.58-0.65 g / cm³, and the angle of repose is between 31-33° (an angle of repose <35° usually indicates good material flowability). The data show that the particles prepared by the present application have excellent flowability, which is due to the improvement of material dispersibility and prevention of caking by internal addition of hydrophilic colloidal silica during the granulation process, and the synergistic effect of external addition of hydrophilic colloidal silica and sodium stearyl fumarate in improving lubricity, which provides a guarantee for smooth filling of the metering rod filling machine.

[0038] The data of "dissolution curve" of each example show that the self-made capsules and the original research product (Tamiflu) have very small difference in dissolution at different time points (5min-45min) (the difference at most time points is ≤3%), and can be quickly dissolved (the dissolution at 15min is ≥95%). This shows that the particle size distribution of the particles prepared by the fluidized bed one-step granulation process is uniform, avoiding the problem of uneven dissolution caused by too high fine powder rate or too many large particles in traditional wet granulation, and the reasonable ratio of disintegrants (low-substituted hydroxypropyl cellulose, cross-linked povidone) in the formula further ensures the uniformity of the dissolution behavior, which is consistent with the quality of the original research product.

[0039] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, component disassembly or combination made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. Oseltamivir phosphate capsules, characterized by: Its contents include oseltamivir phosphate, filler, disintegrant, binder, lubricant and glidant, wherein the glidant is divided into internal glidant and external glidant, wherein the mass ratio of oseltamivir phosphate in the contents is 60%, the mass ratio of the filler in the contents is 25%-30%, the mass ratio of the disintegrant in the contents is 3%-5%, the mass ratio of the binder in the contents is 1%-2%, the mass ratio of the lubricant in the contents is 0.5%-2%, the mass ratio of the internal glidant in the contents is 1%-2%, and the mass ratio of the external glidant in the contents is 1%-2%.

2. The oseltamivir phosphate capsule according to claim 1, characterized in that: The filler is a compound of lactose and pregelatinized starch in a mass ratio of 3:1 to 4:1; the disintegrant is low-substituted hydroxypropyl cellulose or cross-linked polyvinylpyrrolidone; the binder is hydroxypropyl methylcellulose or polyvinylpyrrolidone; the lubricant is sodium stearyl fumarate; and both the internal and external glidants are hydrophilic colloidal silicon dioxide.

3. The oseltamivir phosphate capsule according to claim 2, characterized in that: The sodium stearyl fumarate is added in a manner of adding all of it externally and mixing.

4. An anti-adhesion process for preparing oseltamivir phosphate capsules according to any one of claims 1 to 3 based on fluidized bed one-step granulation, characterized in that: The following steps are involved: S1. Weigh oseltamivir phosphate, a filler, a disintegrant, a binder, a lubricant, an internal glidant, and an external glidant according to the mass ratio of claim 1; S2. dissolving the adhesive in purified water to prepare an adhesive solution; S3. Place oseltamivir phosphate, a filler, a disintegrant, and hydrophilic colloidal silicon dioxide as an internal glidant in a fluidized bed for mixing and preheating, wherein the preheating temperature is controlled at 30-40°C, the mixing speed is 8-12 rpm, and the mixing time is 5-15 min. After mixing and preheating, spray the binder solution prepared in step S2 into the fluidized bed for granulation. The inlet air temperature is controlled at 50-80°C, the inlet air frequency is controlled at 20-40 Hz, the atomization pressure is controlled at 1500-2500 mbar, the material temperature is controlled at 30-40°C, and the liquid addition rate is controlled at 150-300 g / min to complete granulation. After granulation, stop spraying and dry the granules until the moisture content is ≤2.5%. S4. The prepared granules are mixed with a lubricant, sodium stearyl fumarate, and an external glidant, hydrophilic colloidal silicon dioxide, and then filled into capsules to prepare oseltamivir phosphate capsules.

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