A high-efficacy oseltamivir phosphate capsule and its preparation method

Abstract

This invention proposes a high-efficacy oseltamivir phosphate capsule and its preparation method. The oseltamivir phosphate capsule comprises the following components: 120-130 parts of oseltamivir phosphate, 30-45 parts of pregelatinized starch, 5-10 parts of sodium stearate, 5-10 parts of drug-loaded material, 5-10 parts of talc, and 20-25 parts of povidone K30; the drug-loaded material is microcrystalline cellulose and poloxamer. The oseltamivir phosphate capsule prepared by this invention achieves an average cumulative dissolution rate of over 90% within 15 minutes in dissolution media of water and pH 6.8 phosphate buffer solution, exhibiting excellent dissolution. In an accelerated 6-month test, the dissolution rate still reaches over 85%, demonstrating good stability, drug stability, and high efficacy.

Description

Technical Field

[0001] This invention relates to the field of drug preparation technology, and in particular to a highly effective oseltamivir phosphate capsule and its preparation method. Background Technology

[0002] Oseltamivir phosphate is a selective influenza virus neuraminidase inhibitor that inhibits the further increase in influenza virus numbers, thereby suppressing the spread of influenza virus in the body and reducing pathogenicity. It can be used to treat acute, uncomplicated influenza A and B in individuals aged 2 weeks and older, with administration within 48 hours of the first onset of symptoms. It can also be used for the prevention of influenza A and B in patients aged 1 year and older. Dissolution rate is one of the indicators for evaluating the quality of drug preparation. Studies have shown that the in vitro dissolution curve of oseltamivir phosphate capsules is largely consistent with the degree of absorption of the formulation in vivo. Good dissolution rate is an important factor in improving the body's absorption of the drug. Most commercially available oseltamivir phosphate capsules use water as a wetting agent for granulation. Although oseltamivir phosphate itself has good solubility, it is difficult to maintain a completely consistent particle morphology during storage, which can easily lead to adhesion and other problems, resulting in a decrease in dissolution rate after long-term storage. Summary of the Invention

[0003] Therefore, the purpose of this invention is to provide a highly effective oseltamivir phosphate capsule and its preparation method, thereby solving the above-mentioned problems.

[0004] The technical solution of this invention is implemented as follows:

[0005] A highly effective oseltamivir phosphate capsule, by weight, comprises the following components: 120-130 parts of oseltamivir phosphate, 30-45 parts of pregelatinized starch, 5-10 parts of sodium stearate, 5-10 parts of drug-loaded material, 5-10 parts of talc, and 20-25 parts of povidone K30;

[0006] The drug-loaded materials are microcrystalline cellulose and poloxamer.

[0007] Furthermore, by weight, it comprises the following components: 120-130 parts of oseltamivir phosphate, 35-40 parts of pregelatinized starch, 5-8 parts of sodium stearate, 5-10 parts of drug-loaded material, 5-10 parts of talc, and 20-25 parts of povidone K30.

[0008] Furthermore, the drug-loaded material is microcrystalline cellulose and poloxamer in a mass ratio of 1 to 3:1.

[0009] Furthermore, the microcrystalline cellulose has a particle size of 50–200 μm, and the poloxamer is poloxamer 407 and / or poloxamer 188.

[0010] The present invention provides a method for preparing the above-mentioned oseltamivir phosphate capsules. The preparation method includes: mixing oseltamivir phosphate, pregelatinized starch and sodium stearate, dispersing them in a drug-loaded material solution, wet granulating, and finally adding talc and povidone K30, filling the capsules into soft capsule shells to obtain the oseltamivir phosphate capsules.

[0011] This invention improves the dispersibility and stability of the drug system by first premixing oseltamine phosphate with pregelatinized starch and sodium stearate, then dispersing it in a drug-loaded solution of poloxamer and microcrystalline cellulose, and finally wet granulating it with talc and povidone K30.

[0012] Furthermore, the preparation method includes the following steps:

[0013] (1) Take oseltamivir phosphate, pregelatinized starch and sodium stearate, mix them, disperse them in a drug-loaded material solution made of drug-loaded material, stir and disperse, wet granulate, dry, and obtain a premix;

[0014] (2) Add talc and povidone K30 to the premix, mix, and fill into soft capsule shells to obtain the oseltamivir phosphate capsules.

[0015] Furthermore, the mass concentration of the drug-loaded material solution is 3-5%.

[0016] Furthermore, the drug-loaded material is dispersed in water at 6000-8000 rpm for 2-8 minutes to obtain the drug-loaded material solution.

[0017] Furthermore, in step (1), the mixing rate is 80-120 rpm and the time is 5-10 min; the stirring and dispersing rate is 180-220 rpm and the time is 5-10 min.

[0018] Furthermore, in step (2), the mixing time is 5 to 15 minutes.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0020] The present invention uses pregelatinized starch, sodium stearate, microcrystalline cellulose and poloxamer as drug-carrying materials, talc and povidone K30 to prepare oseltamivir phosphate capsules. In dissolution media of water and pH 6.8 phosphate buffer solution, the average cumulative dissolution rate can reach more than 90% within 15 minutes, which shows excellent dissolution rate.

[0021] The oseltamivir phosphate capsules prepared by this invention still achieved a dissolution rate of over 85% in an accelerated 6-month test, demonstrating good stability. By first premixing oseltamivir phosphate with pregelatinized starch and sodium stearate, and then dispersing it in a drug-loaded material solution of poloxamer and microcrystalline cellulose, followed by wet granulation and total mixing with talc and povidone K30, the morphology of the particles can be kept consistent, effectively avoiding adhesion and other issues. At the same time, the drugs in the drug-loaded system have good dispersibility and improved flowability, further reducing drug loss and thus improving the stability of the drug system. The drug is stable and highly effective.

[0022] The oseltamivir phosphate capsules of the present invention have excellent dissolution in vitro, and the oseltamivir phosphate capsules of the present invention have good absorption rate and extent in vivo. Detailed Implementation

[0023] To better understand the technical content of this invention, specific embodiments are provided below to further illustrate the invention.

[0024] Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.

[0025] Unless otherwise specified, all materials and reagents used in the embodiments of this invention are commercially available.

[0026] Example 1

[0027] (1) Weigh out 125g of oseltamivir phosphate, 36g of pregelatinized starch, 6g of sodium stearate, 8g of drug-loaded material, 8g of talc and 22g of povidone K30, and set aside.

[0028] (2) Take the drug-loaded material (m microcrystalline cellulose: m poloxamer = 3:1), stir and dissolve it in water (160g), disperse it at 7000rpm for 5min to obtain a drug-loaded material solution with a mass concentration of 5%, wherein the particle size of microcrystalline cellulose is 100μm and the poloxamer is poloxamer 407.

[0029] (3) Take oseltamivir phosphate, add pregelatinized starch and sodium stearate, mix at 100 rpm for 5 min, then add to the drug-loaded material solution (160 g) in step (1), stir and disperse at 200 rpm for 5 min, wet granulate, dry, and obtain the premix.

[0030] (4) Add talc and povidone K30 to the premix in sequence, mix for 10 min, fill into soft capsule shells, and obtain oseltamivir phosphate capsules.

[0031] Example 2

[0032] (1) Weigh out 125g of oseltamivir phosphate, 32g of pregelatinized starch, 8g of sodium stearate, 6g of drug-loaded material, 10g of talc and 22g of povidone K30, and set aside.

[0033] (2) Take the drug-loaded material (m microcrystalline cellulose: m poloxamer = 3:1), stir and dissolve it in water (160g), disperse it at 7000rpm for 5min, and prepare a drug-loaded material solution with a mass concentration of 3.75%, wherein the particle size of the microcrystalline cellulose is 100μm and the poloxamer is poloxamer 407.

[0034] (3) Take oseltamivir phosphate, add pregelatinized starch and sodium stearate, mix at 100 rpm for 5 min, then add to the drug-loaded material solution (160 g) in step (1), stir and disperse at 200 rpm for 5 min, wet granulate, dry, and obtain the premix.

[0035] (4) Add talc and povidone K30 to the premix in sequence, mix for 10 min, fill into soft capsule shells, and obtain oseltamivir phosphate capsules.

[0036] Example 3

[0037] (1) Weigh out 125g of oseltamivir phosphate, 42g of pregelatinized starch, 6g of sodium stearate, 10g of drug-loaded material, 8g of talc and 22g of povidone K30, and set aside.

[0038] (2) Take the drug-loaded material (m microcrystalline cellulose: m poloxamer = 3:1), stir and dissolve it in water (200g), disperse it at 7000rpm for 5min to obtain a drug-loaded material solution with a mass concentration of 5%, wherein the particle size of the microcrystalline cellulose is 100μm, and the poloxamer is poloxamer 407 and poloxamer 188 in a mass ratio of 1:1.

[0039] (3) Take oseltamivir phosphate, add pregelatinized starch and sodium stearate, mix at 100 rpm for 5 min, then add to the drug-loaded material solution (200 g) in step (1), stir and disperse at 200 rpm for 5 min, wet granulate, dry, and obtain the premix.

[0040] (4) Add talc and povidone K30 to the premix in sequence, mix for 10 min, fill into soft capsule shells, and obtain oseltamivir phosphate capsules.

[0041] Example 4

[0042] The difference between this embodiment and Embodiment 1 lies in the molecular weight of the drug-loaded material, as detailed below:

[0043] (1) Weigh out 125g of oseltamivir phosphate, 36g of pregelatinized starch, 6g of sodium stearate, 8g of drug-loaded material, 8g of talc and 22g of povidone K30, and set aside.

[0044] (2) Take the drug-loaded material (m microcrystalline cellulose: m poloxamer = 3:1), stir and dissolve it in water (160g), disperse it at 7000rpm for 5min, and prepare a drug-loaded material solution with a mass concentration of 5%.

[0045] Among them, 4-1: the particle size of microcrystalline cellulose is 50μm, and the poloxamer is poloxamer 407;

[0046] 4-2: The particle size of the microcrystalline cellulose is 200 μm, and the poloxamer is poloxamer 407.

[0047] (3) Take oseltamivir phosphate, add pregelatinized starch and sodium stearate, mix at 100 rpm for 5 min, then add to the drug-loaded material solution (160 g) in step (1), stir and disperse at 200 rpm for 5 min, wet granulate, dry, and obtain the premix.

[0048] (4) Add talc and povidone K30 to the premix in sequence, mix for 10 min, fill into soft capsule shells, and obtain oseltamivir phosphate capsules.

[0049] Experimental Example 1

[0050] According to the detection method for the dissolution of oseltamivir phosphate capsules in the 2020 edition of the Chinese Pharmacopoeia, Part II, the cumulative dissolution amount was determined using 900 mL of water and pH 6.8 phosphate buffer solution as the dissolution medium. The results are shown in the table below:

[0051] Table 1. Cumulative dissolution rate of oseltamivir phosphate capsules in different media

[0052]

[0053] As shown in Table 1 above, the average cumulative dissolution of oseltamivir phosphate capsules prepared in Examples 1, 4-1, and 4-2 in different media reached over 90% at 15 min, while the cumulative dissolution rate of Example 4-2 was relatively low at 30 min. Compared with Examples 4-1 and 4-2, the drug-loaded material solution formed by microcrystalline cellulose with a particle size of 100 μm and poloxamer can improve the degree of difference in particle size distribution and enhance the solubilization effect, thus contributing to increased dissolution rate.

[0054] Comparative Example 1

[0055] The difference between this comparative example and Example 1 is that the prescription ratio has been adjusted, as follows:

[0056] (1) Weigh out 125g of oseltamivir phosphate, 48g of pregelatinized starch, 6g of sodium stearate, 14g of drug-loaded material, 12g of talc and 22g of povidone K30, and set aside.

[0057] (2) Take the drug-loaded material (m microcrystalline cellulose: m poloxamer = 3:1), stir and dissolve it in water (160g), disperse it at 7000rpm for 5min, and prepare a drug-loaded material solution with a mass concentration of 8.75%, wherein the particle size of the microcrystalline cellulose is 100μm and the poloxamer is poloxamer 407.

[0058] (3) Take oseltamivir phosphate, add pregelatinized starch and sodium stearate, mix at 100 rpm for 5 min, then add to the drug-loaded material solution (160 g) in step (1), stir and disperse at 200 rpm for 5 min, wet granulate, dry, and obtain the premix.

[0059] (4) Add talc and povidone K30 to the premix in sequence, mix for 10 min, fill into soft capsule shells, and obtain oseltamivir phosphate capsules.

[0060] Comparative Example 2

[0061] The difference between this comparative example and Example 1 lies in the adjustment of the preparation process, as follows:

[0062] (1) Weigh out 125g of oseltamivir phosphate, 36g of pregelatinized starch, 6g of sodium stearate, 8g of microcrystalline cellulose (100μm), 8g of talc and 22g of povidone K30, and set aside.

[0063] (2) Take oseltamivir phosphate, add pregelatinized starch and sodium stearate, mix at 100 rpm for 5 min, add 5% microcrystalline cellulose aqueous solution (160 g), wet granulate, dry, and obtain premix.

[0064] (3) Add talc and povidone K30 to the premix in sequence, mix for 10 min, fill into soft capsule shells, and obtain oseltamivir phosphate capsules.

[0065] Experimental Example 2

[0066] The prepared oseltamivir phosphate capsules were placed at 40±2℃ and 75±5%RH for 6 months to observe their stability and detect their dissolution rate. The results are shown in the table below:

[0067] Table 2. Determination results of oseltamivir phosphate capsules

[0068] project 1 month 2 months 3 months 6 months Example 1 99.1％ 98.0％ 96.2％ 85.3％ Example 4-1 98.5％ 97.2％ 95.6％ 86.7％ Comparative Example 1 98.0％ 96.8％ 94.0％ 83.2％ Comparative Example 2 99.5％ 97.6％ 93.0％ 82.3％

[0069] The results in Table 2 above show that the oseltamivir phosphate capsules prepared in Examples 1 and 4-1 still achieved a dissolution rate of over 85% in the accelerated 6-month test, demonstrating good stability. Compared with Comparative Example 2, poloxamer and microcrystalline cellulose, as drug-loaded materials, improved drug encapsulation, dispersibility, and stability of the drug-loaded system, helping to further prevent drug aggregation. While using microcrystalline cellulose alone resulted in better dissolution, the drug stability decreased significantly over time, and the dissolution rate dropped considerably.

[0070] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A highly effective oseltamivir phosphate capsule, characterized in that, The product comprises, by weight, the following components: 120-130 parts oseltamivir phosphate, 30-45 parts pregelatinized starch, 5-10 parts sodium stearate, 5-10 parts drug-loaded material, 5-10 parts talc, and 20-25 parts povidone K30; wherein the drug-loaded material is microcrystalline cellulose and poloxamer in a mass ratio of 1-3:

1. The method for preparing oseltamivir phosphate capsules includes: mixing oseltamivir phosphate, pregelatinized starch and sodium stearate, dispersing them in a drug-loaded material solution, wet granulating, and finally adding talc and povidone K30, filling the capsules into soft capsule shells to obtain the oseltamivir phosphate capsules.

2. The highly effective oseltamivir phosphate capsule according to claim 1, characterized in that, By weight, it comprises the following components: 120-130 parts of oseltamivir phosphate, 35-40 parts of pregelatinized starch, 5-8 parts of sodium stearate, 5-10 parts of drug-loaded material, 5-10 parts of talc, and 20-25 parts of povidone K30.

3. The highly effective oseltamivir phosphate capsule according to claim 1, characterized in that, The microcrystalline cellulose has a particle size of 50~200 μm, and the poloxamer is poloxamer 407 and / or poloxamer 188.

4. The oseltamivir phosphate capsule according to claim 1, characterized in that, The preparation method includes the following steps: (1) Take oseltamivir phosphate, pregelatinized starch and sodium stearate, mix them, disperse them in the drug-loaded material solution made of drug-loaded material, stir and disperse, wet granulate, dry to obtain premix; (2) Add talc and povidone K30 to the premix, mix, and fill into soft capsule shells to obtain the oseltamivir phosphate capsules.

5. The oseltamivir phosphate capsule according to claim 4, characterized in that, The mass concentration of the drug-loaded material solution is 3-5%.

6. The oseltamivir phosphate capsule according to claim 5, characterized in that, Disperse the drug-loaded material in water at 6000-8000 rpm for 2-8 min to obtain the drug-loaded material solution.

7. The oseltamivir phosphate capsule according to claim 4, characterized in that, In step (1), the mixing rate is 80~120 rpm and the time is 5~10 min; the stirring and dispersing rate is 180~220 rpm and the time is 5~10 min.

8. The oseltamivir phosphate capsule according to claim 4, characterized in that, In step (2), the mixing time is 5 to 15 minutes.

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