Oseltamivir phosphate capsule with high drug effect and preparation method of oseltamivir phosphate capsule

Abstract

The invention provides oseltamivir phosphate capsules with a high drug effect and a preparation method of the oseltamivir phosphate capsules. The oseltamivir phosphate capsules are prepared from the following components: 120 to 130 parts of oseltamivir phosphate, 30 to 45 parts of pregelatinized starch, 5 to 10 parts of sodium stearate, 5 to 10 parts of a drug carrying material, 5 to 10 parts of talcum powder and 20 to 25 parts of povidone K30, the medicine carrying material is microcrystalline cellulose and poloxamer. According to the oseltamivir phosphate capsule prepared by the invention, in a dissolution medium of water and a phosphate buffer solution with the pH value of 6.8, the average cumulative dissolution rate can reach 90% or above within 15 minutes, the oseltamivir phosphate capsule has excellent dissolution rate, the dissolution rate still reaches 85% or above in a 6-month accelerated test, and the oseltamivir phosphate capsule has good stability, is stable and has a high drug effect.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, and in particular to a high-efficacy oseltamivir phosphate capsule and a preparation method thereof. Background Art

[0002] Oseltamivir phosphate is a selective influenza virus neuraminidase inhibitor that can inhibit the further increase of influenza virus numbers and thus inhibit the spread of influenza viruses in the body to reduce pathogenicity. It can be used to treat acute, uncomplicated influenza A and B patients aged 2 weeks and above. Patients should use it within 48 hours of the first onset of symptoms. It can also be used to prevent influenza A and B in patients aged 1 year and above. Dissolution 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 consistent with the degree of absorption of its preparations in the body. Good dissolution is an important factor in improving the body's absorption of drugs. 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 keep the particle morphology completely consistent during storage, and it is easy to cause problems such as adhesion, resulting in reduced dissolution after long-term storage. Summary of the invention

[0003] In view of this, the object of the present invention is to provide a highly effective oseltamivir phosphate capsule and a preparation method thereof to solve the above problems.

[0004] The technical solution of the present invention is achieved in this way:

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

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

[0007] Furthermore, the following components are included in parts by weight: 120-130 parts of oseltamivir phosphate, 35-40 parts of pregelatinized starch, 5-8 parts of sodium stearate, 5-10 parts of drug-carrying materials, 5-10 parts of talc and 20-25 parts of povidone K30.

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

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

[0010] The present invention provides a preparation method of the above-mentioned oseltamivir phosphate capsules, which comprises: mixing oseltamivir phosphate, pregelatinized starch and sodium stearate, dispersing them into a drug-carrying material solution made of a drug-carrying material, wet granulating, and finally adding talcum powder and povidone K30, filling them into soft capsule shells, and obtaining the oseltamivir phosphate capsules.

[0011] The invention premixes oseltamivir phosphate with pregelatinized starch and sodium stearate, then disperses the mixture in a drug-carrying material solution of poloxamer and microcrystalline cellulose, and finally wet-granulates the mixture and mixes it with talcum powder and povidone K30, thereby further improving the dispersibility and stability of the drug system.

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

[0013] (1) taking oseltamivir phosphate, pregelatinized starch and sodium stearate, mixing them, dispersing them into a drug-carrying material solution prepared by a drug-carrying material, stirring and dispersing, wet granulating, and drying to obtain a premix;

[0014] (2) Add talcum powder 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-carrying 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 present invention has the following beneficial effects:

[0020] The present invention selects pregelatinized starch, sodium stearate, microcrystalline cellulose and poloxamer as drug-carrying materials, talcum powder and povidone K30 to prepare oseltamivir phosphate capsules, which have an average cumulative dissolution amount of more than 90% within 15 minutes in the dissolution medium of water and pH 6.8 phosphate buffer solution, and have excellent dissolution.

[0021] The oseltamivir phosphate capsules prepared by the present invention still have a dissolution rate of more than 85% in an accelerated 6-month test and have good stability. Oseltamivir phosphate is premixed with pregelatinized starch and sodium stearate, and then dispersed in a drug-carrying material solution of poloxamer and microcrystalline cellulose, and finally wet granulated and mixed with talcum powder and povidone K30, so that the morphology of the particles can be kept consistent, and the occurrence of adhesion and the like can be effectively avoided. At the same time, the dispersibility of each drug in the drug-carrying system is good, the fluidity is improved, and the loss of the drug is better reduced, thereby further improving the stability of the drug system, and the drug is stable and has high efficacy.

[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 speed and degree in vivo. DETAILED DESCRIPTION

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

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

[0025] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0026] Example 1

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

[0028] (2) The drug-carrying material (m microcrystalline cellulose: m poloxamer = 3:1) was taken, dissolved in water (160 g) by stirring, and dispersed at 7000 rpm for 5 min to prepare a drug-carrying material solution with a mass concentration of 5%, wherein the particle size of the microcrystalline cellulose was 100 μm and the poloxamer was poloxamer 407.

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

[0030] (4) Talc and povidone K30 were added to the premix in sequence, mixed for 10 min, and filled into soft capsule shells to prepare oseltamivir phosphate capsules.

[0031] Example 2

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

[0033] (2) The drug-carrying material (m microcrystalline cellulose: m poloxamer = 3:1) was taken, dissolved in water (160 g) by stirring, and dispersed at 7000 rpm for 5 min to obtain a drug-carrying material solution with a mass concentration of 3.75%, wherein the particle size of the microcrystalline cellulose was 100 μm and the poloxamer was poloxamer 407.

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

[0035] (4) Talc and povidone K30 were added to the premix in sequence, mixed for 10 min, and filled into soft capsule shells to prepare oseltamivir phosphate capsules.

[0036] Example 3

[0037] (1) Weigh 125 g of oseltamivir phosphate, 42 g of pregelatinized starch, 6 g of sodium stearate, 10 g of drug-carrying material, 8 g of talc and 22 g 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 (200 g), and disperse it at 7000 rpm for 5 min to prepare a drug-loaded material solution with a mass concentration of 5%, wherein the particle size of the microcrystalline cellulose is 100 μm, 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, add to the drug-loaded material solution (200 g) of step (1), stir and disperse at 200 rpm for 5 min, wet granulate, and dry to obtain a premix.

[0040] (4) Talc and povidone K30 were added to the premix in sequence, mixed for 10 min, and filled into soft capsule shells to prepare oseltamivir phosphate capsules.

[0041] Example 4

[0042] The difference between this embodiment and embodiment 1 is that the molecular weight of the drug-carrying material is different, as follows:

[0043] (1) Weigh 125 g of oseltamivir phosphate, 36 g of pregelatinized starch, 6 g of sodium stearate, 8 g of drug-carrying material, 8 g of talc and 22 g 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 (160 g), and disperse it at 7000 rpm for 5 min to prepare a drug-loaded material solution with a mass concentration of 5%;

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

[0046] 4-2: The particle size of 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, add to the drug-loaded material solution (160 g) of step (1), stir and disperse at 200 rpm for 5 min, wet granulate, and dry to obtain a premix.

[0048] (4) Talc and povidone K30 were added to the premix in sequence, mixed for 10 min, and filled into soft capsule shells to prepare oseltamivir phosphate capsules.

[0049] Test Example 1

[0050] According to the dissolution test method of Oseltamivir Phosphate Capsules in Part II of the Pharmacopoeia 2020, 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 as follows:

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

[0052]

[0053] The results in Table 1 above show that the average cumulative dissolution of the oseltamivir phosphate capsules prepared in Example 1, Example 4-1 and Example 4-2 in different media reached more than 90% at 15 minutes, and the cumulative dissolution of Example 4-2 at 30 minutes was relatively low. Compared with Examples 4-1 and 4-2, the drug-carrying 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 improve the solubilization effect to help increase the solubility.

[0054] Comparative Example 1

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

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

[0057] (2) The drug-loaded material (m microcrystalline cellulose: m poloxamer = 3:1) was taken, dissolved in water (160 g) by stirring, and dispersed at 7000 rpm for 5 min to obtain a drug-loaded material solution with a mass concentration of 8.75%, wherein the particle size of the microcrystalline cellulose was 100 μm and the poloxamer was poloxamer 407.

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

[0059] (4) Talc and povidone K30 were added to the premix in sequence, mixed for 10 min, and filled into soft capsule shells to prepare oseltamivir phosphate capsules.

[0060] Comparative Example 2

[0061] The difference between this comparative example and Example 1 is that the preparation process is adjusted as follows:

[0062] (1) Weigh 125 g of oseltamivir phosphate, 36 g of pregelatinized starch, 6 g of sodium stearate, 8 g of microcrystalline cellulose (100 μm), 8 g of talc and 22 g 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% aqueous solution of microcrystalline cellulose (160 g), wet granulate, and dry to prepare a premix.

[0064] (3) Talc and povidone K30 were added to the premix in sequence, mixed for 10 min, and filled into soft capsule shells to prepare oseltamivir phosphate capsules.

[0065] Test Example 2

[0066] The prepared oseltamivir phosphate capsules were placed at 40±2°C and 75±5% RH for 6 months for stability observation and dissolution testing. The results are shown in the following table:

[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 Example 1 and Example 4-1 still have a dissolution rate of more than 85% in the accelerated 6-month test, and have good stability. Compared with Comparative Example 2, poloxamer and microcrystalline cellulose as drug-carrying materials can improve the dispersibility and stability of the drug-carrying system while improving the drug encapsulation, and help to further prevent drug aggregation. Although microcrystalline cellulose alone has better dissolution, the stability of the drug decreases more with the increase of time, and the dissolution rate is greatly reduced.

[0070] The above is a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several improvements and modifications without departing from the principle of the present invention. 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 composition comprises the following components by weight: 120-130 parts of oseltamivir phosphate, 30-45 parts of pregelatinized starch, 5-10 parts of sodium stearate, 5-10 parts of drug-carrying material, 5-10 parts of talc and 20-25 parts of povidone K30; The drug-carrying materials are microcrystalline cellulose and poloxamer.

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

3. The high-efficacy oseltamivir phosphate capsule according to claim 1, characterized in that: The drug-carrying material is microcrystalline cellulose and poloxamer in a mass ratio of 1 to 3:

1.

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

5. The method for preparing oseltamivir phosphate capsules according to any one of claims 1 to 4, characterized in that: The preparation method comprises: mixing oseltamivir phosphate, pregelatinized starch and sodium stearate, dispersing them into a drug-carrying material solution made of drug-carrying materials, wet granulating, and finally adding talcum powder and povidone K30, filling into soft capsule shells, and obtaining the oseltamivir phosphate capsules.

6. The method for preparing oseltamivir phosphate capsules according to claim 5, characterized in that: The preparation method comprises the following steps: (1) taking oseltamivir phosphate, pregelatinized starch and sodium stearate, mixing them, dispersing them into a drug-carrying material solution prepared by a drug-carrying material, stirring and dispersing, wet granulating, and drying to obtain a premix; (2) Add talcum powder and povidone K30 to the premix, mix, and fill into soft capsule shells to obtain the oseltamivir phosphate capsules.

7. The method for preparing oseltamivir phosphate capsules according to claim 5 or 6, characterized in that: The mass concentration of the drug-carrying material solution is 3-5%.

8. The method for preparing oseltamivir phosphate capsules according to claim 7, characterized in that: The drug-loaded material is dispersed in water at 6000-8000 rpm for 2-8 minutes to prepare the drug-loaded material solution.

9. The method for preparing oseltamivir phosphate capsules according to claim 6, 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.

10. The method for preparing oseltamivir phosphate capsules according to claim 6, characterized in that: In step (2), the mixing time is 5 to 15 minutes.

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