Capsule containing oseltamivir phosphate and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a capsule containing oseltamivir phosphate and application of the capsule. The capsule is composed of oseltamivir phosphate, turmeric, microcrystalline cellulose, sorbitol, povidone and a lubricant, and the prepared capsule is good in dissolution effect, high in quality, low in content of related substances and suitable for further clinical application.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a capsule containing oseltamivir phosphate and a use thereof. Background Art

[0002] Oseltamivir phosphate is an antiviral drug widely used to treat and prevent influenza. It works by inhibiting the neuraminidase activity of influenza virus, thereby preventing the virus from replicating and spreading in host cells. Oseltamivir phosphate belongs to the neuraminidase inhibitor class of drugs, and its structural formula is as follows:

[0003]

[0004] Oseltamivir phosphate may form some impurities or degradation products during the production process, and these substances cannot be ignored in the quality control of drugs. Especially under long-term storage or improper storage conditions, oseltamivir phosphate may undergo hydrolysis, oxidation or other chemical reactions to generate some by-products. If these substances are not adequately controlled, they will affect the efficacy of the drug and may even cause adverse reactions. Therefore, monitoring and controlling the content of these impurities to ensure that they are within the range permitted by regulations is crucial to ensuring the safety and effectiveness of the drug.

[0005] In the prior art, there is no evidence of using oseltamivir phosphate and turmeric as a pharmaceutical composition, and there is no evidence of using them as capsules for verification. Summary of the invention

[0006] Based on the deficiencies of the prior art, a capsule containing oseltamivir phosphate is provided, which solves the defect of high related substances in oseltamivir phosphate. In clinical practice, the safety and effectiveness of the drug are guaranteed to be suitable for further promotion and application.

[0007] Specifically, the inventors solved the problem through the following technical solutions:

[0008] The first object of the present invention is to provide a capsule containing oseltamivir phosphate, wherein the capsule is composed of oseltamivir phosphate, turmeric, a filler, a disintegrant and a lubricant; calculated by weight, specifically as follows:

[0009]

[0010] Furthermore, the filler is selected from a combination of microcrystalline cellulose and sorbitol; the disintegrant is selected from one or two of sodium carboxymethyl starch and povidone K30; and the lubricant is selected from one of magnesium stearate, sodium lauryl sulfate and talc.

[0011] Furthermore, the filler is selected from microcrystalline cellulose and sorbitol; the disintegrant is selected from povidone K30; and the lubricant is selected from magnesium stearate.

[0012] Furthermore, the capsule is composed of the following components in parts by weight, specifically as follows:

[0013]

[0014] Furthermore, the capsule is composed of the following ingredients in parts by weight, specifically as follows:

[0015]

[0016] In a preferred embodiment of the present invention, the weight ratio of microcrystalline cellulose to sorbitol is 2:1.

[0017] The second object of the present invention is to provide a preparation process of the capsule, which is specifically:

[0018] (1) Weigh the prescribed amount of oseltamivir phosphate, turmeric, pregelatinized starch (microcrystalline cellulose, sorbitol), povidone K30, and 1 / 2 magnesium stearate and place them in a wet mixer granulator and mix at 100 rpm for 5 min;

[0019] (2) Weigh an appropriate amount of purified water and add p-aminobenzoic acid as a wetting agent;

[0020] (3) adding the wetting agent described in step (2) into a wet mixing granulator, mixing at 200 rpm for 1 min, and granulating;

[0021] (4) drying the granules obtained in step (3) and mixing with magnesium stearate for 5 minutes to obtain a mixture;

[0022] (5) Filling capsules with the mixture obtained in step (4).

[0023] Furthermore, in the above preparation method, the content of p-aminobenzoic acid is 0.1-0.3%.

[0024] Furthermore, in the above preparation method, the content of p-aminobenzoic acid is 0.2%.

[0025] The third object of the present invention is to provide the use of the capsule in the preparation of antiviral drugs.

[0026] The fourth object of the present invention is to provide a capsule of turmeric and oseltamivir phosphate, the dissolution of the oseltamivir phosphate capsule can meet the pharmacopoeia standard. After accelerated experiments, it was found that the oseltamivir phosphate in Examples 1-3 of the present invention was superior to the commercially available product and no obvious degradation occurred. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 :Oseltamivir phosphate impurity Ⅰ, C 15 H 26 N2O4·H3PO4(3R,4R,5S)-4-Acetylamino-5-amino-3-(l-ethylpropoxy)-l-cyclohexene-1-carboxylic acid methyl ester phosphate.

[0028] Figure 2 :Oseltamivir phosphate impurity Ⅱ, C 11 H 13 NO4, ethyl 3-hydroxy-4-acetamidobenzoate.

[0029] Figure 3 :Oseltamivir phosphate impurity Ⅲ, C 14 H 24 N2O4, (3R, 4R, 5S)-4-Acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid.

[0030] Figure 4 : The maximum single impurity content (impurity I) of each example at the end of 0th month, 1st month, 2nd month, 3rd month and 6th month.

[0031] Figure 5 : The total impurity content (impurity I, impurity II and impurity III) of each example at the end of 0 month, 1 month, 2 months, 3 months and 6 months.

[0032] Figure 6 : Dissolution of each example at the end of 0th month, 1st month, 2nd month, 3rd month and 6th month (5min in 0.1mol / L hydrochloric acid).

[0033] Figure 7 : Comparison of dissolution rates of Examples 1-3 and commercially available product Example 7 at 5 min, 10 min, 15 min, 20 min, 30 min, and 40 min.

[0034] Specific embodiment

[0035] The present invention discloses a capsule containing oseltamivir phosphate and its use. Those skilled in the art can refer to the content of this article and appropriately change the process parameters. It should be particularly pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be within the scope of the present invention. The method and application of the present invention have been described through more embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0036] Example 1: A capsule containing oseltamivir phosphate and a preparation method thereof, as follows

[0037] Material Name Weight(g) Oseltamivir phosphate 98.5 Microcrystalline Cellulose 60 Sorbitol 30 turmeric 31 Povidone K30 10 Magnesium Stearate 3

[0038] The preparation method is as follows:

[0039] (1) Weigh the prescribed amount of oseltamivir phosphate, turmeric, microcrystalline cellulose, sorbitol, povidone K30 and 1 / 2 magnesium stearate and place them in a wet mixer granulator and mix at 100 rpm for 5 min.

[0040] (2) Weigh an appropriate amount of purified water and add p-aminobenzoic acid so that the content of p-aminobenzoic acid is 0.2% as a wetting agent.

[0041] (3) Add the wetting agent described in step (2) into a wet mixing granulator, mix at 200 rpm for 1 min, and granulate.

[0042] (4) drying the granules obtained in step (3) and mixing with magnesium stearate for 5 minutes to obtain a mixture.

[0043] (5) Filling capsules with the mixture obtained in step (4).

[0044] Example 2: A capsule containing oseltamivir phosphate and a preparation method thereof, as follows

[0045]

[0046]

[0047] The preparation method is as follows:

[0048] wherein, an appropriate amount of purified water is weighed, and p-aminobenzoic acid is added so that the content of p-aminobenzoic acid is 0.1% as a wetting agent;

[0049] The other steps are the same as in Example 1.

[0050] Example 3: A capsule containing oseltamivir phosphate and a preparation method thereof, as follows

[0051] Material Name Weight(g) Oseltamivir phosphate 98.5 Microcrystalline Cellulose 80 Sorbitol 40 turmeric 40 Povidone K30 15 Magnesium Stearate 5

[0052] The preparation method is as follows:

[0053] wherein, an appropriate amount of purified water is weighed, and p-aminobenzoic acid is added so that the content of p-aminobenzoic acid is 0.3% as a wetting agent;

[0054] The other steps are the same as in Example 1.

[0055] Comparative Example 1: A capsule containing oseltamivir phosphate and a preparation method thereof, as follows

[0056] Material Name Weight(g) Oseltamivir phosphate 98.5 Pregelatinized starch 90 turmeric 31 Povidone K30 10 Magnesium Stearate 3

[0057] The preparation method is the same as that of Example 1.

[0058] Comparative Example 2: A capsule containing oseltamivir phosphate and a preparation method thereof, as follows

[0059] Material Name Weight(g) Oseltamivir phosphate 98.5 Microcrystalline Cellulose 60 Sorbitol 30 Povidone K30 10 Magnesium Stearate 3

[0060] The preparation method is the same as that of Example 1.

[0061] Comparative Example 3: A capsule containing oseltamivir phosphate and a preparation method thereof, as follows

[0062] Material Name Weight(g) Oseltamivir phosphate 98.5 Microcrystalline Cellulose 60 Sorbitol 30 turmeric 31 Povidone K30 10 Magnesium Stearate 3

[0063] The preparation method is as follows:

[0064] (1) Weigh the prescribed amount of oseltamivir phosphate, turmeric, microcrystalline cellulose, sorbitol, povidone K30 and 1 / 2 magnesium stearate and place them in a wet mixer granulator and mix at 100 rpm for 5 min.

[0065] (2) Weigh an appropriate amount of purified water and add sodium benzoate so that the content of sodium benzoate is 0.2% as a wetting agent.

[0066] (3) Add the wetting agent described in step (2) into a wet mixing granulator, mix at 200 rpm for 1 min, and granulate.

[0067] (4) drying the granules obtained in step (3) and mixing with magnesium stearate for 5 minutes to obtain a mixture.

[0068] (5) Filling capsules with the mixture obtained in step (4).

[0069] Comparative Example 4: A capsule containing oseltamivir phosphate and a preparation method thereof, as follows

[0070]

[0071]

[0072] The preparation method is the same as that of Example 1.

[0073] Comparative Example 5: A capsule containing oseltamivir phosphate and a preparation method thereof, as follows

[0074] Material Name Weight(g) Oseltamivir phosphate 246.26 Pregelatinized starch 120.86 Croscarmellose Sodium 8.25 Povidone K30 12.38 Purified water 61.88 talcum powder 20.63 Sodium stearyl fumarate 4.12

[0075] The preparation method is as follows:

[0076] (1) Weigh the prescribed amount of oseltamivir phosphate, pregelatinized starch, povidone K30 and talc in a wet mixing granulator and mix at 100 rpm for 5 min.

[0077] (2) Weigh an appropriate amount of purified water as a wetting agent.

[0078] (3) Add the wetting agent described in step (2) into a wet mixing granulator, mix at 150 rpm for 2 minutes, and granulate.

[0079] (4) After drying the granules obtained in step (3), a prescribed amount of sodium stearyl fumarate is added and mixed for 5 minutes to obtain a mixture.

[0080] (5) Filling capsules with the mixture obtained in step (4).

[0081] Comparative Example 6: A capsule containing oseltamivir phosphate and a preparation method thereof, as follows

[0082]

[0083]

[0084] Preparation method:

[0085] 1) crushing oseltamivir phosphate, passing through a 100-mesh sieve, dissolving povidone K30 in purified water as a binder for later use;

[0086] 2) Weigh oseltamivir phosphate, pregelatinized starch and low-substituted hydroxypropyl cellulose according to the prescribed amount and mix them evenly;

[0087] 3) Add an appropriate amount of adhesive to make a soft material, sieve through a 20-mesh sieve to make granules, dry at 55-60°C, and sieve through a 20-mesh sieve to make whole granules;

[0088] 4) Take the granules after whole granulation, weigh them, add talcum powder and mix them evenly, determine the content of the main drug in the granules, determine the filling amount, and fill them into No. 2 capsules. Each capsule contains 98.5 mg of oseltamivir phosphate.

[0089] Comparative Example 7: Commercially available oseltamivir phosphate capsules, Anhui****** Biopharmaceutical Co., Ltd.; National Medicine Standard No. H20233869.

[0090] 1. Testing Example Dissolution and Related Substances

[0091] 1) Detection of content of relevant substances:

[0092] Chromatographic conditions and system suitability test: Octylsilane bonded silica gel was used as filler; 0.05 mol / L potassium dihydrogen phosphate solution (pH adjusted to 5.6 with 1 mol / L potassium hydroxide solution)-methanol-acetonitrile (700:245:135) was used as mobile phase; the flow rate was 10 mL per minute; the detection wavelength was 207 nm; the column temperature was 50°C, and the injection volume was 15 μL.

[0093] Test solution: accurately measure 5 g of the capsule contents of Examples 1-3 and Comparative Examples 1-7, add 50 mL of water and shake, filter, take 2 mL, place in a 100 mL volumetric flask, dilute to the mark with the mixed solution, shake well, accurately measure 5 mL, place in a 50 mL volumetric flask, dilute to the mark with the mixed solution, shake well, as the test solution

[0094] Reference solution: Accurately weigh appropriate amounts of impurity I, impurity II and impurity III reference substances, add to the mixed solution to dissolve and quantitatively dilute to make a solution containing 2.2 μg of impurity I, 1.5 μg of impurity II and 3.5 μg of impurity III per 1 mL as the reference solution.

[0095] in,

[0096] Figure 1 :Oseltamivir phosphate impurity Ⅰ, C 15 H 26 N2O4·H3PO4(3R,4R,5S)-4-Acetylamino-5-amino-3-(l-ethylpropoxy)-l-cyclohexene-1-carboxylic acid methyl ester phosphate.

[0097] Figure 2 :Oseltamivir phosphate impurity Ⅱ, C 11 H 13 NO4, ethyl 3-hydroxy-4-acetamidobenzoate.

[0098] Figure 3 :Oseltamivir phosphate impurity Ⅲ, C 14 H 24 N2O4, (3R, 4R, 5S)-4-Acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid.

[0099] 2) Dissolution test

[0100] The concentration was determined by high performance liquid chromatography and the cumulative dissolution was calculated. The chromatographic column was Shiseido C 18The mobile phase was a mixed buffer solution of 50mmol / L potassium dihydrogen phosphate solution (adjusted to pH 6.0 with 1mol / L potassium hydroxide solution): acetonitrile in a volume ratio of 73:27, a flow rate of 1.0mL / min, a detection wavelength of 207nm, and a column temperature of 50°C. The paddle method was used to screen the medium (0.1mol / L hydrochloric acid) and the rotation speed (100r / min) based on the cumulative dissolution, and the dissolution of the relevant examples was detected at 5min, 10min, 15min, 20min, 30min, and 40min, respectively.

[0101] Accelerated test conditions: According to commercial packaging, after accelerated testing (temperature 40±2°C, relative humidity 75%±5%), samples were taken at the end of the 0th month, 1st month, 2nd month, 3rd month, and 6th month of the test to detect the above-mentioned dissolution and the content of related substances.

[0102] in,

[0103] Figure 4 : The maximum single impurity content (impurity I) of each example at the end of 0th month, 1st month, 2nd month, 3rd month and 6th month.

[0104] Figure 5 : The total impurity content (impurity I, impurity II and impurity III) of each example at the end of 0 month, 1 month, 2 months, 3 months and 6 months.

[0105] Figure 6 : Dissolution of each example at the end of 0th month, 1st month, 2nd month, 3rd month and 6th month (5min in 0.1mol / L hydrochloric acid).

[0106] Figure 7 : Comparison of dissolution rates of Examples 1-3 and commercially available product Example 7 at 5 min, 10 min, 15 min, 20 min, 30 min, and 40 min.

Claims

1. A capsule containing oseltamivir phosphate, characterized in that: The capsule is composed of oseltamivir phosphate, turmeric, a filler, a disintegrant and a lubricant; calculated by weight, specifically as follows: The filler is selected from a combination of microcrystalline cellulose and sorbitol; the disintegrant is selected from one or two of sodium carboxymethyl starch and povidone K30; and the lubricant is selected from one of magnesium stearate, sodium lauryl sulfate and talc.

2. The capsule according to claim 1, characterized in that The filler is selected from microcrystalline cellulose and sorbitol; the disintegrant is selected from povidone K30; and the lubricant is selected from magnesium stearate.

3. The capsule according to claim 2, characterized in that The capsule is composed of the following components in parts by weight, specifically as follows:

4. The capsule according to claim 3, characterized in that The capsule is composed of the following components by weight, specifically as follows:

5. The capsule according to claim 3, characterized in that The weight ratio of microcrystalline cellulose to sorbitol is 2:

1.

6. The capsule according to claim 4, characterized in that The capsule preparation process is as follows: (1) Weigh the prescribed amount of oseltamivir phosphate, turmeric, microcrystalline cellulose, sorbitol, povidone K30 and 1 / 2 magnesium stearate and place them in a wet mixer granulator and mix at 100 rpm for 5 min; (2) Weigh an appropriate amount of purified water and add p-aminobenzoic acid as a wetting agent; (3) adding the wetting agent described in step (2) into a wet mixing granulator, mixing at 200 rpm for 1 min, and granulating; (4) drying the granules obtained in step (3) and mixing with magnesium stearate for 5 minutes to obtain a mixture; (5) Filling capsules with the mixture obtained in step (4).

7. The capsule according to claim 6, characterized in that The content of p-aminobenzoic acid is 0.1-0.3%.

8. The capsule according to claim 6, characterized in that The content of p-aminobenzoic acid is 0.2%.

9. An oseltamivir phosphate capsule, characterized in that: It is prepared by the preparation method described in any one of claims 6 to 8.

10. Use of the capsule according to any one of claims 1 to 5 in the preparation of therapeutic antiviral drugs.

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