Oral pharmaceutical composition containing oseltamivir phosphate and application

Abstract

The invention provides an oral pharmaceutical composition containing oseltamivir phosphate and application of the oral pharmaceutical composition. The oral pharmaceutical composition is prepared from the following components in parts by weight: 20 to 40 parts of oseltamivir phosphate, 8 to 10 parts of superoxide dismutase, 3 to 5 parts of quercetin and 0.8 to 1.2 parts of tetrahydromethylpyrimidine carboxylic acid. The oral quick-release film agent prepared from the oral pharmaceutical composition containing oseltamivir phosphate can be used for resisting influenza viruses, and the oral quick-release film agent prepared by the invention can be quickly dissolved out, avoids the liver first-pass effect, improves the bioavailability, achieves higher local drug concentration, quickly relieves symptoms, enhances the anti-influenza virus drug effect, is good in palatability, and can be used for preparing the oral quick-release film agent for resisting influenza viruses. The medicine is convenient for patients to take, improves compliance and reduces side effects.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an oral pharmaceutical composition containing oseltamivir phosphate and an application thereof. Background Art

[0002] Oseltamivir phosphate is a drug for the treatment of influenza virus infection, which can effectively treat influenza A and B. Oseltamivir phosphate is a neuraminidase inhibitor that blocks the replication and reproduction of the virus in host cells by inhibiting the neuraminidase activity of influenza viruses. It mainly targets the neuraminidase of influenza viruses, thereby reducing viral replication, shortening the duration of the disease, and reducing the spread of the virus in the host.

[0003] Currently, conventional oral dosage forms of oseltamivir phosphate, such as capsules, granules, tablets, etc., all have problems of frequent administration and poor patient compliance. Therefore, it is of practical significance to develop a new dosage form of oseltamivir phosphate and apply it to the clinical treatment of influenza virus.

[0004] Films are particularly suitable for bedridden patients, the elderly and children with dysphagia due to their simple preparation method, easy to carry, no need for water or chewing, rapid onset and high patient compliance. Since the sublingual mucosa is rich in venous blood vessels, the drug is directly absorbed into the blood circulation, thus avoiding the first-pass effect of the liver and improving the bioavailability of the drug. Therefore, as a new type of rapid-release solid preparation, film has attracted the attention and application of the pharmaceutical industry.

[0005] Currently, many patents have disclosed technical solutions for oral fast-dissolving films, but the technical solutions are different, and the final effects achieved are also different. There is also no technical solution specifically for oral fast-release films of oseltamivir phosphate. Summary of the invention

[0006] In view of this, the present invention provides an oral pharmaceutical composition containing oseltamivir phosphate and its application.

[0007] The technical solution of the present invention is achieved in this way:

[0008] An oral pharmaceutical composition containing oseltamivir phosphate comprises the following raw materials in parts by weight: 20-40 parts of oseltamivir phosphate, 8-10 parts of superoxide dismutase, 3-5 parts of quercetin, and 0.8-1.2 parts of ectoine.

[0009] Furthermore, the following raw materials are included: 30 parts of oseltamivir phosphate, 9 parts of superoxide dismutase, 4 parts of quercetin, and 1 part of ectoine.

[0010] Application of an oral pharmaceutical composition containing oseltamivir phosphate in the preparation of anti-influenza virus drugs.

[0011] Furthermore, the dosage form of the anti-influenza virus drug is an oral rapid-release film.

[0012] Furthermore, the oral rapid-release film comprises the following raw materials in parts by weight: 20-40 parts of oseltamivir phosphate, 8-10 parts of superoxide dismutase, 3-5 parts of quercetin, 0.8-1.2 parts of ectoine, 15-20 parts of hydroxypropyl methylcellulose, 1-3 parts of xanthan gum, and 5-7 parts of flavoring agents.

[0013] Furthermore, the preparation method of the oral rapid-release film specifically comprises:

[0014] (1) crushing oseltamivir phosphate to control the particle size to 80-90 μm;

[0015] (2) adding the crushed oseltamivir phosphate, superoxide dismutase and quercetin into a phosphate-sodium phosphate buffer and stirring evenly to obtain a drug solution;

[0016] (3) adding hydroxypropyl methylcellulose and xanthan gum into water and stirring evenly to obtain a hydroxypropyl methylcellulose-xanthan gum solution;

[0017] (4) adding the drug solution to the hydroxypropyl methylcellulose-xanthan gum solution, ultrasonically stirring, adding tetrahydromethylpyrimidine carboxylic acid and a flavoring agent, continuing to stir to obtain a film-forming drug solution, degassing, coating, and cutting to obtain a target oral rapid-release film.

[0018] Furthermore, in step (2), the pH of the phosphate-sodium phosphate buffer is 7.2-7.4, and the concentration is 0.01-0.02 mol / L; the solid-to-liquid ratio of the crushed oseltamivir phosphate, superoxide dismutase and quercetin to the phosphate-sodium phosphate buffer is 1:3-5 mg / mL.

[0019] Furthermore, in step (3), the concentration of the hydroxypropyl methylcellulose-xanthan gum solution is 1%-3% w / v.

[0020] Furthermore, in step (4), the volume ratio of the drug solution to the hydroxypropyl methylcellulose-xanthan gum solution is 1:2-4.

[0021] Furthermore, in step (4), the ultrasonic stirring is carried out at 20-30kHz and 40-50°C for 5-15min; and the stirring time is continued for 30-40min.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. The oral rapid-release film prepared by the present invention can dissolve rapidly, avoid the first-pass effect of the liver, improve bioavailability, achieve higher local drug concentration, quickly relieve symptoms, enhance anti-influenza virus efficacy, have good palatability, are convenient for patients to take, improve compliance, and reduce side effects.

[0024] 2. Oseltamivir phosphate of the present invention is used as the main ingredient for fighting influenza virus. The addition of superoxide dismutase can reduce the oxidative stress response caused by viral infection, reduce cell damage, and multi-target intervention improves the overall anti-influenza virus treatment effect; ectomethylpyrimidine carboxylic acid is used as a stabilizer for the drug; quercetin is a natural plant flavonoid with multiple effects of antioxidant, anti-inflammatory and antiviral. The addition of quercetin can not only serve as an antioxidant, but also has anti-inflammatory properties that can relieve local inflammation caused by influenza virus and enhance immune response. DETAILED DESCRIPTION

[0025] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0026] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0027] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0028] The superoxide dismutase of the present invention was purchased from Jiangsu Caiwei Biotechnology Co., Ltd.

[0029] The quercetin of the present invention was purchased from Xi'an Fenghe Biotechnology Co., Ltd.

[0030] The flavoring agent of the present invention is one of sucralose, sweet orange flavor or sucrose.

[0031] Example 1

[0032] An oral pharmaceutical composition containing oseltamivir phosphate comprises the following raw materials in parts by weight: 30 parts of oseltamivir phosphate, 9 parts of superoxide dismutase, 4 parts of quercetin, and 1 part of ectoine.

[0033] The oral rapid-release film of this embodiment comprises the following raw materials in parts by weight: 30 parts of oseltamivir phosphate, 9 parts of superoxide dismutase, 4 parts of quercetin, 1 part of ectoine, 18 parts of hydroxypropyl methylcellulose, 2 parts of xanthan gum, and 6 parts of flavoring agents.

[0034] The preparation method of the oral quick-release film of the present embodiment:

[0035] (1) crushing oseltamivir phosphate to control the particle size to 85±5 μm;

[0036] (2) adding the crushed oseltamivir phosphate, superoxide dismutase and quercetin to a phosphate-sodium phosphate buffer solution (pH = 7.3 ± 0.1) with a solid-liquid ratio of 1:4 mg / mL, and stirring evenly to obtain a drug solution;

[0037] (3) adding hydroxypropyl methylcellulose and xanthan gum into water and stirring evenly to obtain a hydroxypropyl methylcellulose-xanthan gum solution with a concentration of 2% w / v;

[0038] (4) The drug solution is added to the hydroxypropyl methylcellulose-xanthan gum solution at a volume ratio of 1:3, and ultrasonic stirring is performed at 25 kHz and 45° C. for 10 min. Tetrahydromethylpyrimidine carboxylic acid and a flavoring agent are added, and stirring is continued for 35 min to obtain a film-forming drug solution. The film is degassed, coated, and cut to obtain the target oral rapid-release film.

[0039] Example 2

[0040] An oral pharmaceutical composition containing oseltamivir phosphate comprises the following raw materials in parts by weight: 20 parts of oseltamivir phosphate, 8 parts of superoxide dismutase, 3 parts of quercetin, and 0.8 parts of ectoine.

[0041] The oral rapid-release film of this embodiment comprises the following raw materials in parts by weight: 20 parts of oseltamivir phosphate, 8 parts of superoxide dismutase, 3 parts of quercetin, 0.8 parts of ectoine, 15 parts of hydroxypropyl methylcellulose, 1 part of xanthan gum, and 5 parts of flavoring agents.

[0042] The preparation method of the oral quick-release film of the present embodiment:

[0043] (1) crushing oseltamivir phosphate to control the particle size to 85±5 μm;

[0044] (2) adding the crushed oseltamivir phosphate, superoxide dismutase and quercetin to a phosphate-sodium phosphate buffer solution (pH = 7.3 ± 0.1) with a solid-liquid ratio of 1:3 mg / mL, and stirring evenly to obtain a drug solution;

[0045] (3) adding hydroxypropyl methylcellulose and xanthan gum into water and stirring evenly to obtain a hydroxypropyl methylcellulose-xanthan gum solution with a concentration of 1% w / v;

[0046] (4) The drug solution is added to the hydroxypropyl methylcellulose-xanthan gum solution at a volume ratio of 1:2, and ultrasonic stirring is performed at 20 kHz and 40° C. for 5 min. Tetrahydromethylpyrimidine carboxylic acid and a flavoring agent are added, and stirring is continued for 30 min to obtain a film-forming drug solution. The film is degassed, coated, and cut to obtain the target oral rapid-release film.

[0047] Example 3

[0048] An oral pharmaceutical composition containing oseltamivir phosphate comprises the following raw materials in parts by weight: 40 parts of oseltamivir phosphate, 10 parts of superoxide dismutase, 5 parts of quercetin, and 1.2 parts of ectoine.

[0049] The oral rapid-release film of this embodiment comprises the following raw materials in parts by weight: 40 parts of oseltamivir phosphate, 10 parts of superoxide dismutase, 5 parts of quercetin, 1.2 parts of ectoine, 20 parts of hydroxypropyl methylcellulose, 3 parts of xanthan gum, and 7 parts of flavoring agent.

[0050] The preparation method of the oral quick-release film of the present embodiment:

[0051] (1) crushing oseltamivir phosphate to control the particle size to 85±5 μm;

[0052] (2) adding the crushed oseltamivir phosphate, superoxide dismutase and quercetin into a phosphate-sodium phosphate buffer solution (pH = 7.3 ± 0.1) with a solid-liquid ratio of 1:5 mg / mL, and stirring evenly to obtain a drug solution;

[0053] (3) adding hydroxypropyl methylcellulose and xanthan gum into water and stirring evenly to obtain a hydroxypropyl methylcellulose-xanthan gum solution with a concentration of 3% w / v;

[0054] (4) The drug solution is added to the hydroxypropyl methylcellulose-xanthan gum solution at a volume ratio of 1:4, and ultrasonic stirring is performed at 30 kHz and 50° C. for 15 min. Tetrahydromethylpyrimidine carboxylic acid and a flavoring agent are added, and stirring is continued for 40 min to obtain a film-forming drug solution. The film is degassed, coated, and cut to obtain the target oral rapid-release film.

[0055] Comparative Example 1

[0056] The difference from Example 1 is that the oral pharmaceutical composition containing oseltamivir phosphate is prepared into a granule preparation, and the rest is the same as Example 1.

[0057] That is, the preparation method of the oseltamivir phosphate granules of this comparative example:

[0058] (1) crushing oseltamivir phosphate to control the particle size to 85±5 μm;

[0059] (2) adding the crushed oseltamivir phosphate, superoxide dismutase and quercetin to a phosphate-sodium phosphate buffer solution (pH = 7.3 ± 0.1) with a solid-liquid ratio of 1:4 mg / mL, and stirring evenly to obtain a drug solution;

[0060] (3) adding the drug solution to a 5 wt% microcrystalline cellulose solution at a volume ratio of 1:4, adding a flavoring agent, stirring, spray drying, obtaining granules, drying, sieving, and coating to obtain the target oseltamivir phosphate granule preparation.

[0061] Comparative Example 2

[0062] The difference from Example 1 is that the oral pharmaceutical composition containing oseltamivir phosphate is prepared into a capsule preparation, and the rest is the same as Example 1.

[0063] That is, the oseltamivir phosphate capsule preparation of this comparative example includes the following raw materials in parts by weight: 30 parts of oseltamivir phosphate, 9 parts of superoxide dismutase, 4 parts of quercetin, 1 part of ectoine, 4 parts of pregelatinized starch, 2 parts of sodium stearate, 6 parts of povidone K30, and 6 parts of flavoring agent.

[0064] That is, the preparation method of the oseltamivir phosphate capsule preparation of this comparative example:

[0065] (1) crushing oseltamivir phosphate to control the particle size to 85±5 μm;

[0066] (2) mixing the crushed oseltamivir phosphate, superoxide dismutase, quercetin, pregelatinized starch, sodium stearate and flavoring agent, dispersing the mixture into a 5 wt % microcrystalline cellulose solution at a solid-liquid ratio of 1:4 mg / mL, adding tetrahydromethylpyrimidine carboxylic acid, stirring and dispersing, wet granulating, and drying to obtain a premix;

[0067] (3) Add povidone K30 to the premix, mix, and fill into soft capsule shells to obtain the target oseltamivir phosphate capsule preparation.

[0068] Test Example 1

[0069] The oseltamivir phosphate preparations prepared in Examples 1-3 of the present invention and Comparative Examples 1-2, commercially available oseltamivir phosphate granules (Kewei) and commercially available oseltamivir phosphate capsules (Tamiflu) were subjected to dissolution experiments.

[0070] Experimental method: The in vitro dissolution of oral rapid-release film was determined according to the fourth method of the fourth general rules of the Chinese Pharmacopoeia 2015 edition. Ultrasonic degassed PBS (pH = 6.8) was used as the release medium, the temperature was 37 ± 0.5 ° C, and a 2.5 * 3 cm film was taken and fixed in the center of the two-layer disc. The net disc was then placed at the bottom of the dissolution cup so that it was parallel to the rotating surface of the paddle bottom and 25 ± 2 mm apart. At a speed of 50r / min, 0.5min, 1min, 1.5min, 2min, 3min, 4min, 6min, 10min, 15min, 30min, 60min, 5ml of the release solution was taken and supplemented with an equal amount of blank release medium at the same temperature. After filtering through a microporous filter membrane, the filtrate was taken for HPLC determination. Granular preparations and capsule preparations were determined according to their corresponding in vitro dissolution methods. The data results are shown in Table 1.

[0071] Table 1

[0072]

[0073]

[0074] As can be seen from Table 1, the oral rapid-release oseltamivir phosphate films prepared in Examples 1-3 of the present invention can be rapidly dissolved, have a faster release rate than Comparative Example 1 (granules) and Comparative Example 2 (capsules), and are superior to the commercially available oseltamivir phosphate granules and commercially available oseltamivir phosphate capsules.

[0075] Comparative Example 3

[0076] The difference from Example 1 is that superoxide dismutase is missing, and the missing components are distributed according to the ratio of oseltamivir phosphate to quercetin. Others are consistent with Example 1.

[0077] That is, the oral pharmaceutical composition containing oseltamivir phosphate in this comparative example comprises the following raw materials in parts by weight: 37.9 parts of oseltamivir phosphate, 5.1 parts of quercetin, and 1 part of ectoine.

[0078] Comparative Example 4

[0079] The difference from Example 1 is that quercetin is missing, and the missing components are distributed according to the ratio of oseltamivir phosphate to superoxide dismutase. The rest is consistent with Example 1.

[0080] That is, the oral pharmaceutical composition containing oseltamivir phosphate in this comparative example comprises the following raw materials in parts by weight: 33.1 parts of oseltamivir phosphate, 9.9 parts of superoxide dismutase, and 1 part of ectoine.

[0081] Test Example 2

[0082] In vivo pharmacokinetic studies

[0083] 1. Experimental subjects: 110 SD female mice (weight 20±5g).

[0084] 2. Influenza virus: A / PR8 / 8 / 34(H1N1)(PR8), Source: Guangzhou Institute of Respiratory Diseases.

[0085] 2. Virus infection method: dilute the PR8 virus to 200 pfu / 40 μL (2 MLD) with PBS. 50 ), after the mice were anesthetized with isoflurane, 40 μL of the diluted PR8 virus was aspirated with a 100 μL pipette and dripped into the nasal cavity of the mice through both nostrils.

[0086] 3. Experimental groups: 110 mice were divided into a normal group, a virus interference group, Examples 1-3, Comparative Examples 1-4, commercially available oseltamivir phosphate granules and commercially available oseltamivir phosphate capsules, with 10 mice in each group.

[0087] 4. Method of administration:

[0088] Normal group: neither infected with virus nor given medication;

[0089] Virus interference group: only infected with virus but no medication;

[0090] Example 1-3 and Comparative Example 1-4 Group: The drugs prepared in Example 1-3 and Comparative Example 1-4 were first administered 4 hours before virus infection. The drug dosage form was oral rapid-release film administered sublingually to mice, and the granule dosage form and capsule dosage form were administered orally. The dosage was 2 mg in terms of oseltamivir phosphate, and the administration was continued at intervals of 12 hours.

[0091] Commercially available oseltamivir phosphate granules and commercially available oseltamivir phosphate capsules groups: intragastric administration, the first dose was 2 mg in terms of oseltamivir phosphate 4 hours before virus infection, and the doses continued at intervals of 12 hours.

[0092] The death of mice was observed during the period, and the survival rate of mice was calculated after 10 days. The results are shown in Table 2.

[0093] Table 2

[0094]

[0095]

[0096] As can be seen from Table 2, all mice in the normal group survived, and all mice in the virus interference group died, indicating that the model was successfully established. Compared with the virus interference group, the survival rate of the Example 1-3 group was 100%, indicating that the oral rapid-release film of Example 1-3 has a good anti-influenza virus effect, which is better than the commercially available group. The survival rate of the comparative example 3-4 decreased, indicating that the combined use of oseltamivir phosphate with superoxide dismutase and quercetin has a synergistic effect and enhances the anti-influenza virus effect.

[0097] 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. An oral pharmaceutical composition containing oseltamivir phosphate, characterized in that: The preparation comprises the following raw materials in parts by weight: 20-40 parts of oseltamivir phosphate, 8-10 parts of superoxide dismutase, 3-5 parts of quercetin, and 0.8-1.2 parts of ectoine.

2. An oral pharmaceutical composition containing oseltamivir phosphate according to claim 1, characterized in that: The invention comprises the following raw materials: 30 parts of oseltamivir phosphate, 9 parts of superoxide dismutase, 4 parts of quercetin and 1 part of ectoine.

3. Use of the oral pharmaceutical composition containing oseltamivir phosphate according to claim 1 in the preparation of anti-influenza virus drugs.

4. The use according to claim 3, characterized in that The dosage form of the anti-influenza virus drug is an oral rapid-release film.

5. The use according to claim 4, characterized in that The oral rapid-release film comprises the following raw materials in parts by weight: 20-40 parts of oseltamivir phosphate, 8-10 parts of superoxide dismutase, 3-5 parts of quercetin, 0.8-1.2 parts of ectoine, 15-20 parts of hydroxypropyl methylcellulose, 1-3 parts of xanthan gum, and 5-7 parts of flavoring agents.

6. The use according to claim 5, characterized in that The preparation method of the oral rapid-release film specifically comprises: (1) crushing oseltamivir phosphate to control the particle size to 80-90 μm; (2) adding the crushed oseltamivir phosphate, superoxide dismutase and quercetin into a phosphate-sodium phosphate buffer and stirring evenly to obtain a drug solution; (3) adding hydroxypropyl methylcellulose and xanthan gum into water and stirring evenly to obtain a hydroxypropyl methylcellulose-xanthan gum solution; (4) adding the drug solution to the hydroxypropyl methylcellulose-xanthan gum solution, ultrasonically stirring, adding tetrahydromethylpyrimidine carboxylic acid and a flavoring agent, continuing to stir to obtain a film-forming drug solution, degassing, coating, and cutting to obtain a target oral rapid-release film.

7. The use according to claim 6, characterized in that In step (2), the pH of the phosphate-sodium phosphate buffer is 7.2-7.4, and the concentration is 0.01-0.02 mol / L; the solid-to-liquid ratio of the crushed oseltamivir phosphate, superoxide dismutase and quercetin to the phosphate-sodium phosphate buffer is 1:3-5 mg / mL.

8. The use according to claim 6, characterized in that In step (3), the concentration of the hydroxypropyl methylcellulose-xanthan gum solution is 1%-3% w / v.

9. The use according to claim 6, characterized in that In step (4), the volume ratio of the drug solution to the hydroxypropyl methylcellulose-xanthan gum solution is 1:2-4.

10. The use according to claim 6, characterized in that In step (4), the ultrasonic stirring is carried out at 20-30kHz and 40-50°C for 5-15min; and the stirring time is continued for 30-40min.

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