Oseltamivir tablet and preparation method

Abstract

The application provides oseltamivir tablets and a preparation method, the oseltamivir tablets comprising, in terms of weight fractions, 230-250 parts of sustained-release granules, 45-65 parts of immediate-release granules, 10-20 parts of a glidant, and 20-30 parts of a binder, wherein the sustained-release granules contain 110-130 parts of oseltamivir free base, and the immediate-release granules contain 25-35 parts of oseltamivir free base.The oseltamivir tablets have a small single tablet weight and good sustained-release effect, and the patient's medication compliance is strong; by optimizing the particle size and preparation process of the immediate-release granules to reduce the deviation of the initial dissolution rate, the drug quality is controllable and the drug efficacy is stable.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to an oseltamivir tablet and a preparation method. BACKGROUND

[0002] Influenza is an acute respiratory infection disease caused by influenza virus, and its typical clinical symptoms are rapid high fever, systemic pain, significant fatigue and lesions of organs and tissues other than respiratory tract. Due to the easy variation of influenza virus, it can lead to outbreaks and pose a major threat to public health. Oseltamivir is one of the most effective drugs for influenza virus, which is designed based on the molecular structure of the natural substrate of neuraminidase and the spatial structure of the catalytic center of neuraminidase.

[0003] Tamiflu is a drug for treating influenza A developed by Roche in 1999 and marketed in Switzerland. It contains oseltamivir phosphate as an active ingredient and is formulated into a suspension or a capsule, which is a fast-release drug. In order to maintain an effective blood drug concentration, it needs to be taken several times a day, and the patient's compliance is poor. It is easy to miss taking medicine or not taking medicine on time, which leads to poor curative effect. Therefore, the international application with publication number WO2021057881A1 discloses an oseltamivir preparation, which is composed of a tablet core, a controlled-release film, a fast-release layer and an isolation layer from inside to outside. It can achieve sustained release for at least 24 hours with once-a-day administration, but it has the disadvantages of large initial dissolution deviation and unsatisfactory bioavailability.

[0004] Therefore, the present application is proposed. SUMMARY

[0005] The present application solves the problems of large initial dissolution deviation and unsatisfactory sustained-release effect of the existing oseltamivir preparation.

[0006] The present application provides an oseltamivir tablet, which comprises, by weight fraction, 230-250 parts of sustained-release granules, 45-65 parts of fast-release granules, 10-20 parts of a glidant, and 20-30 parts of a binder, wherein the sustained-release granules contain 110-130 parts of oseltamivir free base, and the fast-release granules contain 25-35 parts.

[0007] Compared with oseltamivir phosphate, the use of oseltamivir free base as a raw material can reduce the initial dissolution deviation. Meanwhile, the active ingredient is divided into fast-release and sustained-release parts, which can reduce the frequency of taking medicine to achieve the sustained-release effect. Preferably, the oseltamivir tablet comprises, by weight fraction, 235-245 parts of sustained-release granules, 55-60 parts of fast-release granules, 16-19 parts of a glidant, and 22-26 parts of a binder, wherein the sustained-release granules contain 115-125 parts of oseltamivir free base, and the fast-release granules contain 28-32 parts.

[0008] Preferably, the immediate-release granules comprise 25-35 parts of oseltamivir free base, 2-5 parts of surfactant, 8-13 parts of stabilizer, and 10-15 parts of filler; the sustained-release granules comprise 12-14 parts of isolation layer prepared from high molecular material and 210-230 parts of immediate-release granules. By preparing part of the oseltamivir free base into sustained-release granules, the bitterness of the oseltamivir free base is effectively reduced, and the patient compliance is high.

[0009] Preferably, the particle size of the immediate-release granules is in the range of 15 μm < D 90 < 200 μm. By limiting the particle size of the immediate-release granules, the deviation of the initial dissolution rate of the immediate-release granules is further reduced, which is crucial for the quality control of the drug and the exertion of the drug efficacy.

[0010] Preferably, the stabilizer is at least one of tryptophan, aspartic acid, phenylalanine, and glutamic acid. The specific amino acids containing carboxyl and amino groups can provide an acidic environment and protect the amine groups in the oseltamivir free base; in addition, part of the amino acids contain benzene ring structures, which can absorb light to improve the stability of the oseltamivir free base under light conditions.

[0011] The application also provides a preparation method of the oseltamivir tablets.

[0012] S1, dissolving a prescription amount of oseltamivir free base and surfactant in an organic solvent according to 1 g: 40-60 ml to obtain solution A; adding ammonium bicarbonate to a prescription amount of filler and stabilizer according to 4-8 g: 1 g to obtain mixture B, and dissolving the mixture B in deionized water according to 1 g: 10-15 ml to obtain solution C; adding the solution C to the solution A and stirring at a high speed of 9000-12000 rpm for 4-10 min, and spray drying to obtain immediate-release granules;

[0013] S2, placing the immediate-release granules in a fluidized bed, adjusting the fluidized temperature to 42-48 ℃, and pumping the isolation sustained-release liquid into the fluidized bed in a bottom spraying mode, with an air inlet amount of 48-56 m 3 / h, an atomization pressure of 0.9-1.2 bar, a feeding speed of 10-15 ml / min, and continuing the fluidization after the spraying is completed until the water content of the granules is less than 1%, to obtain sustained-release granules;

[0014] S3, putting a prescription amount of sustained-release granules, immediate-release microparticles, glidant, and binder into a multidimensional mixer and mixing for 4-8 min, tabletting, and coating.

[0015] The oseltamivir free base is pretreated, and the ammonium bicarbonate in the emulsion is volatilized to form a porous structure, which improves the dissolution rate of the immediate-release granules and reduces the dissolution deviation, and overcomes the problem of low solubility of oseltamivir itself. Meanwhile, the specific filler can make the porous structure have good compressibility, so that the preparation of tablets becomes possible. The immediate-release granules are coated by bottom spraying to prepare the sustained-release granules, so that the coating layer becomes the main factor to control the release rate, and the sustained-release effect is stable and controllable.

[0016] Preferably, the isolation sustained-release liquid in step S2 is prepared by the following method: the prescription high molecular material is mixed with water to form a 30% aqueous solution, and the prescription amount of surfactant and lubricant is added and stirred at 2000-2500 rpm for 24-30 min. By adding part of the round lubricant in the isolation sustained-release liquid, the substantial shear on the polymer during stirring can be avoided, so as to affect the sustained-release effect.

[0017] Preferably, step S3 is carried out as follows: the prescription amount of sustained-release granules, immediate-release microparticles, binder and part of the glidant are put into a multi-dimensional mixer and mixed for 3-5 min, and the remaining glidant is added and stirred for about 1-3 min, and then the tablets are pressed and coated. By using part of the glidant during mixing, the uniformity of the sustained-release granules and the immediate-release granules during mixing can be improved, and the batch uniformity can be improved. By adding before tabletting, the conventional lubrication effect can be achieved.

[0018] Preferably, the glidant includes at least one of colloidal silicon dioxide, magnesium stearate, talc, microcrystalline cellulose and calcium stearate. Preferably, the binder includes any one of povidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, aluminum silicate or calcium carbonate. Preferably, the high molecular material is any one of cellulose acetate, hydroxypropyl methyl cellulose, polyethylene oxide, polyvinyl alcohol and methacrylic acid-ethyl acrylate copolymer RL.

[0019] Compared with the prior art, the oseltamivir tablets and the preparation method have the following beneficial effects: 1) the oseltamivir tablets have small single tablet weight and good sustained-release effect, and the patient's compliance is strong; 2) by limiting the particle size and preparation process of the immediate-release granules, the initial dissolution deviation of the immediate-release granules is reduced, the drug quality is controllable, and the drug efficacy is stable; 3) by using specific stabilizers and fillers, the stability of the oseltamivir free base tablets is improved. DETAILED DESCRIPTION

[0020] In order to make the above objectives, characteristics and advantages of the present application more apparent and comprehensible, specific embodiments of the present application are described in detail below. If specific conditions are not indicated in the embodiments, conventional conditions or manufacturer's recommended conditions are used. If the manufacturers of the reagents or instruments are not indicated, they are all conventional products that can be purchased on the market. It should be noted that the features in the embodiments of the present application can be combined with each other without conflict.

[0021] Oseltamivir can act on the influenza virus surface glycoprotein-neuraminidase (NA), thereby inhibiting viral replication and transmission in the respiratory tract, and is a highly selective influenza virus NA inhibitor. Because the stability of oseltamivir phosphate is better than that of oseltamivir free base, the related products currently on the market all use oseltamivir phosphate as the active ingredient, and the dosage forms on the market include capsules, dry suspensions and granules. The existing capsules on the market have a dissolution rate of only 57.8 ± 20.9% within 5 minutes in a gastric acid environment, with low initial dissolution and large deviations; and the active ingredient usually exists in the form of micropowder, resulting in poor flowability of the effective ingredient and limiting the production capacity when filling capsules.

[0022] Generally, increasing the specific surface area can improve the initial dissolution; however, for oseltamivir phosphate, even if it is prepared by a grinder to have a very small particle size, the increase in the initial dissolution is still not ideal (about 85%), and the fluctuation is great, which is not conducive to quality control; and oseltamivir free base has good solubility, but its stability is poor.

[0023] Example 1

[0024] An oseltamivir tablet, which comprises the following raw material components:

[0025]

[0026]

[0027] The following method is used for preparation:

[0028] 1) Preparation of sustained-release granules

[0029] A 30% aqueous solution is prepared by adding water to the prescription amount of hydroxypropyl methylcellulose, and the prescription amount of simethicone is added for 30 minutes of circulating stirring at 2000 rpm, and is ready for use;

[0030] The prescription amount of oseltamivir free base, polyvinyl pyrrolidone, lactose and fumaric acid is placed in a fluidized bed, the fluidization temperature is adjusted to 48°C, the air inlet amount is 50 m 3 / h, the sustained-release coating liquid is pumped in with a bottom spraying mode, the atomization pressure is 1.0 bar, the feeding speed is 18 ml / min, and after the spraying is completed, the fluidization is continued until the water content of the granules is less than 1%;

[0031] 2) Preparation of immediate-release microparticles

[0032] Mix the prescription amount of oseltamivir free base, polyvinylpyrrolidone, lactose, fumaric acid uniformly, add water to make soft material, pass 20 mesh sieve to granulate, dry at 55-60°C, pass 20 mesh sieve to granulate;

[0033] 3) Preparation of tablets

[0034] Prepare the coating liquid by adding Opadry 85F to 150 ml of 85% ethanol and stirring for 10 min; mix the sustained-release granules, immediate-release microparticles, and the prescription amount of magnesium stearate, povidone, and talc in a multi-dimensional mixer for 4 min, and press 1000 tablets; coat with the coating liquid, perform full inspection, package, and store, to obtain the product.

[0035] Example 2

[0036] An oseltamivir tablet, which comprises the following raw materials:

[0037]

[0038] Prepare by the following method:

[0039] 1) Preparation of sustained-release granules

[0040] Prepare a 30% aqueous solution by adding water to the prescription amount of cellulose acetate, and add the prescription amount of simethicone and stir at 2000 rpm for 30 min;

[0041] Dissolve the prescription amount of oseltamivir free base and Tween-80 in dichloromethane at a ratio of 1:50 (g / ml) to obtain solution A; add ammonium bicarbonate to the prescription amount of lactose and tartaric acid at a ratio of 5:1 g / g to obtain mixture B, and dissolve mixture B in deionized water at a ratio of 1:10 (g / ml) to obtain solution C; add solution C to solution A and stir at high speed for 6 min at 10000 rpm. Spray dry the obtained emulsion to obtain microparticles D, with a feed flow rate of 18 ml / min, a gas flow rate of 45 m 3 / h, and an outlet temperature of 36°C.

[0042] Place the microparticles D in a fluidized bed, adjust the fluidized temperature to 50°C, and pump in the sustained-release coating liquid in a bottom-spraying manner at an air inlet amount of 52 m 3 / h, with an atomization pressure of 0.9 bar, a feed speed of 15 ml / min, and continue fluidization after spraying until the water content of the granules is less than 1%;

[0043] 2) Preparation of immediate-release microparticles

[0044] Dissolve the prescribed amount of oseltamivir free base and Tween-80 in dichloromethane at a ratio of 1:50 (g / ml) to obtain solution A; dissolve the prescribed amount of lactose and tartaric acid in deionized water at a ratio of 5:1 g / g to obtain mixture B, add ammonium bicarbonate to mixture B to obtain solution C; add solution C to solution A and stir at 10000 rpm for 6 min. Spray dry the obtained emulsion to obtain microparticles D at a feed flow rate of 18 ml / min, a gas flow rate of 45 m 3 / h, and an outlet temperature of 36°C.

[0045] 3) Preparation of tablets

[0046] Prepare a coating solution by adding Opadry 85F to 180 ml of 85% ethanol and stirring for 10 min; add the sustained-release granules, immediate-release microparticles, and the prescribed amount of colloidal silicon dioxide, hydroxypropyl cellulose, and talc to a multi-dimensional mixer and mix for 5 min, then compress 1000 tablets; coat the tablets with the coating solution, perform a full inspection, package, and store, to obtain the product.

[0047] Example 3

[0048] An oseltamivir tablet, which comprises the following raw materials:

[0049]

[0050]

[0051] Prepare by the following method:

[0052] 1) Preparation of sustained-release granules

[0053] Prepare a 30% aqueous solution by adding water to the prescribed amount of polyethylene glycol, and add the prescribed amount of simethicone and stir at 2400 rpm for 25 min;

[0054] Dissolve the prescribed amount of oseltamivir free base and Tween-80 in dichloromethane at a ratio of 1:50 (g / ml) to obtain solution A; dissolve the prescribed amount of lactose and aspartic acid in deionized water at a ratio of 5:1 g / g to obtain mixture B, add ammonium bicarbonate to mixture B to obtain solution C; add solution C to solution A and stir at 11000 rpm for 5 min. Spray dry the obtained emulsion to obtain microparticles D at a feed flow rate of 18 ml / min, a gas flow rate of 45 m 3 / h, and an outlet temperature of 36°C.

[0055] Place the microparticles D in a fluidized bed, adjust the fluidized temperature to 45°C, and set the air inlet amount to 50 m 3The solution A is sprayed into the fluidized bed at a rate of 18 ml / min, the inlet temperature is 36°C, and the outlet temperature is 36°C.

[0056] 3) Preparation of immediate-release microparticles

[0057] The prescription amount of oseltamivir free base and Tween-80 are dissolved in dichloromethane at a ratio of 1:50 (g / ml) to obtain solution A; the prescription amount of lactose and aspartic acid are mixed at a ratio of 5:1 g / g to obtain mixture B, and mixture B is dissolved in deionized water at a ratio of 1:12 (g / ml) to obtain solution C; solution C is added to solution A and stirred at 11000 rpm for 5 min. The obtained emulsion is subjected to spray drying to obtain microparticles D, the feeding flow rate is 18 ml / min, the gas flow rate is 45 m 3 / h, and the outlet temperature is 36°C.

[0058] 3) Preparation of tablets

[0059] Opadry 85F is added to 180 ml of 85% ethanol and stirred for 10 min to prepare a coating solution; the sustained-release granules, immediate-release microparticles, and prescription amount of magnesium stearate, hydroxypropyl methyl cellulose, and talc are mixed in a multi-dimensional mixer for 5 min, and 1000 tablets are pressed; the coating solution is used for coating, full inspection, packaging, and storage, and the tablets are obtained.

[0060] Example 4

[0061] An oseltamivir tablet, the raw material composition of which is as follows:

[0062]

[0063]

[0064] The following method is used for preparation:

[0065] 1) Preparation of sustained-release granules

[0066] The prescription amount of simethicone and talc are added to a 30% aqueous solution of polyethylene glycol and stirred at 2400 rpm for 25 min;

[0067] Dissolve the prescribed amount of oseltamivir free base and Tween-80 in dichloromethane at a ratio of 1:50 (g / ml) to obtain solution A; dissolve the mixture of the prescribed amount of lactose, aspartic acid, phenylalanine and talc in ammonium bicarbonate at a ratio of 5:1 g / g in deionized water at a ratio of 1:12 (g / ml) to obtain solution C; add solution C to solution A and stir at 11000 rpm for 5 min. Spray dry the obtained emulsion to obtain microparticles D at a feed flow rate of 18 ml / min, a gas flow rate of 45 m 3 / h, and an outlet temperature of 36°C.

[0068] Place the microparticles D in a fluid bed, adjust the fluidization temperature to 45°C, and pump in the sustained-release coating liquid in a bottom-spraying manner at an air inlet amount of 50 m 3 / h, an atomization pressure of 1.1 bar, a feed speed of 12 ml / min, and continue fluidization until the water content of the granules is less than 1% after spraying is completed.

[0069] 4) Preparation of immediate-release microparticles

[0070] Dissolve the prescribed amount of oseltamivir free base and Tween-80 in dichloromethane at a ratio of 1:50 (g / ml) to obtain solution A; dissolve the mixture of the prescribed amount of lactose, aspartic acid, phenylalanine and talc in ammonium bicarbonate at a ratio of 5:1 g / g in deionized water at a ratio of 1:12 (g / ml) to obtain solution C; add solution C to solution A and stir at 11000 rpm for 5 min. Spray dry the obtained emulsion to obtain microparticles D at a feed flow rate of 18 ml / min, a gas flow rate of 45 m 3 / h, and an outlet temperature of 36°C.

[0071] 3) Preparation of tablets

[0072] Prepare the coating liquid by adding Opadry 85F to 180 ml of 85% ethanol and stirring for 10 min; add the sustained-release granules, the immediate-release microparticles, and the prescribed amount of magnesium stearate and hydroxypropyl methyl cellulose to a multi-dimensional mixer, mix for 5 min, and press 1000 tablets; coat with the coating liquid, perform full inspection, package, and store, to obtain the tablets.

[0073] Example 5

[0074] An oseltamivir tablet, which comprises the following raw materials:

[0075]

[0076]

[0077] Prepare by the following method:

[0078] 1) Preparation of sustained-release granules

[0079] The prescription cellulose acetate was dissolved in water to form a 30% aqueous solution, and the prescription amount of simethicone and talc was added and stirred at 2400 rpm for 25 min, ready for use;

[0080] The prescription amount of oseltamivir free base and Tween-80 was dissolved in dichloromethane at a ratio of 1:50 (g / ml) to obtain solution A; the prescription amount of lactose, aspartic acid, phenylalanine and talc was added to ammonium bicarbonate at a ratio of 5:1 g / g to obtain mixture B, and mixture B was dissolved in deionized water at a ratio of 1:12 (g / ml) to obtain solution C; solution C was added to solution A and stirred at 11000 rpm for 5 min. The obtained emulsion was spray dried to obtain microparticles D, the feeding flow rate was 12 ml / min, the gas flow rate was 55 m 3 / h, and the outlet temperature was 42°C, and the average particle size D90 of microparticles D was less than 200 μm.

[0081] Microparticles D were placed in a fluidized bed, the fluidized temperature was adjusted to 45°C, the air inlet amount was 58 m 3 / h, and the release coating solution was pumped in a bottom spraying manner, the atomization pressure was 1.2 bar, the feeding speed was 8 ml / min, and after spraying was completed, the fluidization was continued until the water content of the particles was less than 1%.

[0082] 2) Preparation of immediate-release microparticles

[0083] The prescription amount of oseltamivir free base and Tween-80 was dissolved in dichloromethane at a ratio of 1:50 (g / ml) to obtain solution A; the prescription amount of lactose, aspartic acid, phenylalanine and talc was added to ammonium bicarbonate at a ratio of 5:1 g / g to obtain mixture B, and mixture B was dissolved in deionized water at a ratio of 1:12 (g / ml) to obtain solution C; solution C was added to solution A and stirred at 11000 rpm for 5 min. The obtained emulsion was spray dried to obtain microparticles D, the feeding flow rate was 12 ml / min, the gas flow rate was 55 m 3 / h, and the outlet temperature was 42°C, and the average particle size D90 of microparticles D was less than 200 μm.

[0084] 3) Preparation of tablets

[0085] Obtalicil 85F was added to 180 ml of 85% ethanol and stirred for 10 min to prepare a coating solution, which was ready for use; the release particles, the immediate-release microparticles, and the prescription amount of colloidal silicon dioxide and hydroxypropyl methyl cellulose were put into a multi-dimensional mixer and mixed for 4 min, then the prescription amount of magnesium stearate was added and stirred for about 3 min, and 1000 tablets were pressed; the coating solution was used for coating, full inspection, packaging, and storage, and the tablets were obtained.

[0086] Glidants are generally added to improve the flowability of granules and powders by reducing the interparticulate friction, usually in a lubrication step before tabletting to facilitate the flow of particulate material into the die cavities of the tablet press. The applicant has found that by using part of the glidant during the mixing process it is possible to improve the uniformity of the immediate release granules, the sustained release granules during the mixing process and to improve the batch uniformity, while the addition before tabletting serves the usual lubrication purpose.

[0087] Comparative Example 1

[0088] The immediate release pellets, sustained release pellets were prepared by the method of Example 16 of the patent application with the application number PCT / CN2020117625, and tablets were prepared by the tablet preparation method of Example 5, and the raw material composition was compressed into tablets.

[0089] Comparative Example 2

[0090] The tablets were prepared by the method of Example 5, the only difference being that the active ingredient was in the form of immediate release granules, that is, the sustained release granules were not coated.

[0091] Verification Example

[0092] To further prove the superiority of the present application, the inventors carried out mixing uniformity, dissolution, and long-term stability experiments on the products obtained in the examples and comparative examples of the present application.

[0093] 1. Dissolution data

[0094] The oseltamivir tablets prepared in Examples 1-5 and Comparative Examples 1-2 were subjected to dissolution experiments to ensure that the shapes of the oseltamivir tablets in each example were substantially the same, and a commercially available product, Tamiflu, was used as a control. Dissolution test II was used for in vitro dissolution testing. The test conditions were: 900 mL of 0.1 N HCI solution as the dissolution medium, a temperature of 37.5°C, a rotation speed of 50 rpm, and 6 samples per test group. Sampling was carried out at the midpoint between the top of the paddle and the liquid surface, 10 mm from the inner wall of the container, at 3 min, 1 h, 4 h, 8 h, and 16 h. The specific determination method is a prior art and will not be described here.

[0095] Table 1. Dissolution data for different groups of products

[0096]

[0097] As can be seen from Table 1, compared with the commercially available product, the present application can reduce the initial dissolution deviation and reduce the amount of excipients by forming a porous structure with oseltamivir free base, limiting the particle size of the immediate release granules and / or the pellet core, adjusting the addition order of the glidant, and adding talc in the sustained release material configuration to avoid substantial shearing of the high molecular polymer during the mixing operation.

[0098] 2. Stability data

[0099] The oseltamivir tablets prepared in Examples 2-5 and Comparative Example 1 were subjected to an accelerated test at 40°C and 75% humidity for 6 months, and the active ingredient content and related substances of the samples were determined at the 6th month.

[0100] Table 2 Stability data of products in different groups

[0101]

[0102] As shown in Table 2, the stability of the oseltamivir tablets prepared in the examples of the present application is at least equivalent to that of Comparative Example 1; and the stability of the tablets can be further improved by adding specific combinations of amino acids.

[0103] Experimental Example 1 Optimization of dissolution stability

[0104] Fast-release microparticles were prepared using oseltamivir free base and oseltamivir phosphate as raw materials, and the samples were ground to different particle sizes using a grinder. The dissolution rate within 5 minutes was determined using the dissolution test method II, and the specific determination conditions were as above. The results are shown in Table 1.

[0105] Table 1 Average dissolution and standard deviation of different particle sizes and components

[0106]

[0107]

[0108] As shown in Table 1, when oseltamivir free base is used as the active ingredient, the initial dissolution rate of the fast-release microparticles within 5 minutes is significantly higher than that of oseltamivir phosphate when the particle size is <200 μm. When the particle size D90 is <15 μm, the flowability of the particles is poor, and they are not suitable for large-scale production of tablets. Therefore, the preferred particle size of the fast-release microparticles is 50-200 μm.

[0109] Experimental Example 2 Animal pharmacokinetics

[0110] Dosing regimen: A four-formulation four-period crossover test was used (healthy beagle dogs, body weight 9-11.5 kg, half male and half female, divided into three groups, 6 dogs per group, fasted, orally administered by gavage), wherein the first experimental group was administered the oseltamivir formulation prepared in Example 5 (150 mg), the second experimental group was administered the formulation prepared in Comparative Example 1, the third experimental group was administered the formulation prepared in Comparative Example 2, and the fourth experimental group was administered commercially available Tamiflu capsules of 75 mg size, twice a day as a reference formulation.

[0111] Blood samples from dogs were collected at 0.5, 1, 2, 4, 6, 8, 10, and 24 hours to obtain pharmacokinetic parameters, including the area under the curve (AUC) and the maximum blood drug concentration (C). max The results are shown in Table 2.

[0112] Table 2 Pharmacokinetic data of different groups

[0113]

[0114]

[0115] As shown in Table 2, the active ingredient in Comparative Example 2 exists in a uniform immediate-release particle form, resulting in C in the beagle's body. max The concentration was far higher than that of commercially available formulations, with extremely poor sustained-release effect and increased risk of toxic side effects; however, Example 5, by preparing sustained-release granules and immediate-release microparticles from oseltamivir free base and combining them in a specific ratio, reduced C in beagle dogs. max Slightly lower than commercially available formulations, while AUC 0-24 This is comparable to and superior to Comparative Example 1 (87.4%), achieving a good sustained-release effect and high bioavailability. Clearly, the ratio of sustained-release particles to immediate-release microparticles significantly affects C. max It has a significant impact; studies have found that when the ratio of sustained-release granules to immediate-release microparticles is 3:1 (based on active ingredients), its efficacy is comparable to that of commercially available formulations, and the sustained-release effect is optimal.

[0116] Experiment Example 3: Formula Optimization

[0117] Compared to oseltamivir phosphate, the free base of oseltamivir has poor stability, and light exposure is one of the important factors affecting drug stability. Therefore, based on Example 2, the applicant prepared tablets using different components and placed them in HDPE bottles for experiments. The experimental conditions were: irradiation at 25°C and 60% relative humidity for 12 hours each, followed by light protection treatment, with a light intensity of 60 lx, and an experimental period of 90 days.

[0118] The total impurity content was measured and calculated according to the impurity analysis method for "oseltamivir phosphate capsules" listed in the United States Pharmacopeia (USP) monograph on pharmaceuticals. The results are shown in Table 3.

[0119] Table 3. Effects of different components on tablet stability

[0120]

[0121]

[0122] Compared with weak acids such as tartaric acid and fumaric acid, some amino acids such as aspartic acid, glutamic acid and tryptophan as amphoteric substances can improve the stability of the tablet under light conditions. The reason may be that the amino acids contain amino groups which can effectively prevent the amine groups in oseltamivir free base from reacting to produce impurities; and aspartic acid and glutamic acid can provide an acidic environment, and phenylalanine and the like containing benzene ring structure can have certain light absorption to ultraviolet rays. As can be seen from Table 3, when aspartic acid: phenylalanine = 1:1, the total impurity content of the tablet under light environment is the lowest and significantly lower than that of Example 2.

[0123] Although the present application has been disclosed with reference to the above examples, the present application is not limited to the above examples. Any person skilled in the art can make various modifications and changes without departing from the spirit and scope of the present application, and the scope of protection of the present application should be limited by the scope defined in the claims.

Claims

1. An oseltamivir tablet, characterized in that, By weight, it includes 235-245 parts of sustained-release granules, 55-60 parts of immediate-release granules, 16-19 parts of gliding agent, and 22-26 parts of binder, wherein the sustained-release granules contain 115-125 parts of oseltamivir free base and the immediate-release granules contain 28-32 parts. The immediate-release particles comprise 2-5 parts of surfactant, 8-13 parts of stabilizer, and 10-15 parts of filler; the sustained-release particles comprise 12-14 parts of an isolation layer prepared from polymer materials and 210-230 parts of immediate-release particles. The particle size range of the immediate-release particles is 15μm < D90 < 200μm; The stabilizer is aspartic acid: phenylalanine = 1:

1.

2. The method for preparing oseltamivir tablets according to claim 1, characterized in that, include: S1. Dissolve the prescribed amount of oseltamivir free base and surfactant in an organic solvent at a ratio of 1g:40-60ml to obtain solution A; add the prescribed amount of filler and stabilizer to ammonium bicarbonate at a ratio of 4-8g:1g to obtain mixture B; dissolve mixture B in deionized water at a ratio of 1g:10-15ml to obtain solution C; add solution C to solution A and stir at high speed of 9000-12000rpm for 4-10min, then spray dry to obtain immediate-release granules; S2. Place the immediate-release granules in a fluidized bed, adjust the fluidization temperature to 42-48℃, the air inlet volume to 48-56m3 / h, pump the isolation and slow-release liquid in a bottom spray manner, the atomization pressure to 0.9-1.2bar, the feed rate to 10-15ml / min, and continue fluidizing until the granule moisture content is less than 1% after spraying to obtain slow-release granules. S3. Add the prescribed amount of sustained-release granules, immediate-release microparticles, gliding agent, and binder to a multi-dimensional mixer and mix for 4-8 minutes. Compress into tablets and coat.

3. The method for preparing oseltamivir tablets according to claim 2, characterized in that, The isolation and sustained-release solution described in step S2 is prepared by the following method: water is added to the prescription polymer material to make a 30% aqueous solution, and the prescribed amount of surfactant and lubricant are added and stirred at 2000-2500 rpm for 24-30 min.

4. The method for preparing oseltamivir tablets according to claim 2, characterized in that, Step S3 is carried out as follows: The prescribed amount of sustained-release granules, immediate-release microparticles, binder and part of the gliding agent are put into a multi-dimensional mixer and mixed for 3-5 minutes. Then, the remaining gliding agent is added and the mixture is stirred for about 1-3 minutes. The mixture is then tableted and coated.

5. The oseltamivir tablet according to claim 4, characterized in that, The flow aid includes at least one of colloidal silica, magnesium stearate, talc, microcrystalline cellulose, and calcium stearate.

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