Oseltamivir phosphate granules and preparation method thereof

Abstract

According to the oseltamivir phosphate granules and the preparation method thereof, the granules are prepared by mixing the medicine-containing granules, the blank granules and the pharmaceutically acceptable auxiliary materials, and by selecting the specific auxiliary materials and the proportion of the auxiliary materials, the prepared granules maintain a high dissolution speed and achieve a good taste masking effect; according to the present invention, the traditional Chinese medicine composition has advantages of good taste, high content uniformity, high dissolution speed, good fluidity, low related substance content, good stability and the like, can meet different administration dosage requirements, and is suitable for children administration, and the pharmaceutical composition can be used for children, and can be used for preparing drugs for children, such that the pharmaceutical composition has characteristics of good taste, high content uniformity, high dissolution speed, good fluidity, low related substance content, and the like.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to an oseltamivir phosphate granule and its preparation method. Background Technology

[0002] Oseltamivir phosphate is primarily used clinically for the treatment of influenza A and B in adults and children over 1 year of age, and for the prevention of influenza A and B in adults and adolescents aged 13 years and older. Patients should use it within 48 hours of the first onset of symptoms. The dosage varies depending on the patient's physical condition. Oseltamivir phosphate has advantages such as effectiveness against both influenza A and B viruses, low likelihood of drug resistance, good patient tolerance, and high safety. It is a national strategic reserve drug for the prevention and control of influenza pandemics in my country and other countries around the world.

[0003] Currently, oseltamivir phosphate is available in the following dosage forms in my country: capsules, dry suspensions, and granules. The main capsule strength is 75mg. The recommended weight-dosage chart for children over 1 year old is shown in the table below:

[0004]

[0005] It is evident that capsules, due to their large dosage, are difficult to administer accurately to pediatric patients, especially young children, compromising safety. Furthermore, capsules are unsuitable for the elderly, children, and patients with severe influenza who have difficulty swallowing. Dry suspensions and granules overcome these limitations of capsules.

[0006] Oseltamivir phosphate contains amide and ester bonds in its molecular structure, making it sensitive to moisture and heat and prone to degradation. Furthermore, the presence of amino groups in its molecular structure allows it to undergo Maillard reactions with reducing sugars, leading to the formation of impurities. Additionally, oseltamivir phosphate itself has a bitter taste, requiring high-sweetening agents to mask it.

[0007] Patent CN101389323A discloses a pharmaceutical composition containing oseltamivir phosphate. It selects erythritol with a reducing sugar content of less than 0.01% as an excipient, and adds a high-sweetener, a water-soluble polymer, and an anti-caking agent for wet granulation. This yields a pharmaceutical composition containing oseltamivir phosphate with good stability, especially in inhibiting discoloration caused by temperature and humidity changes during storage. However, controlling the reducing sugar content of the erythritol to below 0.01% is difficult, and domestic excipient suppliers are currently unable to provide erythritol excipients with low reducing sugar content.

[0008] Patent CN 118903024 A discloses an oseltamivir phosphate granule and its preparation method. In the process of preparing oseltamivir phosphate granules, erythritol and dextrin are mixed and ground and then heated to 120℃-125℃. The aqueous solution of soluble starch and oseltamivir phosphate needs to be frozen to 0℃. The temperature control of the preparation is very limited, which is difficult to achieve in production and is difficult to commercialize. Summary of the Invention

[0009] The purpose of this invention is to provide an oseltamivir phosphate granule formulation based on existing technology. This granule formulation is made by mixing drug-containing granules, blank granules, and pharmaceutically acceptable excipients. By selecting specific excipients and the ratio between them, the granules maintain a high dissolution rate and achieve a good taste masking effect, maximally suppressing the growth of impurities during the granulation process. It has advantages such as good taste, high content uniformity, fast dissolution rate, good flowability, low content of related substances, and good stability. At the same time, the dosage is flexible and can meet different dosage requirements, making it suitable for children.

[0010] Another object of the present invention is to provide a method for preparing the above-mentioned oseltamivir phosphate granules.

[0011] The technical solution of the present invention is as follows:

[0012] For this invention, the active ingredient oseltamivir phosphate contains amide and ester bonds in its molecular structure, which can undergo Maillard reactions with reducing sugars, leading to impurities. Furthermore, it is sensitive to damp heat, and the preparation process generally suffers from impurity growth and poor stability. This invention uses erythritol as a filler. Erythritol, as a filler, primarily affects particle shape and, being a non-reducing sugar, can improve the stability of oseltamivir phosphate. However, the reducing sugar content in the erythritol used in current technologies needs to be controlled below 0.01%, which is difficult to achieve, and domestic excipient suppliers are currently unable to provide it.

[0013] To address this issue, the present invention prepares granules in two parts: blank granules and drug-containing granules. The blank granules do not contain oseltamivir phosphate but contain a portion of erythritol; the drug-containing granules contain oseltamivir phosphate and the remaining erythritol. This significantly reduces the contact amount and contact area between oseltamivir phosphate and erythritol, thereby further improving the stability of oseltamivir phosphate.

[0014] The oseltamivir phosphate granules mentioned in this invention are made by mixing drug-containing granules, blank granules, and pharmaceutically acceptable excipients. The drug-containing granules are made of oseltamivir phosphate, erythritol, and povidone; the blank granules are made of erythritol, povidone, acesulfame potassium, sodium saccharin, sucrose stearate, dextrin, medium-chain triglycerides, and corn starch; and the pharmaceutically acceptable excipients are flavorings and colloidal silica.

[0015] In drug-containing granules, erythritol, as a filler, mainly affects the formability of the granules; povidone, as a binder, mainly affects the adhesion of the granules. In one embodiment, the drug-containing granules mentioned in this invention are made from the following components in parts by weight: 10-15 parts of oseltamivir phosphate, 80-150 parts of erythritol, and 1-5 parts of povidone.

[0016] In a preferred embodiment, the medicated granules mentioned in this invention are made from the following components in parts by weight: 12 parts oseltamivir phosphate, 90-140 parts erythritol, and 2-4 parts povidone.

[0017] In a more preferred embodiment, the drug-containing granules mentioned in this invention are made from the following components in parts by weight: 12 parts oseltamivir phosphate, 98-135 parts erythritol, and 3 parts povidone.

[0018] For example, the medicated granules mentioned in this invention are made from the following components in parts by weight: 12 parts oseltamivir phosphate, 98 parts erythritol, and 3 parts povidone.

[0019] For example, the medicated granules mentioned in this invention are made from the following components in parts by weight: 12 parts oseltamivir phosphate, 118 parts erythritol, and 3 parts povidone.

[0020] For example, the medicated granules mentioned in this invention are made from the following components in parts by weight: 12 parts oseltamivir phosphate, 135 parts erythritol, and 3 parts povidone.

[0021] In blank granules, erythritol, as a filler, mainly affects the granule's formability; povidone, as a binder, mainly affects the granule's adhesion; acesulfame potassium, sodium saccharin, and flavoring, as flavoring agents, mainly affect the finished product's taste; medium-chain triglycerides and dextrin, as thickeners, mainly affect the settling rate of insoluble granules after reconstitution; sucrose stearate, as a solubilizer, reduces the surface tension between the liquid and solid, making it easier for the liquid to spread on the solid surface. In granules, it helps the drug components disperse and dissolve better. In a preferred embodiment, the flavoring is peach powder flavoring.

[0022] In one embodiment of the present invention, the weight ratio of the active component oseltamivir phosphate to erythritol in the blank particles is 0.02-0.18:1, and may be, but is not limited to, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.10:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, 0.17:1, or 0.18:1. Preferably, the weight ratio of the active component oseltamivir phosphate to erythritol in the blank particles is 0.05-0.12:1, and more preferably, the weight ratio of the active component oseltamivir phosphate to erythritol in the blank particles is 0.07-0.09:1.

[0023] In one embodiment, the weight ratio of oseltamivir phosphate to povidone in blank particles is 1-8:1, which may be, but is not limited to, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1. Preferably, the weight ratio of oseltamivir phosphate to povidone in blank particles is 3-5:1, and more preferably, the weight ratio of oseltamivir phosphate to povidone in blank particles is 4:1.

[0024] In one embodiment, the weight ratio of oseltamivir phosphate to acesulfame potassium in the blank granules is 20-60:1, which may be, but is not limited to, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1 or 60:1. Preferably, the weight ratio of oseltamivir phosphate to acesulfame potassium in the blank granules is 30-50:1. More preferably, the weight ratio of oseltamivir phosphate to acesulfame potassium in the blank granules is 40:1.

[0025] In one embodiment, the weight ratio of oseltamivir phosphate to sodium saccharin in the blank granules is 20-60:1, which may be, but is not limited to, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1 or 60:1. Preferably, the weight ratio of oseltamivir phosphate to sodium saccharin in the blank granules is 30-50:1, and more preferably, the weight ratio of oseltamivir phosphate to sodium saccharin in the blank granules is 40:1.

[0026] In one embodiment, the weight ratio of oseltamivir phosphate to sucrose stearate in the blank particles is 20-60:1, which may be, but is not limited to, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1 or 60:1. Preferably, the weight ratio of oseltamivir phosphate to sucrose stearate in the blank particles is 30-50:1, and more preferably, the weight ratio of oseltamivir phosphate to sucrose stearate in the blank particles is 40:1.

[0027] In one embodiment, the weight ratio of oseltamivir phosphate to dextrin in the blank granules is 10-20:1, which may be, but is not limited to, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1. Preferably, the weight ratio of oseltamivir phosphate to dextrin in the blank granules is 12-18:1, and more preferably, the weight ratio of oseltamivir phosphate to dextrin in the blank granules is 15:1.

[0028] In one embodiment, the weight ratio of oseltamivir phosphate to medium-chain triglycerides in the blank particles is 10-20:1, which may be, but is not limited to, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1. Preferably, the weight ratio of oseltamivir phosphate to medium-chain triglycerides in the blank particles is 12-18:1, and more preferably, the weight ratio of oseltamivir phosphate to medium-chain triglycerides in the blank particles is 15:1.

[0029] In one embodiment, the weight ratio of oseltamivir phosphate to corn starch in the blank granules is 0.8-1.8:1, which may be, but is not limited to, 0.8:1, 0.9:1, 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1 or 1.8:1. Preferably, the weight ratio of oseltamivir phosphate to corn starch in the blank granules is 1.0-1.5:1, and more preferably, the weight ratio of oseltamivir phosphate to corn starch in the blank granules is 1.2:1.

[0030] In this invention, pharmaceutically acceptable excipients are flavorings and colloidal silica, preferably, peach powder flavoring. In one embodiment, the weight ratio of oseltamivir phosphate to peach powder flavoring in the excipients is 5-15:1, which may be, but is not limited to, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, or 15:1. Preferably, the weight ratio of oseltamivir phosphate to peach powder flavoring in the excipients is 6-10:1, and more preferably, the weight ratio of oseltamivir phosphate to peach powder flavoring in the excipients is 8:1.

[0031] In one embodiment, the weight ratio of oseltamivir phosphate to colloidal silica in the excipients is 20-60:1, which may be, but is not limited to, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1 or 60:1. Preferably, the weight ratio of oseltamivir phosphate to colloidal silica in the excipients is 30-50:1, and more preferably, the weight ratio of oseltamivir phosphate to colloidal silica in the excipients is 40:1.

[0032] The oseltamivir phosphate granules mentioned in this invention are prepared by mixing drug-containing granules, blank granules, and pharmaceutically acceptable excipients. The drug-containing granules are composed of the following components in parts by weight: 12 parts oseltamivir phosphate, 90-140 parts erythritol, and 2-4 parts povidone; wherein the weight ratio of oseltamivir phosphate to erythritol in the blank granules is 0.05-0.12:1; the weight ratio of oseltamivir phosphate to povidone in the blank granules is 3-5:1; the weight ratio of oseltamivir phosphate to acesulfame potassium in the blank granules is 30-50:1; the weight ratio of oseltamivir phosphate to blank granules... The weight ratio of sodium saccharin to oseltamivir phosphate is 30-50:1; the weight ratio of oseltamivir phosphate to sucrose stearate in blank granules is 30-50:1; the weight ratio of oseltamivir phosphate to dextrin in blank granules is 12-18:1; the weight ratio of oseltamivir phosphate to medium-chain triglycerides in blank granules is 12-18:1; the weight ratio of oseltamivir phosphate to medium-chain triglycerides in blank granules is 1.0-1.5:1; the weight ratio of oseltamivir phosphate to peach powder flavoring in excipients is 6-10:1; and the weight ratio of oseltamivir phosphate to colloidal silica in excipients is 30-50:1.

[0033] The oseltamivir phosphate granules mentioned in this invention are prepared by mixing drug-containing granules, blank granules, and pharmaceutically acceptable excipients. The drug-containing granules are composed of the following components in parts by weight: 12 parts oseltamivir phosphate, 98-135 parts erythritol, and 3 parts povidone; wherein the weight ratio of oseltamivir phosphate to erythritol in the blank granules is 0.07-0.09:1; the weight ratio of oseltamivir phosphate to povidone in the blank granules is 4:1; and the weight ratio of oseltamivir phosphate to acesulfame potassium in the blank granules is 40:1. The weight ratio of oseltamivir to sodium saccharin in the blank granules was 40:1; the weight ratio of oseltamivir phosphate to sucrose stearate in the blank granules was 40:1; the weight ratio of oseltamivir phosphate to dextrin in the blank granules was 15:1; the weight ratio of oseltamivir phosphate to medium-chain triglycerides in the blank granules was 15:1; the weight ratio of oseltamivir phosphate to corn starch in the blank granules was 1.2:1; the weight ratio of oseltamivir phosphate to peach powder flavoring in the excipients was 8:1; and the weight ratio of oseltamivir phosphate to colloidal silica in the excipients was 40:1.

[0034] For example, the granule is made by mixing medicated granules, blank granules, and pharmaceutically acceptable excipients. The medicated granules are made from the following components in parts by weight: 12 parts oseltamivir phosphate, 98 parts erythritol, and 3 parts povidone. The blank granules are made from the following components in parts by weight: 170 parts erythritol, 3 parts povidone, 0.3 parts acesulfame potassium, 0.3 parts sodium saccharin, 0.3 parts sucrose stearate, 0.8 parts dextrin, 0.8 parts medium-chain triglycerides, and 10 parts corn starch. Among the pharmaceutically acceptable excipients, there are 8 parts peach powder flavoring and 0.3 parts colloidal silica.

[0035] For example, the granule is made by mixing medicated granules, blank granules, and pharmaceutically acceptable excipients. The medicated granules are made from the following components in parts by weight: 12 parts oseltamivir phosphate, 118 parts erythritol, and 3 parts povidone. The blank granules are made from the following components in parts by weight: 150 parts erythritol, 3 parts povidone, 0.3 parts acesulfame potassium, 0.3 parts sodium saccharin, 0.3 parts sucrose stearate, 0.8 parts dextrin, 0.8 parts medium-chain triglycerides, and 10 parts corn starch. Among the pharmaceutically acceptable excipients, there are 8 parts peach powder flavoring and 0.3 parts colloidal silica.

[0036] For example, the granule is made by mixing medicated granules, blank granules, and pharmaceutically acceptable excipients. The medicated granules are made from the following components in parts by weight: 12 parts oseltamivir phosphate, 135 parts erythritol, and 3 parts povidone. The blank granules are made from the following components in parts by weight: 133 parts erythritol, 3 parts povidone, 0.3 parts acesulfame potassium, 0.3 parts sodium saccharin, 0.3 parts sucrose stearate, 0.8 parts dextrin, 0.8 parts medium-chain triglycerides, and 10 parts corn starch. Among the pharmaceutically acceptable excipients, there are 8 parts peach powder flavoring and 0.3 parts colloidal silica.

[0037] The present invention also provides a method for preparing the above-mentioned oseltamivir phosphate granules, comprising the following steps:

[0038] (1) Pretreatment: Sieve oseltamivir phosphate and excipients and set aside for later use;

[0039] (2) Preparation of drug-containing granules: Oseltamivir phosphate, erythritol and povidone are mixed evenly, and an ethanol aqueous solution is added to make a soft material, which is then granulated. The wet granules are dried and granulated to obtain drug-containing granules.

[0040] (3) Preparation of blank particles: Erythritol, povidone, acesulfame potassium, sodium saccharin, sucrose stearate, dextrin, medium chain triglycerides and corn starch are mixed evenly, and an ethanol aqueous solution is added to make a soft material, which is then granulated. The obtained wet particles are dried and granulated to obtain blank particles.

[0041] (4) Mixing: Mix the medicated granules obtained in step (2), the blank granules obtained in step (3), and the fragrance and colloidal silica in the excipients to obtain granules.

[0042] For the purposes of this invention, in step (1), oseltamivir phosphate is passed through a 40-80 mesh sieve, preferably through a 60 mesh sieve. The excipients include erythritol, povidone, acesulfame potassium, sodium saccharin, sucrose stearate, dextrin, medium-chain triglycerides, corn starch, peach powder flavoring, and colloidal silica, all passed through a 40-80 mesh sieve, preferably through a 60 mesh sieve.

[0043] For the purposes of this invention, in step (2), the volume content of the ethanol aqueous solution is 60%-80%, which may be, but is not limited to, 60%, 65%, 70%, 75% or 80%, and preferably, the volume content of the ethanol aqueous solution is 70%.

[0044] In step (2), the drying temperature is 40-50℃, and the drying is carried out until the moisture content is <1%. Preferably, the drying temperature is 45℃. When granulating, the screen aperture is 0.8mm-1.2mm, preferably 1.0mm. The rotation speed is 300-1000rpm, preferably 600rpm.

[0045] For the purposes of this invention, in step (3), the volume content of the ethanol aqueous solution is 60%-80%, which may be, but is not limited to, 60%, 65%, 70%, 75% or 80%, and preferably, the volume content of the ethanol aqueous solution is 70%.

[0046] In step (3), the drying temperature is 40-50℃, and the drying is carried out until the moisture content is <1%. Preferably, the drying temperature is 45℃. When granulating, the screen aperture is 0.8mm-1.2mm, preferably 1.0mm, and the rotation speed is 300-1000rpm, preferably 600rpm.

[0047] The method of this invention for preparing oseltamivir phosphate granules requires no special equipment or excipients, and the preparation method is simple. It solves the problem of impurity growth and poor stability that are common in the preparation process of oseltamivir phosphate, which contains amide and ester bonds and is sensitive to humid heat. This method can greatly increase patient compliance, especially in children.

[0048] The advantages of using the technical solution of this invention are as follows:

[0049] This invention provides oseltamivir phosphate granules, which are made by mixing drug-containing granules, blank granules, and pharmaceutically acceptable excipients. By selecting specific excipients and the ratio between them, the granules maintain a high dissolution rate and achieve a good taste masking effect, maximally inhibiting the growth of impurities during the granulation process. They have advantages such as good taste, high content uniformity, fast dissolution rate, good flowability, low content of related substances, and good stability. At the same time, the dosage is flexible and can meet different dosage requirements, making them suitable for children.

[0050] The method provided by this invention solves the problem that the active ingredient oseltamivir phosphate contains amide and ester bonds in its molecular structure and is sensitive to moisture and heat, making it prone to degradation impurities. When preparing granules, conventional excipients are selected, which reduces the requirements for production equipment, lowers production energy consumption, simplifies production steps, and is suitable for large-scale industrial production. Detailed Implementation

[0051] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0052] Example 1

[0053] An oseltamivir phosphate granule formulation, comprising drug-containing granules, blank granules, and pharmaceutically acceptable excipients, is described below:

[0054]

[0055] The specific preparation method is as follows:

[0056] (1) Pretreatment: Oseltamivir phosphate and excipients (erythritol, povidone, acesulfame potassium, saccharin sodium, sucrose stearate, dextrin, medium chain triglycerides, corn starch, peach powder flavoring and colloidal silica) are passed through a 60-mesh sieve and set aside for later use;

[0057] (2) Preparation of drug-containing granules: Oseltamivir phosphate, erythritol and povidone were mixed evenly, and 70% ethanol aqueous solution was added to make soft material, granulated, and the obtained wet granules were dried in an oven at 45℃ until the moisture content was <1%, and then granulated again. The sieve aperture was 1.0 mm and the rotation speed was 600 rpm to obtain drug-containing granules.

[0058] (3) Preparation of blank particles: Erythritol, povidone, acesulfame potassium, sodium saccharin, sucrose stearate, dextrin, medium chain triglycerides and corn starch were mixed evenly, and 70% ethanol aqueous solution was added to make a soft material. The material was granulated and the resulting wet particles were dried in an oven at 45°C until the moisture content was <1%. The particles were then sized with a sieve aperture of 1.0 mm and a rotation speed of 600 rpm to obtain blank particles.

[0059] (4) Mixing: Mix the medicated granules obtained in step (2), the blank granules obtained in step (3), and the fragrance and colloidal silica in the excipients to obtain granules.

[0060] Example 2

[0061] An oseltamivir phosphate granule formulation, comprising drug-containing granules, blank granules, and pharmaceutically acceptable excipients, is described below:

[0062]

[0063] The preparation method is the same as in Example 1, except that the amount of some components added is different.

[0064] Example 3

[0065] An oseltamivir phosphate granule formulation, comprising drug-containing granules, blank granules, and pharmaceutically acceptable excipients, is described below:

[0066]

[0067] The preparation method is the same as in Example 1, except that the amount of some components added is different.

[0068] Comparative Example 1

[0069] The specific formula of oseltamivir phosphate granules is as follows:

[0070]

[0071]

[0072] The specific preparation method is as follows:

[0073] (1) Pretreatment: Oseltamivir phosphate and excipients (erythritol, povidone, acesulfame potassium, saccharin sodium, sucrose stearate, dextrin, medium chain triglycerides, corn starch, peach powder flavoring and colloidal silica) are passed through a 60-mesh sieve and set aside for later use;

[0074] (2) Granule preparation: Oseltamivir phosphate and excipients (erythritol, povidone, acesulfame potassium, sodium saccharin, sucrose stearate, dextrin, medium chain triglyceride, corn starch) were mixed evenly, and 70% ethanol aqueous solution was added to make a soft mass. The granules were then granulated, and the resulting wet granules were dried in an oven at 45°C until the moisture content was <1%. The granules were then sized with a sieve aperture of 1.0 mm and a rotation speed of 600 rpm to obtain granules.

[0075] (3) Mixing: Mix the granules obtained in step (2) with the fragrance and colloidal silica in the excipients to obtain granules.

[0076] Comparative Example 2

[0077] An oseltamivir phosphate granule formulation, comprising drug-containing granules, blank granules, and pharmaceutically acceptable excipients, is described below:

[0078]

[0079] The specific preparation method is as follows:

[0080] (1) Pretreatment: Oseltamivir phosphate and excipients (mannitol, povidone, acesulfame potassium, sodium saccharin, sucrose stearate, dextrin, medium chain triglycerides, corn starch, peach powder flavoring and colloidal silica) are passed through a 60-mesh sieve and set aside for later use;

[0081] (2) Preparation of drug-containing granules: Oseltamivir phosphate, mannitol and povidone were mixed evenly, and 70% ethanol aqueous solution was added to make soft material, granulated, and the obtained wet granules were dried in an oven at 45℃ until the moisture content was <1%, and then granulated again. The sieve aperture was 1.0 mm and the rotation speed was 600 rpm to obtain drug-containing granules.

[0082] (3) Preparation of blank particles: Mannitol, povidone, acesulfame potassium, sodium saccharin, sucrose stearate, dextrin, medium chain triglycerides and corn starch were mixed evenly, and 70% ethanol aqueous solution was added to make a soft material. The granules were then granulated, and the resulting wet particles were dried in an oven at 45°C until the moisture content was <1%. The particles were then sized with a sieve aperture of 1.0 mm and a rotation speed of 600 rpm to obtain blank particles.

[0083] (4) Mixing: Mix the medicated granules obtained in step (2), the blank granules obtained in step (3), and the fragrance and colloidal silica in the excipients to obtain granules.

[0084] Comparative Example 3

[0085] An oseltamivir phosphate granule formulation, comprising drug-containing granules, blank granules, and pharmaceutically acceptable excipients, is described below:

[0086]

[0087] The specific preparation method is as follows:

[0088] (1) Pretreatment: Oseltamivir phosphate and excipients (erythritol, povidone, acesulfame potassium, saccharin sodium, sucrose stearate, dextrin, medium chain triglycerides, corn starch, peach powder flavoring and colloidal silica) are passed through a 60-mesh sieve and set aside for later use;

[0089] (2) Preparation of drug-containing granules: Oseltamivir phosphate, erythritol and povidone were mixed evenly, purified water was added to make a soft material, granulated, and the obtained wet granules were dried in an oven at 45°C until the moisture content was <1%, and then granulated again. The sieve aperture was 1.0 mm and the rotation speed was 600 rpm to obtain drug-containing granules.

[0090] (3) Preparation of blank particles: Erythritol, povidone, acesulfame potassium, sodium saccharin, sucrose stearate, dextrin, medium chain triglycerides and corn starch were mixed evenly, purified water was added to make a soft material, granulated, and the obtained wet particles were dried in an oven at 45°C until the moisture content was <1%, and then granulated again. The sieve aperture was 1.0 mm and the rotation speed was 600 rpm to obtain blank particles.

[0091] (4) Mixing: Mix the medicated granules obtained in step (2), the blank granules obtained in step (3), and the fragrance and colloidal silica in the excipients to obtain granules.

[0092] Comparative Example 4

[0093] An oseltamivir phosphate granule formulation, comprising drug-containing granules, blank granules, and pharmaceutically acceptable excipients, is described below:

[0094]

[0095]

[0096] The specific preparation method is as follows:

[0097] (1) Pretreatment: Oseltamivir phosphate and excipients (erythritol, povidone, acesulfame potassium, saccharin sodium, sucrose stearate, dextrin, medium chain triglycerides, corn starch, peach powder flavoring and colloidal silica) are passed through a 60-mesh sieve and set aside for later use;

[0098] (2) Preparation of drug-containing granules: Oseltamivir phosphate, erythritol and povidone were mixed evenly, and 70% ethanol aqueous solution was added to make soft material, granulated, and the obtained wet granules were dried in an oven at 45℃ until the moisture content was <1%, and then granulated again. The sieve aperture was 1.0 mm and the rotation speed was 600 rpm to obtain drug-containing granules.

[0099] (3) Preparation of blank particles: Erythritol, povidone, acesulfame potassium, sodium saccharin, sucrose stearate, dextrin, medium chain triglycerides and corn starch were mixed evenly, and 70% ethanol aqueous solution was added to make a soft material. The material was granulated and the resulting wet particles were dried in an oven at 45°C until the moisture content was <1%. The particles were then sized with a sieve aperture of 1.0 mm and a rotation speed of 600 rpm to obtain blank particles.

[0100] (4) Mixing: Mix the medicated granules obtained in step (2), the blank granules obtained in step (3), and the fragrance and colloidal silica in the excipients to obtain granules.

[0101] Comparative Example 5

[0102] An oseltamivir phosphate granule formulation, comprising drug-containing granules, blank granules, and pharmaceutically acceptable excipients, is described below:

[0103]

[0104]

[0105] The specific preparation method is as follows:

[0106] (1) Pretreatment: Oseltamivir phosphate and excipients (erythritol, povidone, acesulfame potassium, saccharin sodium, sucrose stearate, dextrin, medium chain triglycerides, corn starch, peach powder flavoring and colloidal silica) are passed through a 60-mesh sieve and set aside for later use;

[0107] (2) Preparation of drug-containing granules: Oseltamivir phosphate, erythritol and povidone were mixed evenly, and 70% ethanol aqueous solution was added to make soft material, granulated, and the obtained wet granules were dried in an oven at 45℃ until the moisture content was <1%, and then granulated again. The sieve aperture was 1.0 mm and the rotation speed was 600 rpm to obtain drug-containing granules.

[0108] (3) Preparation of blank particles: Erythritol, povidone, acesulfame potassium, sodium saccharin, sucrose stearate, dextrin, medium chain triglycerides and corn starch were mixed evenly, and 70% ethanol aqueous solution was added to make a soft material. The material was granulated and the resulting wet particles were dried in an oven at 45°C until the moisture content was <1%. The particles were then sized with a sieve aperture of 1.0 mm and a rotation speed of 600 rpm to obtain blank particles.

[0109] (4) Mixing: Mix the medicated granules obtained in step (2), the blank granules obtained in step (3), and the fragrance and colloidal silica in the excipients to obtain granules.

[0110] Effect verification

[0111] 1. Stability investigation of the examples and comparative examples, the specific experimental results are shown in Tables 1-3.

[0112] Table 1. Stability test results

[0113]

[0114] Table 2 Stability test results

[0115]

[0116]

[0117] Table 3. Stability test results

[0118]

[0119] The samples in Examples 1-3 and Comparative Examples 1-6 were subjected to a 24-month stability study. The results showed that the impurity content in the samples of Examples 1-3 was low, and the increase in impurities after 24 months was not significant, indicating good stability.

[0120] In Comparative Example 1, the one-pot granulation method significantly increased the contact amount and contact area between oseltamivir phosphate and erythritol, resulting in poor sample stability. In Comparative Example 2, mannitol was replaced with erythritol, and the results showed that the stability of the sample was slightly worse after the replacement with mannitol, indicating that mannitol and erythritol have poor compatibility, which may be related to the presence of reducing sugars in mannitol. In Comparative Example 3, the granulation solvent was changed from 70% ethanol aqueous solution to purified water, and the sample stability was poor, which may be related to the moisture sensitivity of oseltamivir phosphate.

[0121] The amount of sucrose stearate in Comparative Example 4 was too low, and the amount of corn starch in Comparative Example 5 was too low, with a high content of impurities and poor stability.

[0122] 2. The mixing uniformity of the examples and comparative examples was investigated. The specific experimental results are shown in Table 4.

[0123] Table 4 Mixing Uniformity RSD

[0124] sample Mixing uniformity RSD% Example 1 1.31 Example 2 1.46 Example 3 1.27 Comparative Example 1 2.56 Comparative Example 2 1.87 Comparative Example 3 1.94 Comparative Example 4 2.61 Comparative Example 5 5.32

[0125] The RSD results of the mixing uniformity of the samples in Examples 1-3 and Comparative Examples 1-5 show that the RSD results of the mixing uniformity of the samples in Examples 1-3 are smaller, indicating that the mixing is more uniform.

[0126] The mixing uniformity RSD of Comparative Example 5 is greater than 5%, which may be related to the reduced amount of corn starch. As a dispersant, the reduced amount of corn starch leads to a poorer dispersion effect, thus affecting the mixing uniformity of the sample.

[0127] 3. The dispersibility and redispersibility, and dissolution rate of the examples and comparative examples were investigated. The specific experimental results are shown in Table 5.

[0128] Table 5. Investigation of Dispersion and Redispersion

[0129] sample Dispersion redistribution Dissolution Example 1 Disperse evenly within 15 seconds 3 times 15min ≥ 85% Example 2 Disperse evenly within 15 seconds 3 times 15min ≥ 85% Example 3 Disperse evenly within 15 seconds 3 times 15min ≥ 85% Comparative Example 1 Disperse evenly within 15 seconds 3 times 15min ≥ 85% Comparative Example 2 Disperse evenly within 15 seconds 3 times 15min ≥ 85% Comparative Example 3 Disperse evenly within 15 seconds 3 times 15min ≥ 85% Comparative Example 4 Disperse evenly within 30 seconds 5 times 15min ≥ 85% Comparative Example 5 Disperse evenly within 30 seconds 6 times 15min ≥ 85%

[0130] The samples in Examples 1-3 and Comparative Examples 1-3 showed good dispersibility and redispersibility, indicating that oseltamivir phosphate granules are easily dispersed and redispersed when added to water during use. However, the samples in Comparative Examples 4 and 5 showed poor dispersibility and redispersibility, which is related to the reduced amount of sucrose stearate and corn starch. Sucrose stearate acts as a solubilizer, and corn starch acts as a dispersant. When oseltamivir phosphate granules are taken with water, they can increase the dispersibility and redispersibility of the samples. Therefore, reducing the amount of both will lead to poor dispersibility and redispersibility of the samples, resulting in a worse user experience.

[0131] Dissolution rate: The dissolution rate of the samples in Examples 1-3 and Comparative Examples 1-5 was relatively fast, all ≥85% at 15 min, which is considered rapid dissolution.

[0132] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A oseltamivir phosphate granule, characterized in that, The granule is made from a mixture of medicated granules, blank granules, and pharmaceutically acceptable excipients. The medicated granules are made from oseltamivir phosphate, erythritol, and povidone. The blank granules are made from erythritol, povidone, acesulfame potassium, sodium saccharin, sucrose stearate, dextrin, medium-chain triglycerides, and corn starch. The pharmaceutically acceptable excipients are flavorings and colloidal silica.

2. The oseltamivir phosphate granules according to claim 1, characterized in that, The medicated granules are made from the following components in parts by weight: 10-15 parts oseltamivir phosphate, 80-150 parts erythritol, and 1-5 parts povidone; preferably, 12 parts oseltamivir phosphate, 90-140 parts erythritol, and 2-4 parts povidone; more preferably, 12 parts oseltamivir phosphate, 98-135 parts erythritol, and 3 parts povidone.

3. The oseltamivir phosphate granules according to claim 2, characterized in that, The weight ratio of oseltamivir phosphate to erythritol in the blank granules is 0.02-0.18:1, preferably 0.05-0.12:1, and more preferably 0.07-0.09:1; the weight ratio of oseltamivir phosphate to povidone in the blank granules is 1-8:1, preferably 3-5:1, and more preferably 4:1; the weight ratio of oseltamivir phosphate to acesulfame potassium in the blank granules is 20-60:1, preferably 30-50:1, and more preferably 40:1; the weight ratio of oseltamivir phosphate to sodium saccharin in the blank granules is 20-60:1, preferably 30-50:1, and more preferably 40:

1. The weight ratio of oseltamivir phosphate to sucrose stearate in the blank granules is 20-60:1, preferably 30-50:1, and more preferably 40:1; the weight ratio of oseltamivir phosphate to dextrin in the blank granules is 10-20:1, preferably 12-18:1, and more preferably 15:1; the weight ratio of oseltamivir phosphate to medium-chain triglycerides in the blank granules is 10-20:1, preferably 12-18:1, and more preferably 15:1; the weight ratio of oseltamivir phosphate to corn starch in the blank granules is 0.8-1.8:1, preferably 1.0-1.5:1, and more preferably 1.2:

1.

4. The oseltamivir phosphate granules according to claim 3, characterized in that, The weight ratio of oseltamivir phosphate to the fragrance in the excipients is 5-15:1, preferably 6-10:1, and more preferably 8:1; the fragrance is peach powder fragrance; the weight ratio of oseltamivir phosphate to colloidal silica in the excipients is 20-60:1, preferably 30-50:1, and more preferably 40:

1.

5. The oseltamivir phosphate granules according to claim 4, characterized in that, The medicated granules are made from the following components in parts by weight: 12 parts oseltamivir phosphate, 90-140 parts erythritol, and 2-4 parts povidone; wherein the weight ratio of oseltamivir phosphate to erythritol in the blank granules is 0.05-0.12:1; the weight ratio of oseltamivir phosphate to povidone in the blank granules is 3-5:1; the weight ratio of oseltamivir phosphate to acesulfame potassium in the blank granules is 30-50:1; the weight ratio of oseltamivir phosphate to sodium saccharin in the blank granules is 30-50:1; the weight ratio of oseltamivir phosphate to sodium saccharin in the blank granules is 30-50:

1. The weight ratio of oseltamivir phosphate to sucrose stearate in the blank particles is 30-50:1; the weight ratio of oseltamivir phosphate to dextrin in the blank particles is 12-18:1; the weight ratio of oseltamivir phosphate to medium-chain triglycerides in the blank particles is 12-18:1; the weight ratio of oseltamivir phosphate to medium-chain triglycerides in the blank particles is 1.0-1.5:1; the weight ratio of oseltamivir phosphate to peach powder flavoring in the excipients is 6-10:1; and the weight ratio of oseltamivir phosphate to colloidal silica in the excipients is 30-50:

1.

6. The oseltamivir phosphate granules according to claim 5, characterized in that, The medicated granules are made from the following components in parts by weight: 12 parts oseltamivir phosphate, 98-135 parts erythritol, and 3 parts povidone; wherein the weight ratio of oseltamivir phosphate to erythritol in the blank granules is 0.07-0.09:1; the weight ratio of oseltamivir phosphate to povidone in the blank granules is 4:1; the weight ratio of oseltamivir phosphate to acesulfame potassium in the blank granules is 40:1; and the weight ratio of oseltamivir phosphate to sodium saccharin in the blank granules is 40:

1. The weight ratio of oseltamivir phosphate to sucrose stearate in the blank granules is 40:1; the weight ratio of oseltamivir phosphate to dextrin in the blank granules is 15:1; the weight ratio of oseltamivir phosphate to medium-chain triglycerides in the blank granules is 15:1; the weight ratio of oseltamivir phosphate to corn starch in the blank granules is 1.2:1; the weight ratio of oseltamivir phosphate to peach powder flavoring in the excipients is 8:1; and the weight ratio of oseltamivir phosphate to colloidal silica in the excipients is 40:

1.

7. The method for preparing oseltamivir phosphate granules according to claim 1, characterized in that, Includes the following steps: (1) Pretreatment: Sieve oseltamivir phosphate and excipients and set aside for later use; (2) Preparation of drug-containing granules: Oseltamivir phosphate, erythritol and povidone are mixed evenly, and an ethanol aqueous solution is added to make a soft material, which is then granulated. The wet granules are dried and granulated to obtain drug-containing granules. (3) Preparation of blank particles: Erythritol, povidone, acesulfame potassium, sodium saccharin, sucrose stearate, dextrin, medium chain triglycerides and corn starch are mixed evenly, and an ethanol aqueous solution is added to make a soft material, which is then granulated. The obtained wet particles are dried and granulated to obtain blank particles. (4) Mixing: Mix the medicated granules obtained in step (2), the blank granules obtained in step (3), and the fragrance and colloidal silica in the excipients to obtain granules.

8. The method for preparing oseltamivir phosphate granules according to claim 7, characterized in that, In step (1), the sample is passed through a 40-80 mesh sieve, preferably a 60 mesh sieve.

9. The method for preparing oseltamivir phosphate granules according to claim 7, characterized in that, In step (2), the volume content of the ethanol aqueous solution is 60%-80%, preferably 70%; the drying temperature is 40-50℃, and the ethanol is dried until the moisture content is <1%, preferably 45℃; during granulation, the sieve aperture is 0.8mm-1.2mm, preferably 1.0mm, and the rotation speed is 300-1000rpm, preferably 600rpm.

10. The method for preparing oseltamivir phosphate granules according to claim 7, characterized in that, In step (3), the volume content of the ethanol aqueous solution is 60%-80%, preferably 70%; the drying temperature is 40-50℃, and the water content is dried to <1%, preferably 45℃; during granulation, the sieve aperture is 0.8mm-1.2mm, preferably 1.0mm, and the rotation speed is 300-1000rpm, preferably 600rpm.

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