A microcapsule of oseltamivir or a pharmaceutically acceptable salt thereof and a method for preparing the same

Abstract

The present application relates to a kind of microcapsules of oseltamivir or its pharmaceutically acceptable salt and its preparation method, belong to the field of pharmaceutical preparations.The preparation method includes drying using centrifugal spray dryer, and using process parameters such as atomizer frequency 25Hz-50Hz, the microcapsule particle prepared using the preparation method is uniform, taste masking is good, yield is high, and stability is good.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and more particularly to a microcapsule of oseltamivir or a pharmaceutically acceptable salt thereof, and a method for preparing the same. Background Technology

[0002] Oseltamivir phosphate, chemically named (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester phosphate, has the following chemical structural formula:

[0003]

[0004] Oseltamivir phosphate has a strong inhibitory activity against neuraminidase and is effective against both influenza A and B viruses.

[0005] Oseltamivir phosphate is a drug with an extremely bitter taste, and currently available dosage forms include granules, capsules, and dry suspensions. Current methods for masking the taste of oseltamivir phosphate include coating, adding flavoring agents, or encapsulation. Although there are no microcapsules for oseltamivir phosphate in current technology, microencapsulation could also be used as a method of masking the taste.

[0006] CN104622825A discloses an azithromycin dispersible tablet, and discloses a method for microencapsulating azithromycin with a weight ratio of 1:0.2-0.4 to a water-insoluble polymer to mask the taste.

[0007] CN109156606A discloses a method for preparing microcapsules using a centrifugal spray dryer, wherein the inlet air temperature is 100℃~120℃, the atomization pressure is 0.2MPa~0.5MPa, the peristaltic pump speed for conveying the spray mixture is 10r / min~20r / min, and the outlet air temperature is 60℃~75℃.

[0008] However, the inventors discovered that the oseltamivir phosphate microcapsules prepared using the weight ratio described in CN104622825A have disadvantages such as poor taste masking, slow release rate, and poor stability; the oseltamivir phosphate microcapsules prepared using the method described in CN109156606A have disadvantages such as easy agglomeration or blocky shape, unevenness, low yield, and poor stability.

[0009] Therefore, it is still necessary to study oseltamivir phosphate microcapsules with good taste masking performance, rapid release, high yield, and good stability, as well as their preparation method. Summary of the Invention Invention Overview

[0011] One object of the present invention is to provide a method for preparing microcapsules of oseltamivir or its pharmaceutically acceptable salts, the method comprising drying using a centrifugal spray dryer with an atomizer frequency of 25Hz-50Hz. The microcapsule particles prepared by this method are uniform, have good taste masking properties, high yield, and good stability, thus solving the problems of easy agglomeration or blocky formation, unevenness, low yield, poor taste masking properties, and poor stability in the preparation of microcapsules of oseltamivir or its pharmaceutically acceptable salts.

[0012] Another object of the present invention is to provide microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof, wherein the microcapsules are prepared by the above-described preparation method and include oseltamivir or a pharmaceutically acceptable salt thereof, a capsule material and optionally a pore-forming agent. The microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof have good taste masking properties, fast release rate and good stability, thereby solving the problems of poor taste masking properties, slow release rate and poor stability of microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof. Invention Details

[0014] In a first aspect, the present invention provides a method for preparing microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof.

[0015] A method for preparing microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0016] (1) Dissolve oseltamivir or a pharmaceutically acceptable salt thereof in water to obtain a first solution;

[0017] (2) Dissolve the capsule material and the pore-forming agent in a solvent to obtain a second solution;

[0018] (3) Mix the first solution and the second solution to obtain an emulsion;

[0019] (4) The emulsion described in step (3) is dried using a centrifugal spray dryer to obtain microcapsules of oseltamivir or its pharmaceutically acceptable salts; the atomizer frequency of the centrifugal spray dryer is 25Hz-50Hz; the microcapsules of oseltamivir or its pharmaceutically acceptable salts prepared using a centrifugal spray dryer and an atomizer frequency of 25Hz-50Hz are uniform and have a high yield. In the prior art, such as the study on spray drying conditions of microencapsulated cantharidin microparticles by Luo Chaojie et al. (China Food Additives, No. 12, 2016, 127-132), the lower the atomizer frequency, the easier it is to stick to the tower or cause moisture powder, which will result in a low product yield. However, this may be due to the difference in components and their content. The present invention is completely opposite to the theory of the prior art. At a lower atomizer frequency of 25Hz-35Hz, the microcapsules obtained are very uniform, while the microcapsules obtained at frequencies above 50Hz are more sticky. In some preferred embodiments, the atomizer frequency of the centrifugal spray dryer is 25Hz-35Hz, resulting in a high microcapsule yield, uniform particle size, thorough drying, and no sticking. In some more preferred embodiments, the atomizer frequency of the centrifugal spray dryer is 35Hz, resulting in an even higher microcapsule yield, uniform particle size, thorough drying, and no sticking.

[0020] The pharmaceutically acceptable salt may be a phosphate, hydrochloride, hydrobromide, sulfate, acetate, citrate, lactate, ascorbate, maleate, tartrate, malate, or succinate. In some embodiments, the pharmaceutically acceptable salt is a phosphate.

[0021] The centrifugal spray dryer operates at a pump speed of 20-40 rpm. Microcapsules of oseltamivir or its pharmaceutically acceptable salts prepared at this pump speed are uniform and do not clump. Higher pump speeds increase the amount of solvent processed per unit time, reducing atomization and preventing localized drying that leads to semi-dry particles and adhesion. However, excessively high pump speeds can result in insufficient drying, clumping, and low yield. In some preferred embodiments, the pump speed is 25-40 rpm. In some embodiments, the pump speed is 25-35 rpm. In some embodiments, the pump speed is 25-30 rpm. In some embodiments, the pump speed is 30-40 rpm. In some embodiments, the pump speed is 35-40 rpm. In some more preferred embodiments, the pump speed is 30 rpm. Microcapsules of oseltamivir or its pharmaceutically acceptable salts prepared at this pump speed are uniform, do not clump, and have a high yield.

[0022] The centrifugal spray dryer operates at a fan frequency of 25Hz-50Hz. Using this frequency range ensures sufficient heat supply per unit time, rapid heat exchange, timely drying, and prevents clumping or agglomeration. Furthermore, the fan power does not exceed the weight of the microcapsules, preventing them from being carried away from the collector, resulting in a high yield. In some embodiments, the centrifugal spray dryer operates at a fan frequency of 30Hz-45Hz. In some preferred embodiments, the fan frequency is 30Hz-35Hz. In some even more preferred embodiments, the centrifugal spray dryer operates at a fan frequency of 30Hz. Microcapsules of oseltamivir or its pharmaceutically acceptable salts prepared using this frequency are uniform, do not clump, and have a high yield.

[0023] The inlet air temperature of the centrifugal spray dryer is 70℃-110℃. Within this range, the heat is sufficient to dry the solvent per unit time, preventing product adhesion and irregular clumping. Simultaneously, the suitable temperature avoids excessive solvent evaporation, particle shrinkage, and subsequent removal from the collector, leading to reduced yield and other drawbacks. In some preferred embodiments, the inlet air temperature of the centrifugal spray dryer is 90℃-110℃. Within this range, the prepared microcapsule particles are uniform, resulting in a high yield. In some more preferred embodiments, the inlet air temperature of the centrifugal spray dryer is 90℃. Using this inlet air temperature results in uniform microcapsule particles and an even higher yield.

[0024] The outlet air temperature of the centrifugal spray dryer is 40℃-70℃. Within this range, the heat is sufficient to dry the solvent per unit time, preventing product adhesion and irregular clumping. Simultaneously, the suitable temperature avoids excessive solvent evaporation, particle shrinkage, and subsequent removal from the collector, leading to reduced yield and other drawbacks. In some preferred embodiments, the outlet air temperature of the centrifugal spray dryer is 45℃-65℃. In some more preferred embodiments, the outlet air temperature is 50℃-60℃. In some most preferred embodiments, the outlet air temperature is 55℃. Using this inlet air temperature results in uniform microcapsule particles and a higher yield.

[0025] The solid content of the emulsion, based on its total weight, is 10.00 wt% to 25.00 wt%. Using this range of solid content results in high microcapsule yields, uniform size, and moderate particle size. In some embodiments, the solid content of the emulsion is 12.00 wt% to 20.00 wt%. In some embodiments, the solid content of the emulsion is 15.00 wt% to 19.00 wt%. In some preferred embodiments, the solid content of the emulsion is 17.00 wt% to 19.00 wt%, which results in a higher microcapsule yield. In some more preferred embodiments, the solid content of the emulsion is 18.55 wt%, which results in an even higher microcapsule yield.

[0026] The solvent includes at least one selected from ethyl acetate, acetone, methanol, and ethanol. In some preferred embodiments, the solvent is ethyl acetate. Using ethyl acetate as a solvent is beneficial for the dissolution of the encapsulation material in the solvent and the formation of microcapsules. Ethyl cellulose dissolves quickly in ethyl acetate, and the ethyl acetate solution of ethyl cellulose can form an emulsion with the first solution without agglomerating or dissolving into one phase.

[0027] The encapsulation material includes at least one selected from ethyl cellulose, Eutectic L100-55, HPMCAS-L, HPMCP HP-55, PLGA, and gelatin. In some preferred embodiments, the encapsulation material is ethyl cellulose. Microcapsules prepared using ethyl cellulose as the encapsulation material have high yields, good taste masking properties, and especially good impurity stability.

[0028] The weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:0.5-1.0:2.0. Using this weight ratio range results in a high microcapsule yield, all greater than 80%. In some embodiments, the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:0.6-1.0:2.0. In some embodiments, the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:0.6-1.0:1.0. In some embodiments, the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:1.0-1.0:2.0. Within this weight ratio range, oseltamivir or its pharmaceutically acceptable salt and the encapsulation material can form microcapsules with good taste masking properties. In some embodiments, the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:1.0-1.0:1.5. In some embodiments, the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:1.5-1.0:2.0. In some preferred embodiments, the weight ratio of oseltamivir phosphate to the encapsulation material is 1.0:0.8-1.0:1.2. In some more preferred embodiments, the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:0.9-1.0:1.1. In some even more preferred embodiments, the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:1.0. Using this weight ratio results in high microcapsule yield, good taste masking, and high dissolution.

[0029] The porogen includes at least one selected from polyethylene glycol 4000, polyethylene glycol 2000, polyethylene glycol 1000, polyethylene glycol 800, and polyethylene glycol 400. Microcapsules prepared using this porogen have a fast dissolution rate, with a dissolution rate exceeding 79% within 5 minutes. In some embodiments, the porogen is polyethylene glycol 1000 or mannitol. Microcapsules prepared using polyethylene glycol 1000 or mannitol as the porogen have a fast dissolution rate and good taste masking properties. In some embodiments, the porogen is polyethylene glycol 1000. Microcapsules prepared using polyethylene glycol 1000 as the porogen have good taste masking properties, a fast dissolution rate, and a high yield.

[0030] The porogen content, based on the total weight of the microcapsules, is 0.25 wt% to 10.00 wt%. In some embodiments, the porogen content, based on the total weight of the microcapsules, is 0.25 wt% to 2.00 wt%, resulting in microcapsules with good taste masking and high yield. In some embodiments, the porogen content, based on the total weight of the microcapsules, is 2.00 wt% to 4.00 wt%, resulting in microcapsules with fast dissolution. In some embodiments, the porogen content, based on the total weight of the microcapsules, is 4.00 wt% to 6.00 wt%, resulting in microcapsules with fast dissolution. In some embodiments, the porogen content, based on the total weight of the microcapsules, is 6.00 wt% to 8.00 wt%, resulting in microcapsules with fast dissolution. In some embodiments, the porogen content is 8.00 wt%-10.00 wt% based on the total weight of the microcapsules, resulting in microcapsules with a rapid dissolution rate. In some preferred embodiments, the porogen content is 1.80 wt%-2.20 wt% based on the total weight of the microcapsules, resulting in microcapsules with a rapid dissolution rate and good taste masking properties.

[0031] According to some embodiments of the present invention, a method for preparing microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof includes the following steps:

[0032] (1) Dissolve oseltamivir or a pharmaceutically acceptable salt thereof in water to obtain a first solution;

[0033] (2) Dissolve the capsule material and the pore-forming agent in a solvent to obtain a second solution;

[0034] (3) Mix the first solution and the second solution to obtain an emulsion;

[0035] (4) The emulsion described in step (3) is dried using a centrifugal spray dryer to obtain microcapsules of oseltamivir or its pharmaceutically acceptable salts; the pump speed of the centrifugal spray dryer is 30 rpm.

[0036] According to some embodiments of the present invention, a method for preparing microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof includes the following steps:

[0037] (1) Dissolve oseltamivir or a pharmaceutically acceptable salt thereof in water to obtain a first solution;

[0038] (2) Dissolve the capsule material and the pore-forming agent in a solvent to obtain a second solution;

[0039] (3) Mix the first solution and the second solution to obtain an emulsion;

[0040] (4) The emulsion described in step (3) is dried using a centrifugal spray dryer to obtain microcapsules of oseltamivir or its pharmaceutically acceptable salts; the pump speed of the centrifugal spray dryer is 30 rpm; the fan frequency of the centrifugal spray dryer is 35 Hz.

[0041] According to some embodiments of the present invention, a method for preparing microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof includes the following steps:

[0042] (1) Dissolve oseltamivir or a pharmaceutically acceptable salt thereof in water to obtain a first solution;

[0043] (2) Dissolve the capsule material and the pore-forming agent in a solvent to obtain a second solution;

[0044] (3) Mix the first solution and the second solution to obtain an emulsion;

[0045] (4) The emulsion described in step (3) is dried using a centrifugal spray dryer to obtain microcapsules of oseltamivir or its pharmaceutically acceptable salts; the pump speed of the centrifugal spray dryer is 30 rpm; the fan frequency of the centrifugal spray dryer is 35 Hz; the inlet air temperature of the centrifugal spray dryer is 90 ℃; and the outlet air temperature of the centrifugal spray dryer is 55 ℃.

[0046] According to some preferred embodiments of the present invention, a method for preparing microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof includes the following steps:

[0047] (1) Dissolve oseltamivir or a pharmaceutically acceptable salt thereof in water to obtain a first solution;

[0048] (2) Dissolve the capsule material and the pore-forming agent in a solvent to obtain a second solution;

[0049] (3) Mix the first solution and the second solution to obtain an emulsion;

[0050] (4) The emulsion obtained in step (3) is dried using a centrifugal spray dryer to obtain microcapsules of oseltamivir or its pharmaceutically acceptable salts; the pump speed of the centrifugal spray dryer is 30 rpm; the fan frequency of the centrifugal spray dryer is 35 Hz; the inlet air temperature of the centrifugal spray dryer is 90 ℃; the outlet air temperature of the centrifugal spray dryer is 55 ℃; the solid content of the emulsion is 17.00 wt%-19.00 wt% based on the total weight of the emulsion; the solvent is ethyl acetate; the microcapsule particles prepared by this method are uniform, have a higher yield, and good stability.

[0051] According to some preferred embodiments of the present invention, a method for preparing microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof includes the following steps:

[0052] (1) Dissolve oseltamivir or a pharmaceutically acceptable salt thereof in water to obtain a first solution;

[0053] (2) Dissolve the capsule material and the pore-forming agent in a solvent to obtain a second solution;

[0054] (3) Mix the first solution and the second solution to obtain an emulsion;

[0055] (4) The emulsion described in step (3) is dried using a centrifugal spray dryer to obtain microcapsules of oseltamivir or its pharmaceutically acceptable salts; the pump speed of the centrifugal spray dryer is 30 rpm; the capsule material includes ethyl cellulose. Oseltamivir microcapsules prepared in this way have uniform particles, high yield, good taste masking properties, and good impurity stability.

[0056] According to some preferred embodiments of the present invention, a method for preparing microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof includes the following steps:

[0057] (1) Dissolve oseltamivir or a pharmaceutically acceptable salt thereof in water to obtain a first solution;

[0058] (2) Dissolve the capsule material and the pore-forming agent in a solvent to obtain a second solution;

[0059] (3) Mix the first solution and the second solution to obtain an emulsion;

[0060] (4) The emulsion described in step (3) is dried using a centrifugal spray dryer to obtain microcapsules of oseltamivir or its pharmaceutically acceptable salts; the pump speed of the centrifugal spray dryer is 30 rpm; the pore-forming agent is polyethylene glycol 1000. The oseltamivir microcapsules prepared by this method have uniform particles, high yield, good taste masking properties, and good impurity stability.

[0061] According to some preferred embodiments of the present invention, a method for preparing microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof includes the following steps:

[0062] (1) Dissolve oseltamivir or a pharmaceutically acceptable salt thereof in water to obtain a first solution;

[0063] (2) Dissolve the capsule material and the pore-forming agent in a solvent to obtain a second solution;

[0064] (3) Mix the first solution and the second solution to obtain an emulsion;

[0065] (4) The emulsion obtained in step (3) is dried using a centrifugal spray dryer to obtain microcapsules of oseltamivir or its pharmaceutically acceptable salts; the pump speed of the centrifugal spray dryer is 30 rpm; the capsule material is ethyl cellulose; the pore-forming agent is polyethylene glycol 1000; the weight ratio of oseltamivir or its pharmaceutically acceptable salts to the capsule material is 1.0:1.0, and the content of the pore-forming agent is 1.80 wt%-2.20 wt% based on the total weight of the microcapsules. The microcapsules of oseltamivir or its pharmaceutically acceptable salts prepared in this way have uniform particles, fast dissolution rate, good taste masking properties, high yield, and good impurity stability.

[0066] According to some preferred embodiments of the present invention, a method for preparing microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof includes the following steps:

[0067] (1) Dissolve oseltamivir or a pharmaceutically acceptable salt thereof in water to obtain a first solution;

[0068] (2) Dissolve the capsule material and the pore-forming agent in a solvent to obtain a second solution;

[0069] (3) Mix the first solution and the second solution to obtain an emulsion;

[0070] (4) The emulsion obtained in step (3) is dried using a centrifugal spray dryer to obtain microcapsules of oseltamivir or its pharmaceutically acceptable salts; the pump speed of the centrifugal spray dryer is 30 rpm; the fan frequency of the centrifugal spray dryer is 35 Hz; the inlet air temperature of the centrifugal spray dryer is 90°C; the outlet air temperature of the centrifugal spray dryer is 55°C; and the solid content of the emulsion is 17.00 wt%-19% based on the total weight of the emulsion. The solvent is ethyl acetate; the capsule material is ethyl cellulose; the pore-forming agent is polyethylene glycol 1000; the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the capsule material is 1.0:1.0, and the content of the pore-forming agent is 1.80wt%-2.20wt% based on the total weight of the microcapsules. Microcapsules of oseltamivir or its pharmaceutically acceptable salt prepared in this manner have uniform particle size, fast dissolution rate, good taste masking properties, high yield, and good impurity stability.

[0071] Secondly, the present invention provides microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof prepared according to the preparation method described in the first aspect; the microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof have good taste masking properties, fast release rate, and good stability, thus solving the problems of poor taste masking properties, slow release rate, and poor stability of oseltamivir microcapsules.

[0072] Thirdly, the present invention provides microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof.

[0073] A microcapsule of oseltamivir or a pharmaceutically acceptable salt thereof, comprising: oseltamivir or a pharmaceutically acceptable salt thereof, a capsule material, and a pore-forming agent.

[0074] The encapsulation material includes at least one selected from ethyl cellulose, Eutectic L100-55, HPMCAS-L, HPMCP HP-55, PLGA, and gelatin. In some preferred embodiments, the encapsulation material is ethyl cellulose. Microcapsules prepared using ethyl cellulose as the encapsulation material have high yields, good taste masking properties, and especially good impurity stability.

[0075] The porogen includes at least one selected from polyethylene glycol 4000, polyethylene glycol 2000, polyethylene glycol 1000, polyethylene glycol 800, and polyethylene glycol 400. Microcapsules prepared using this porogen have a fast dissolution rate, with a dissolution rate exceeding 79% within 5 minutes. In some embodiments, the porogen is polyethylene glycol 1000 or mannitol. Microcapsules prepared using polyethylene glycol 1000 or mannitol as the porogen have a fast dissolution rate and good taste masking properties. In some embodiments, the porogen is polyethylene glycol 1000. Microcapsules prepared using polyethylene glycol 1000 as the porogen have good taste masking properties, a fast dissolution rate, and a high yield.

[0076] The weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:0.5-1.0:2.0. Using this weight ratio range results in high microcapsule yields, all greater than 80%. In some embodiments, the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:0.6-1.0:2.0. In some embodiments, the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:0.6-1.0:1.0. In some embodiments, the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:1.0-1.0:2.0. Within this weight ratio range, oseltamivir or its pharmaceutically acceptable salt and the encapsulation material can form microcapsules with good taste masking properties. In some embodiments, the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:1.0-1.0:1.5. In some embodiments, the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:1.5-1.0:2.0. In some preferred embodiments, the weight ratio of oseltamivir phosphate to the encapsulation material is 1.0:0.8-1.0:1.2. In some more preferred embodiments, the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:0.9-1.0:1.1. In some even more preferred embodiments, the weight ratio of oseltamivir or its pharmaceutically acceptable salt to the encapsulation material is 1.0:1.0. Using this weight ratio, the resulting microcapsules have a high yield and good taste masking properties.

[0077] The porogen content, based on the total weight of the microcapsules, is 0.25 wt% to 10.00 wt%. In some embodiments, the porogen content, based on the total weight of the microcapsules, is 0.25 wt% to 2.00 wt%, resulting in microcapsules with good taste masking and high yield. In some embodiments, the porogen content, based on the total weight of the microcapsules, is 2.00 wt% to 4.00 wt%, resulting in microcapsules with fast dissolution. In some embodiments, the porogen content, based on the total weight of the microcapsules, is 4.00 wt% to 6.00 wt%, resulting in microcapsules with fast dissolution. In some embodiments, the porogen content, based on the total weight of the microcapsules, is 6.00 wt% to 8.00 wt%, resulting in microcapsules with fast dissolution. In some embodiments, the porogen content is 8.00 wt%-10.00 wt% based on the total weight of the microcapsules, resulting in microcapsules with a rapid dissolution rate. In some preferred embodiments, the porogen content is 1.80 wt%-2.20 wt% based on the total weight of the microcapsules, resulting in microcapsules with a rapid dissolution rate and good taste masking properties.

[0078] The content of oseltamivir or a pharmaceutically acceptable salt thereof, based on the total weight of the microcapsules, is 30 wt% to 66.5 wt%. In some embodiments, the content of oseltamivir or a pharmaceutically acceptable salt thereof, based on the total weight of the microcapsules, is 35 wt% to 60 wt%. In some embodiments, the content of oseltamivir or a pharmaceutically acceptable salt thereof, based on the total weight of the microcapsules, is 40 wt% to 55 wt%. In some embodiments, the content of oseltamivir or a pharmaceutically acceptable salt thereof, based on the total weight of the microcapsules, is 45 wt% to 55 wt%. In some embodiments, the content of oseltamivir or a pharmaceutically acceptable salt thereof, based on the total weight of the microcapsules, is 48 wt% to 52 wt%.

[0079] In some embodiments, a microcapsule of oseltamivir or a pharmaceutically acceptable salt thereof comprises: oseltamivir or a pharmaceutically acceptable salt thereof, a capsule material, and a pore-forming agent, wherein the capsule material is ethyl cellulose; the pore-forming agent is polyethylene glycol 1000; the weight ratio of oseltamivir or a pharmaceutically acceptable salt thereof to the capsule material is 1.0:0.5-1.0:2.0 based on the total weight of the microcapsules; the content of the pore-forming agent is 0.25wt%-10.00wt%; and the content of oseltamivir or a pharmaceutically acceptable salt thereof is 30wt%-66.5wt%.

[0080] The pharmaceutically acceptable salt may be a phosphate, hydrochloride, hydrobromide, sulfate, acetate, citrate, lactate, ascorbate, maleate, tartrate, malate, or succinate. In some embodiments, the pharmaceutically acceptable salt is a phosphate.

[0081] Beneficial effects

[0082] Compared with the prior art, one of the technical solutions of the present invention has at least one of the following beneficial effects:

[0083] (1) Microcapsules of oseltamivir or its pharmaceutically acceptable salts prepared by centrifugal spray dryer and nebulizer frequency of 25Hz-50Hz are uniform and have a high yield. Microcapsules obtained at a lower nebulizer frequency of 25Hz-35Hz are very uniform, while microcapsules obtained at frequencies above 50Hz are more viscous.

[0084] (2) Furthermore, the atomizer frequency of the centrifugal spray dryer of the present invention is 25Hz-35Hz, resulting in high microcapsule yield, uniform particles, thorough drying and no sticking.

[0085] (3) Furthermore, the atomizer frequency of the centrifugal spray dryer is 35Hz, resulting in a higher yield of microcapsules, uniform particle size, thorough drying, and no sticking.

[0086] (4) This invention discloses a centrifugal spray dryer with a pump speed of 20-40 rpm. Microcapsules of oseltamivir or its pharmaceutically acceptable salts prepared using this pump speed are uniform and do not clump. Preferably, the pump speed is 25-40 rpm, resulting in uniform, non-clumping microcapsules of oseltamivir or its pharmaceutically acceptable salts prepared at this speed, with a high yield. More preferably, the pump speed is 30 rpm, resulting in uniform, non-clumping microcapsules of oseltamivir or its pharmaceutically acceptable salts prepared at this speed, with an even higher yield.

[0087] (5) The fan frequency of the centrifugal spray dryer is 25Hz-50Hz. Using this fan frequency range ensures sufficient heat supply per unit time, rapid heat exchange, timely drying, and prevents clumping or agglomeration. Furthermore, the fan power does not exceed the weight of the microcapsules, preventing them from being carried away from the collector. Preferably, the fan frequency of the centrifugal spray dryer is 30Hz-35Hz. Oseltamivir microcapsule particles prepared using this fan frequency are uniform, do not agglomerate, and have a high yield. More preferably, the fan frequency of the centrifugal spray dryer is 30Hz. Oseltamivir microcapsule particles prepared using this fan frequency are uniform, do not agglomerate, and have an even higher yield.

[0088] (6) The inlet air temperature of the centrifugal spray dryer is 70℃-110℃. Within this range, the heat per unit time is sufficient to dry the solvent, preventing product adhesion and irregular clumping. Simultaneously, the suitable temperature prevents excessive solvent evaporation, particle shrinkage, and subsequent removal from the collector, leading to reduced yield and other disadvantages. The preferred inlet air temperature of the centrifugal spray dryer is 90℃-110℃. Within this range, the prepared microcapsule particles are uniform, resulting in a high yield. A more preferred inlet air temperature is 90℃, as this temperature yields even more uniform microcapsule particles and a higher yield.

[0089] (7) The outlet air temperature of the centrifugal spray dryer is 40℃-70℃. Within this range, the heat per unit time is sufficient to dry the solvent, preventing product adhesion and irregular clumps. Simultaneously, the suitable temperature prevents excessive solvent evaporation, particle shrinkage, and subsequent removal from the collector, leading to reduced yield and other disadvantages. The preferred outlet air temperature of the centrifugal spray dryer is 45℃-65℃. A more preferred outlet air temperature is 50℃-60℃. The most preferred outlet air temperature is 55℃. Using this temperature results in uniform microcapsule particles and a higher yield.

[0090] (8) The solid content of the emulsion, based on its total weight, is 10.00 wt%-25.00 wt%. Using this range of solid content results in a high yield, uniform size, and suitable particle size of the microcapsules. Preferably, the solid content of the emulsion is 17.00 wt%-19.00 wt%, which yields a relatively high microcapsule yield. More preferably, the solid content of the emulsion is 18.55 wt%, which yields an even higher microcapsule yield.

[0091] (9) The pump speed of the centrifugal spray dryer is 30 rpm, the fan frequency is 35 Hz, the inlet air temperature is 90 ℃, and the outlet air temperature is 55 ℃. The solid content of the emulsion is 17.00 wt%-19.00 wt% based on the total weight of the emulsion. This makes the process parameters work together to produce uniform microcapsules that do not clump together. Compared with process parameters outside this range, the yield is higher.

[0092] (10) In the preparation method described in this invention, ethyl acetate is preferred as the solvent. Using ethyl acetate as the solvent is beneficial to the dissolution of the capsule material in the solvent and the formation of microcapsules. Ethyl cellulose dissolves quickly in ethyl acetate, and the ethyl acetate solution of ethyl cellulose can form an emulsion with the first solution without agglomerating or dissolving into one phase.

[0093] (11) In this invention, ethyl cellulose is preferably used as the capsule material. Microcapsules prepared using ethyl cellulose as the capsule material have high yield, good taste masking properties, and especially good impurity stability.

[0094] (12) Based on the total weight of the microcapsules, the content of the porogen in the preparation method of the present invention is 0.25wt%-2.00wt%. Microcapsules prepared with porogens in this content range have good taste masking properties and high yield. The content of the porogen is preferably 1.80wt%-2.20wt%. Microcapsules prepared with porogens in this content have fast dissolution rate and good taste masking properties. The porogen is preferably polyethylene glycol 1000. Microcapsules prepared with polyethylene glycol 1000 as the porogen have good taste masking properties, fast dissolution rate, and high yield.

[0095] (13) The preferred formulation of the present invention uses ethyl cellulose as the capsule material and polyethylene glycol 1000 as the pore-forming agent. The weight ratio of oseltamivir or its pharmaceutically acceptable salt to the capsule material is 1.0:1.0. The content of the pore-forming agent is 1.80wt%-2.20wt% based on the total weight of the microcapsules. The formulation components and formulation ratios can synergistically complement each other. The oseltamivir or its pharmaceutically acceptable salt microcapsules prepared in this way have better taste masking properties, dissolution rate, yield, and impurity stability than those using individual technical features and other alternative technical features, resulting in unexpected technical effects.

[0096] Terminology Explanation

[0097] The term "bitterness value" refers to the percentage of the electronic tongue test result of the sample to the electronic tongue test result of the raw material.

[0098] The term "solid content" indicates the percentage of the mass of solids used relative to the mass of the solvent.

[0099] In this invention, Hz represents Hertz; rpm represents rotational speed, i.e., revolutions per minute; HPMCAS represents hydroxypropyl methylcellulose acetate succinate; HPMCAS-L represents L-type hydroxypropyl methylcellulose acetate succinate; HPMCP represents hydroxypropyl methylcellulose phthalate; HPMCP HP-55 represents HP-55 type hydroxypropyl methylcellulose phthalate; PLGA represents polylactic acid-glycolic acid copolymer; PEG represents polyethylene glycol; mM represents millimoles per liter; mL represents milliliters; mol / L represents moles per liter; g represents grams; pH represents acidity / alkalinity; HPLC represents high performance liquid chromatography; mL / min represents milliliters per minute; min represents minutes; μL represents microliters; nm represents nanometers.

[0100] Term "D" 90"Cost per unit area" refers to the particle size at which the cumulative particle size distribution of a sample reaches 90%. Physically, it means that 90% of the particles are smaller than this value, for example, "D". 90 "Not larger than 100μm" means that "particles not larger than 100μm account for 90%". 10 This refers to the particle size corresponding to a cumulative particle size distribution number of 10% for a sample; D 50 It refers to the particle size corresponding to when the cumulative particle size distribution number of a sample reaches 50%.

[0101] The terms “optional” or “optionally” mean that the event or situation described below may, but is not necessarily, occur. For example, “optionally other pharmaceutically acceptable excipients” means that other pharmaceutically acceptable excipients may or may not be present.

[0102] In the foregoing description of this invention, all figures disclosed herein, whether or not the words “approximately” or “about” are used, are approximate values. Each figure may vary by less than 10% or by a difference that is considered reasonable by those skilled in the art, such as 1%, 2%, 3%, 4%, or 5%.

[0103] "Pharmaceutical acceptable" here means: a substance or compound that, to the extent of adequate medical judgment, is suitable for contact with human and lower animal tissues without undesirable toxicity, irritation, allergic reactions or similar reactions, and has a reasonably reasonable benefit / risk ratio.

[0104] The terms "percentage by weight" or "wt%" are defined as the weight of a single component in a formulation divided by the total weight of all components in the formulation, then multiplied by 100. In some cases, if the formulation has an outer coating, the total weight may or may not include the coating weight. Detailed Implementation

[0105] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0106] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0107] Detection method:

[0108] 1. Particle size detection

[0109] Instrument: Malvern MS2000 particle size analyzer

[0110] Procedure: Use the dry method to determine particle size. Set the air pressure to 2.0 bar, the injection volume to 50%, and the injection / background time to 10 s / 10 s. Then add an appropriate amount of sample for testing. Perform three parallel tests and take the average value.

[0111] 2. Bitterness value test

[0112] Detection method: Electronic tongue detection method

[0113] 1) Solution preparation

[0114] Standard solution: a solution containing 30 mM potassium chloride and 0.3 mM tartaric acid.

[0115] Negative solution: Mix 500 mL of water, 300 mL of ethanol and 8.3 mL of hydrochloric acid, and dilute to 1000 mL with purified water.

[0116] Positive solution: Take 7.46g potassium chloride, 500mL water, 300ml ethanol and 0.56g potassium hydroxide, and dilute to 1000mL with purified water.

[0117] Internal solution: a mixture of 3.33 mol / L potassium chloride solution and saturated silver chloride solution.

[0118] Reference electrode immersion solution: 3.33 mol / L potassium chloride solution.

[0119] Blank solution: Dissolve 1.49g of potassium chloride in 2L of purified water to form a blank solution.

[0120] Reference solution: Take 65.7 mg of oseltamivir phosphate raw material, add 100 g of blank solution to dissolve and form a reference solution.

[0121] Test solution: Take 1 tablet of test sample, add 150g of blank solution, disintegrate and filter to obtain the test solution.

[0122] 2) Operation

[0123] Transfer the test solution to the graduation mark on the test cup, select the AN0 sensor, and activate the sensor and reference electrode for 24 hours. Run the equipment for testing. After each test, clean with both negative and positive solutions.

[0124] 3. Dissolution detection method (paddle method):

[0125] 1) Dissolution conditions: Add 900 ml of pH 1.2 hydrochloric acid solution to the dissolution vessel, stir at 50 rpm, and keep the temperature constant at 37.0℃.

[0126] 2) Solution preparation:

[0127] pH 1.0 hydrochloric acid medium: Measure about 9 ml of hydrochloric acid (AR), dilute with water to 1000 ml, mix well, and degas by sonication for 15 min to obtain the medium.

[0128] Dissolution medium: Add purified water or hydrochloric acid solution to adjust the pH to 1.0. Hydrochloric acid medium is then prepared until the pH is 1.20.

[0129] Test solution: Take the equivalent of 98.53 mg of oseltamivir phosphate powder and put it into the preheated dissolution medium. Take samples at 2 min, 5 min, 10 min, 15 min, 20 min and 30 min respectively. Take 2 mL of the solution from the dissolution vessel and filter it through a filter membrane (Jinteng PES, 0.45 μm, Φ13 mm). Discard 1 mL of the initial filtrate and take the subsequent filtrate. Detect the content by high performance liquid chromatography.

[0130] Preparation of the reference solution: Accurately weigh approximately 22 mg of oseltamivir phosphate reference standard (equivalent to 16.7 mg of oseltamivir) into a 200 ml volumetric flask. Add 150 ml of dissolution medium, sonicate to dissolve, cool to room temperature, and then dilute to volume with the dissolution medium. Shake well to obtain the solution. Prepare two parallel solutions.

[0131] Blank solution: dissolution medium

[0132] 3) Chromatographic conditions

[0133] Instrument: High-performance liquid chromatograph;

[0134] Chromatographic column: Welch Xtimate C8, 4.6*150mm, 5μm; or YMC-Triart C8, 4.6*150mm, 5μm;

[0135] Mobile phase: 0.05 mol / L potassium dihydrogen phosphate buffer solution at pH 6.0 - methanol - acetonitrile = 40:40:20 (v / v);

[0136] Flow rate: 1.2 mL / min;

[0137] Running time: 5 minutes;

[0138] Injection volume: 10 μL;

[0139] Column temperature: 50℃;

[0140] Detection wavelength: 207nm.

[0141] 4) Mobile phase preparation method

[0142] 0.05 mol / L pH 6.0 potassium dihydrogen phosphate buffer solution: Weigh 6.8 g of anhydrous potassium dihydrogen phosphate, add 1000 ml of ultrapure water, stir to dissolve completely, adjust the pH to 6.0 with 1 mol / L potassium hydroxide solution, filter with a water-based microporous membrane, and collect the filtrate.

[0143] Mobile phase: Mix 0.05 mol / L pH 6.0 potassium dihydrogen phosphate buffer solution, methanol, and acetonitrile in a volume ratio of 40:40:20, and degas by sonication for 15 min.

[0144] 5) Calculation formula

[0145] Calculate the dissolution rate (%) of oseltamivir in each dissolution vessel using the following formula:

[0146] In the formula:

[0147]

[0148] Ms: The amount of the main peak reference standard in reference solution 1, in mg;

[0149] Ru: Area of ​​the main peak of the test solution;

[0150] Rs: Average peak area of ​​the main peak in reference solution 1;

[0151] Ps: Content of oseltamivir phosphate reference standard, %;

[0152] Ds: Dilution factor of reference solution 1;

[0153] Du: Medium volume, 900mL;

[0154] S: Labelling amount of oseltamivir phosphate microcapsule powder.

[0155] Example 1: Screening of capsule materials

[0156] Microcapsule prescriptions: as shown in Table 1.

[0157] Table 1: Prescriptions for capsule material selection

[0158]

[0159]

[0160] Preparation method: Oseltamivir phosphate was dissolved in water according to the dosage specified in the prescription to obtain a first solution; the capsule material was dissolved in the solvent to obtain a second solution; the first and second solutions were mixed to obtain an emulsion with a solid content of 18.55%; the inlet air temperature was set to 90°C, the outlet air temperature to 55°C, the fan frequency to 35Hz, the nebulizer frequency to 35Hz, and the pump speed to 30rpm, and the oseltamivir phosphate microcapsules were obtained by spray drying.

[0161] Testing: The oseltamivir phosphate microcapsules prepared in this example were tested for yield, product state, dissolution rate and bitterness value. The results are shown in Table 2.

[0162] Table 2: Test Results of Capsule Material Screening

[0163]

[0164] The results show that:

[0165] (1) In terms of yield, the yield of ethyl cellulose and HPMCAS-L as carriers both reached over 90%, while the yield of UTICH L100-55 was low and the material was difficult to collect due to its filamentous nature.

[0166] (2) Based on the product dissolution at 5 min, the dissolution of products using ethyl cellulose and HPMCAS-L as carriers both reached over 60%, while the dissolution of UTICH L100-55 at 5 min was only 46.4%.

[0167] (3) In terms of the masking effect, the bitterness of ethyl cellulose and Eutec L100-55 as carriers is less than 40%.

[0168] (4) The overall yield is greater than 80%, the dissolution rate is greater than 60% in 5 minutes, the bitterness value is less than 40%, and the preferred carrier is ethyl cellulose.

[0169] Example 2: Solvent Screening

[0170] Microcapsule prescriptions: as shown in Table 3

[0171] Table 3: Recipes for Solvent Screening

[0172]

[0173] Preparation method: Same as in Example 1.

[0174] Testing: The dissolution time of ethyl cellulose and the dissolution status of the first and second solutions were recorded during the preparation process. The results are shown in Table 4.

[0175] Table 4: Test Results of Capsule Material Screening

[0176]

[0177] The results show that:

[0178] (1) In terms of dissolution rate, ethyl cellulose dissolves fastest in ethyl acetate. The ethyl cellulose solution and the aqueous solution form an emulsion that does not separate into layers or agglomerate. Therefore, ethyl acetate is preferred as the solvent.

[0179] Example 3: Screening of the ratio of active pharmaceutical ingredient to encapsulation material

[0180] Microcapsule prescriptions: as shown in Table 5.

[0181] Table 5: Formulas for screening the ratio of active pharmaceutical ingredient to encapsulation material

[0182]

[0183] Preparation method: Oseltamivir phosphate was dissolved in water according to the dosage specified in the prescription to obtain a first solution; the capsule material was dissolved in the solvent to obtain a second solution; the first and second solutions were mixed to obtain an emulsion with a solid content of 18.55%; the inlet air temperature was set to 90°C, the outlet air temperature to 75°C, the fan frequency to 35Hz, the nebulizer frequency to 35Hz, and the pump speed to 30rpm, and the oseltamivir phosphate microcapsules were obtained by spray drying.

[0184] Testing: The oseltamivir phosphate microcapsules prepared in this example were tested for yield, dissolution rate and bitterness value. The results are shown in Table 6.

[0185] Table 6: Detection Results of the Ratio Screening for Active Pharmaceutical Ingredients and Encapsulation Materials

[0186]

[0187] The results show that:

[0188] (1) When the ratio of active pharmaceutical ingredient to carrier is 1:0.5-1:2, the yield is greater than 80%.

[0189] (2) When the ratio of active pharmaceutical ingredient (API) to carrier is 1:1, the dissolution rate is greater than 60% within 5 minutes. When the ratio of API to carrier is 1:0.5 and 1:2, the dissolution rate is less than 50% within 5 minutes. When the ratio of API to carrier is 1:0.5, the carrier is insufficient and cannot form microcapsules, resulting in a large amount of bitter API being exposed, and the bitterness value is very high.

[0190] (3) As the proportion of carrier increases, the bitterness value decreases, but the dissolution also decreases. When the ratio of raw material to carrier is 1:1, not only is the bitterness value smaller and the yield higher, but the dissolution is also significantly higher than other ratios.

[0191] (4) In summary, the preferred ratio of active pharmaceutical ingredient to carrier is 1:1.

[0192] Example 4: Screening of pore-forming agents

[0193] Microcapsule prescriptions: as shown in Table 7.

[0194] Table 7: Formulations for pore-forming agent screening

[0195]

[0196]

[0197] Preparation method: Oseltamivir phosphate was dissolved in water according to the dosage specified in the prescription to obtain a first solution; the capsule material and pore-forming agent were dissolved in a solvent to obtain a second solution; the first and second solutions were mixed to obtain an emulsion with a solid content of 18.55%; the inlet air temperature was set to 90°C, the outlet air temperature to 75°C, the fan frequency to 35Hz, the nebulizer frequency to 35Hz, and the pump speed to 30rpm, and the oseltamivir phosphate microcapsules were obtained by spray drying.

[0198] Testing: The oseltamivir phosphate microcapsules prepared in this example were tested for yield, dissolution rate and bitterness value. The results are shown in Table 8.

[0199] Table 8: Test Results of Pore-Forming Agent Screening

[0200]

[0201] The results show that:

[0202] (1) Mannitol had a lower yield as a porogen, while PEG 1000 had the highest yield as a porogen, followed by PEG 2000.

[0203] (2) The bitterness value is lower when mannitol and PEG 1000 are used as porogens.

[0204] (3) All four porogens dissolved more than 60% within 5 minutes, but PEG 1000 had the highest dissolution rate within 5 minutes.

[0205] (4) Selecting PEG1000, lactose or PEG2000 as porogens can improve yield and dissolution. Considering both high yield and low bitterness value, PEG1000 is preferred as the porogen.

[0206] Example 5: Screening of pore-forming agent dosage

[0207] Microcapsule prescription: see Table 9.

[0208] Oseltamivir phosphate was dissolved in water, and ethyl cellulose and a pore-forming agent were dissolved in ethyl acetate. The two solutions were mixed to form an emulsion. The inlet temperature was set to 90°C, the outlet temperature to 75°C, the fan frequency to 35Hz, the atomizer frequency to 25Hz, and the pump speed to 30rpm.

[0209] Table 9: Formulations for screening pore-forming agent dosage

[0210]

[0211] Preparation method: Oseltamivir phosphate was dissolved in water according to the dosage specified in the prescription to obtain a first solution; the capsule material and pore-forming agent were dissolved in a solvent to obtain a second solution; the first and second solutions were mixed to obtain an emulsion with a solid content of 18.55%; the inlet air temperature was set to 90°C, the outlet air temperature to 75°C, the fan frequency to 35Hz, the nebulizer frequency to 25Hz, and the pump speed to 30rpm, and the oseltamivir phosphate microcapsules were obtained by spray drying.

[0212] Testing: The oseltamivir phosphate microcapsules prepared in this example were tested for yield, dissolution rate and bitterness value. The results are shown in Table 10.

[0213] Table 10: Test Results of Pore-Forming Agent Dosage Screening

[0214]

[0215] The results show that:

[0216] (1) At 2 min, the dissolution of the product gradually increases with the increase of porogen; when the porogen reaches 6%-10%, the product dissolution is relatively stable.

[0217] (2) At 5 min, L5-2, although containing only 2% porogen, can dissolve rapidly, with a 22% increase in dissolution compared to 2 min, thus achieving the effect of rapid release.

[0218] (3) As the proportion of porogen increases, the bitterness value increases. When the porogen reaches 4% or more, the bitterness value is greater than 40%.

[0219] (4) In summary, in order to ensure that the product dissolves less in the oral cavity to reduce bitterness, and to ensure that dissolution is not affected after swallowing, the preferred dose is 2%.

[0220] Example 6: Temperature Screening

[0221] Microcapsule formulation and preparation method: 80g of oseltamivir phosphate was dissolved in 80g of water, and 80g of ethyl cellulose and 3.2g of ethyl cellulose were dissolved in 800g of ethyl acetate. The two solutions were mixed to form an emulsion. The parameters were set according to Table 11, and the microcapsules of oseltamivir phosphate were obtained by spray drying. The yields were calculated.

[0222] Table 11: Temperature Screening Setting Parameters

[0223]

[0224] Testing: The oseltamivir phosphate microcapsules prepared in this example were tested for product status and yield. The results are shown in Table 12.

[0225] Table 12: Detection results of temperature screening

[0226]

[0227] The results show that:

[0228] (1) When the air inlet is 70℃ and the air outlet is 45℃, the heat per unit time is insufficient to dry all the solvents, causing the product to stick together and form irregular clumps. Subsequent steps such as crushing and sieving are required, which affects the development of downstream processes and prolongs the process steps.

[0229] (2) When the air inlet temperature is 90℃-110℃, the heat energy increases, the drying effect is good, and the product is a uniform powder. At 110℃, the temperature is too high and the yield decreases.

[0230] (3) When the air inlet temperature is 90°C and the air outlet temperature is 55°C, the product yield is the highest and the product is uniform and does not clump. Therefore, the air inlet temperature is 90°C and the air outlet temperature is 55°C.

[0231] Example 7: Wind Turbine Frequency Investigation

[0232] Microcapsule formulation and preparation method: 80g of oseltamivir phosphate was dissolved in 80g of water, and 80g of ethyl cellulose and 3.2g of ethyl cellulose were dissolved in 800g of ethyl acetate. The two solutions were mixed to form an emulsion. The parameters were set according to Table 13, and the microcapsules of oseltamivir phosphate were obtained by spray drying. The yields were calculated.

[0233] Table 13: Setting parameters for wind turbine frequency testing

[0234]

[0235] Testing: The oseltamivir phosphate microcapsules prepared in this example were tested for their product status and yield. The results are shown in Table 14.

[0236] Table 14: Test Results of Fan Frequency Examination

[0237]

[0238] The results show that:

[0239] (1) When the fan frequency is 25Hz or below, the atomization effect remains unchanged, but the product is prone to sticking together and forming clumps. Subsequent crushing and sieving steps are required, which affects the development of downstream processes and prolongs the process steps.

[0240] (2) When the fan frequency is 45Hz or higher, the yield decreases.

[0241] (3) Based on the above product yield and powder state, the highest yield and uniform product are obtained when the fan frequency is 35Hz.

[0242] Example 8: Atomizer Frequency Investigation

[0243] Microcapsule formulation and preparation method: 80g of oseltamivir phosphate was dissolved in 80g of water, and 80g of ethyl cellulose and 3.2g of ethyl cellulose were dissolved in 800g of ethyl acetate. The two solutions were mixed to form an emulsion. The parameters were set according to Table 15, and the microcapsules of oseltamivir phosphate were obtained by spray drying. The yields were calculated.

[0244] Table 15: Setting parameters for atomizer frequency testing

[0245]

[0246] Testing: The oseltamivir phosphate microcapsules prepared in this example were tested for product status and yield. The results are shown in Table 16.

[0247] Table 16: Test Results of Atomizer Frequency Examination

[0248]

[0249]

[0250] The results show that:

[0251] (1) When the atomizer frequency is 25-35Hz, the product is uniform and free of lumps; when the atomizer frequency exceeds 45Hz, the product begins to agglomerate, and subsequent steps such as crushing and sieving are required, which affects the development of downstream processes and prolongs the process steps.

[0252] (2) Increasing the atomizer frequency improves the atomization effect, disperses the solvent solution into smaller droplets, and results in smaller droplet radii and faster heat exchange. However, because the solvent used is an emulsion of ethyl acetate and water, the boiling points and specific heat capacities of the two substances differ significantly. This causes some of the lower-boiling-point ethyl acetate to evaporate first, resulting in semi-dry particles that clump together. Conversely, at lower atomizer frequencies of 25-35Hz, the atomization effect is not as good as at 45-50Hz, but it ensures thorough drying of the product without clumping.

[0253] (3) When the product is uniform and does not clump together, the product yield is highest when the atomizer is 35Hz.

[0254] (4) Based on the above product form and yield, a 35Hz atomizer can produce a uniform, non-clumping product with a high yield.

[0255] Example 9: Pump Speed ​​Test

[0256] Microcapsule formulation and preparation method: 80g of oseltamivir phosphate was dissolved in 80g of water, and 80g of ethyl cellulose and 3.2g of ethyl cellulose were dissolved in 800g of ethyl acetate. The two solutions were mixed to form an emulsion. The parameters were set according to Table 17, and the microcapsules of oseltamivir phosphate were obtained by spray drying. The yields were calculated.

[0257] Table 17: Setting parameters for pump speed test

[0258]

[0259] Testing: The oseltamivir phosphate microcapsules prepared in this example were tested for their product status and yield. The results are shown in Table 18.

[0260] Table 18: Test Results of Pump Speed ​​Examination

[0261]

[0262] The results show that:

[0263] (1) When the pump speed is 10 rpm, the product clumps together, and some of them are in the shape of strips and blocks. Subsequent crushing and sieving steps are required, which affects the development of downstream processes and prolongs the process steps.

[0264] (2) With other parameters fixed, as the pump speed increases to 20-40 rpm, the amount of solvent processed per unit time increases, and the atomization effect decreases, preventing the product from being locally dried and forming semi-dry particles that stick together. The yield is highest at a pump speed of 30 rpm, so the preferred pump speed is 30 rpm.

[0265] Example 10: Solid content investigation

[0266] Microcapsule formulation and preparation method: 80g of oseltamivir phosphate was dissolved in 80g of water, and 80g of ethyl cellulose and 3.2g of ethyl cellulose were dissolved in 800g of ethyl acetate. The two solutions were mixed to form an emulsion. The parameters were set according to Table 19, and the microcapsules of oseltamivir phosphate were obtained by spray drying. The yields were calculated.

[0267] Table 19: Setting parameters for solid content investigation

[0268]

[0269]

[0270] Testing: The oseltamivir phosphate microcapsules prepared in this example were tested for their product state, particle size and yield. The results are shown in Table 20.

[0271] Table 20: Detection results of solid content examination

[0272]

[0273] The results show that:

[0274] (1) The product is a uniform powder under different solid contents.

[0275] (2) As the solid content increases, the particle size of the product gradually increases.

[0276] (3) Under the same conditions, excessively small particle sizes are prone to electrostatic adhesion to the walls. As the particle size gradually increases, the electrostatic effect becomes less than the gravitational effect, and the product is carried away by the fan, leading to a decrease in product yield. When the solid content is 18.55%, the product particle size just reaches the maximum limit that the fan can carry away and is retained, increasing the yield. As the solid content continues to increase, the product particle size continues to increase, the product gravity increases, the fan power is insufficient, resulting in a small amount of product accumulating, and the yield begins to decline.

[0277] Comparative Example 1: Oseltamivir phosphate microcapsules with EPO as the encapsulation material

[0278] 80g of oseltamivir phosphate was dissolved in 80g of water, and 80g of EPO and 3.2g of pore-forming agent were dissolved in a certain amount of ethyl acetate. The two solutions were mixed to form an emulsion. The inlet air temperature was set to 90℃, the outlet air temperature to 55℃, the fan frequency to 35Hz, the nebulizer frequency to 35Hz, the pump speed to 30rpm, and the solid content to 18.55%. Oseltamivir phosphate microcapsules with the formulation number L12-03 were obtained by spray drying.

[0279] Example 11: Stability Data

[0280] Stability under intermediate conditions: An appropriate amount of oseltamivir phosphate prepared according to prescription number L10-4 in Example 10 was added to a headspace vial, capped, and placed under intermediate conditions (30°C, RH 65%) for 3 months. The growth of impurities was detected at 0 months, 1 month, 2 months, and 3 months, respectively. The results are shown in Table 21.

[0281] Stability of influencing factors: Take appropriate amounts of oseltamivir phosphate microcapsules prepared according to prescription number L10-4 in Example 10 and oseltamivir phosphate microcapsules with prescription number L12-03 in Comparative Example 1, add them to headspace vials, cap them, and place them at room temperature (75%RH, 25℃), high humidity (92.5%RH, 25℃), 40℃ (75%RH, 40℃), and 60℃ (uncontrolled humidity, 60℃) for 5 days and 10 days, respectively. The impurity content was measured after 0 days and 5 days under each condition. The results are shown in Tables 22-24.

[0282] Table 21: Intermediate condition impurity stability of oseltamivir phosphate microcapsules with prescription number L10-4.

[0283]

[0284]

[0285] Table 22: Factors affecting the stability of USP impurity A

[0286]

[0287] Table 23: Factors affecting the stability of USP impurity C

[0288]

[0289] Table 24: Stability of Total Influencing Factors

[0290]

[0291] Note: USP impurity A, USP impurity B, and USP impurity C mentioned in this invention represent the contents of <oseltamivir phosphate capsules> in the United States Pharmacopeia (USP) 39-NF34.<OSELTAMIVIR PHOSPHATE CAPSULES> The impurities A, B, and C in this paper are impurity A, impurity B, and impurity C.

[0292] The results show that:

[0293] (1) The results of the intermediate condition stability over 3 months show that the oseltamivir phosphate microcapsules with prescription number L10-4 have good stability.

[0294] (2) The results of the influencing factors show that the oseltamivir phosphate microcapsules with prescription number L10-4 have good stability.

[0295] (3) The results of the influencing factors show that the stability of oseltamivir phosphate microcapsules with prescription number L10-4 is similar to that of oseltamivir phosphate. After being placed at room temperature (75%RH, 25℃), high humidity (92.5%RH, 25℃), 40℃ high temperature (75%RH, 40℃), and 60℃ high temperature (uncontrolled humidity, 60℃) for 5 days and 10 days, there were no significant changes in USP impurity A, USP impurity C and total impurities, indicating that the raw materials and excipients of oseltamivir phosphate microcapsules with prescription number L10-4 are compatible.

[0296] (4) The results of the influencing factors show that the stability of oseltamivir phosphate microcapsules with ethyl cellulose formulation number L10-4 is better than that of oseltamivir phosphate microcapsules with EPO formulation number L12-3.

[0297] (5) The oseltamivir phosphate microcapsules with EPO formulation number L12-3 have poor stability. When placed at room temperature (75% RH, 25℃), high humidity (92.5% RH, 25℃), 40℃ high temperature (75% RH, 40℃), and 60℃ high temperature (uncontrolled humidity, 60℃) for 5 days and 10 days, the USP impurity A, USP impurity C and total impurities are significantly increased.

[0298] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A method for preparing microcapsules of oseltamivir or a pharmaceutically acceptable salt thereof, characterized in that, The process includes the following steps: (1) dissolving oseltamivir or a pharmaceutically acceptable salt thereof in water to obtain a first solution; (2) dissolving the capsule material and the pore-forming agent in a solvent to obtain a second solution; wherein the capsule material is ethyl cellulose, the pore-forming agent is selected from at least one of polyethylene glycol 2000, polyethylene glycol 1000, mannitol and lactose, and the solvent is ethyl acetate; the weight ratio of oseltamivir or a pharmaceutically acceptable salt thereof to the capsule material is 1.0:0.8-1.0:1.2; and the pore-forming agent is present in the total weight of the microcapsules. The content is 1.80wt%-2.20wt%; (3) The first solution and the second solution are mixed to obtain an emulsion, and the solid content of the emulsion is 10.00wt%-25.00wt% based on the total weight of the emulsion; (4) The emulsion in step (3) is dried using a centrifugal spray dryer to obtain microcapsules of oseltamivir or its pharmaceutically acceptable salts; the atomizer frequency of the centrifugal spray dryer is 25Hz-35Hz; the pump speed of the centrifugal spray dryer is 20 rpm-40 rpm; the fan frequency of the centrifugal spray dryer is 30Hz-35Hz; the inlet air temperature of the centrifugal spray dryer is 90℃-110℃; and the outlet air temperature of the centrifugal spray dryer is 50℃-60℃.

2. According to the preparation method of claim 1, the atomizer frequency of the centrifugal spray dryer is 35Hz.

3. According to the preparation method of claim 1, the pump speed of the centrifugal spray dryer is 30 rpm; the fan frequency of the centrifugal spray dryer is 35 Hz; the inlet air temperature of the centrifugal spray dryer is 90°C; and the outlet air temperature of the centrifugal spray dryer is 55°C.

4. A microcapsule prepared by the preparation method according to any one of claims 1-3.

5. The microcapsule according to claim 4, comprising: The microcapsule contains oseltamivir phosphate, a capsule material, and a pore-forming agent; the capsule material is ethyl cellulose, and the pore-forming agent is selected from at least one of polyethylene glycol 2000, polyethylene glycol 1000, mannitol, and lactose; the weight ratio of oseltamivir phosphate to the capsule material is 1.0:0.8-1.0:1.2; the content of the pore-forming agent is 1.80wt%-2.20wt% based on the total weight of the microcapsules; and the content of oseltamivir phosphate is 45wt%-55wt% based on the total weight of the microcapsules.

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