An oseltamivir composition and a method of preparing the same

Abstract

The present application relates to a kind of oseltamivir compositions and its preparation method, belong to the field of pharmaceutical preparation.The composition oseltamivir or its pharmaceutically acceptable salt, taste masking agent and optionally other pharmaceutically acceptable auxiliary materials.The taste masking agent is a kind of water-insoluble material or a kind of enteric material.The composition is convenient to take, good taste masking, good taste, fast release, good stability.The preparation method is good in reproducibility, and preparation is simple.

Description

TECHNICAL FIELD

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

[0002] Oseltamivir phosphate, chemical name (3R, 4R, 5S)-4-acetyl-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester phosphate. The chemical structure is as follows:

[0003]

[0004] Oseltamivir phosphate has strong inhibitory activity on neuraminidase, and is effective on both type A and type B influenza viruses.

[0005] Oseltamivir phosphate currently on the market in the form of granules, capsules, and dry suspensions. Capsules are not easy to swallow, and the suitable population is limited. It is extremely difficult for the elderly, critically ill patients and children who have difficulty swallowing to take, and it is also very dangerous. Dry suspensions need to be prepared with water before use, which is relatively cumbersome and not suitable for patients who lack water sources or have difficulty moving themselves. Granules or dry suspensions are suitable for preparing liquid preparations before use, which is convenient for the elderly, children and people who are not suitable for swallowing. However, oseltamivir phosphate is a drug with a particularly bitter taste, so its pharmaceutical composition is difficult to swallow, and most children have difficulty taking medicine. Infants, children and the elderly generally have low acceptance, often reject or discontinue medication, which significantly affects the efficacy. In addition, oseltamivir phosphate has poor stability, and it is difficult to ensure the stability of oseltamivir phosphate preparations with masking agents, and even the stability of oseltamivir phosphate preparations may be worse.

[0006] Patent US20060078614A1 discloses a technology effect of using a polymer film to achieve taste masking and rapid release, but the polymer film contains a blend of water-insoluble polymers and gastric-soluble polymers, i.e. at least two taste masking agents are needed to achieve the technical effects of taste masking and rapid release. The complexity of the auxiliary materials will make the stability worse, the taste worse, and the preparation more difficult.

[0007] Patent CN201310355363.2 discloses a kind of oseltamivir freeze-dried oral disintegrating tablets and its preparation method, without using taste masking technology, we refer to the prescription process of the patent to freeze-drying and tabletting, with oseltamivir, single dose specification is 10mg of freeze-dried oral disintegrating tablets slightly bitter, although adult can barely accept, but infants, children are more difficult to accept;When the single dose specification of oseltamivir is increased to 30mg, even 75mg specification, it is found that the taste is very bitter, difficult to accept.In addition, adult needs 75mg oseltamivir per medication, single dose specification 10mg of oral disintegrating tablets needs to be taken 7-8 tablets at the same time, which is very inconvenient for adults, especially for the elderly who generally have difficulty swallowing, memory loss or difficulty moving.Also, the patent uses freeze-drying process, its equipment is expensive, the production cost is high, which will greatly increase the medication cost burden of patients;And the oral disintegrating tablets prepared by freeze-drying method have the problems of large friability, small physical strength, which is not conducive to packaging and transportation, easy to absorb moisture, poor stability and other problems.

[0008] Patent CN201310290328.7 discloses a kind of oral disintegrating tablets for infants and children and its preparation method, polyacrylic resin IV is used as coating material to coat drug-containing pellets, which has complex process and is not easy to control.Pellet coating is followed by tabletting, which often causes pellet rupture, and further exposes the raw drug and releases bitter taste.In addition, due to the limitation of the drug loading of the pellets, the amount of oseltamivir per tablet is limited to 5-50mg, which is suitable for children, and adults need to take at least two tablets each time, which is very inconvenient for the elderly.In addition, the oral disintegrating tablets prepared according to the patent have poor stability (see Example 12, Comparative Example 4), which cannot guarantee the stability of the expiration date.

[0009] Therefore, it is urgent to develop an oseltamivir preparation which is convenient to take, has wide medication population, good compliance, good stability and simple preparation. SUMMARY SUMMARY

[0011] To solve the above problems of inconvenience, bitter taste, poor taste, poor stability and difficult preparation, the applicant proposes the following invention.

[0012] In a first aspect, the present application provides a composition containing oseltamivir or a pharmaceutically acceptable salt thereof and a taste masking agent.The composition is convenient to take, has good taste masking property, good taste, fast release, good stability and simple preparation.

[0013] In a second aspect, the present application provides a preparation method of the above-mentioned composition, which is simple to operate, has good reproducibility, and the composition prepared by the method has good uniformity, good taste masking property, fast release and good stability. DETAILED DESCRIPTION

[0015] In a first aspect, the present application provides a composition comprising oseltamivir or a pharmaceutically acceptable salt thereof and a taste masking agent.

[0016] A composition comprising: oseltamivir or a pharmaceutically acceptable salt thereof, a taste masking agent which is a water insoluble material or an enteric material, and optionally other pharmaceutically acceptable excipients.

[0017] The pharmaceutically acceptable salt can include a phosphate salt, a fumarate salt, a citrate salt or a malate salt.

[0018] The water insoluble material includes ethyl cellulose, in which case the oseltamivir or salt thereof and the taste masking agent in the composition have good compatibility, the composition has a fast release speed, good taste masking effect and stability.

[0019] The enteric material includes a methacrylic acid-ethyl acrylate copolymer, a methacrylic acid-methyl methacrylate copolymer or hydroxypropyl methyl cellulose acetate succinate. In some embodiments, the taste masking agent is a methacrylic acid-ethyl acrylate copolymer L30D-55. In some embodiments, the taste masking agent is a methacrylic acid-methyl methacrylate copolymer L100. In some embodiments, the taste masking agent is a methacrylic acid-methyl methacrylate copolymer S100. In some embodiments, the taste masking agent is a methacrylic acid-methyl acrylate-methyl methacrylate copolymer FS30D. In some preferred embodiments, the taste masking agent is a methacrylic acid-ethyl acrylate copolymer L100-55, in which case the oseltamivir or salt thereof and the taste masking agent in the composition have good compatibility, the composition has a fast release speed, good taste masking effect and stability.

[0020] The weight ratio of the oseltamivir or pharmaceutically acceptable salt thereof to the taste masking agent can be 1.0:0.3-1.0:3.0. Within this range, the prepared composition can achieve good taste masking effect, good mouthfeel, while ensuring the stability of the composition, and even extending the shelf life of the composition. In some embodiments, the weight ratio of the oseltamivir or pharmaceutically acceptable salt thereof to the taste masking agent is 1.0:0.4-1.0:2.0. In some embodiments, the weight ratio of the oseltamivir or pharmaceutically acceptable salt thereof to the taste masking agent is 1.0:0.5-1.0:1.0. In some embodiments, the weight ratio of the oseltamivir or pharmaceutically acceptable salt thereof to the taste masking agent is 1.0:0.6-1.0:0.9. In some embodiments, the weight ratio of the oseltamivir or pharmaceutically acceptable salt thereof to the taste masking agent is 1.0:0.7-1.0:0.8. In some preferred embodiments, the weight ratio of the oseltamivir or pharmaceutically acceptable salt thereof to the taste masking agent is 1.0:0.3-1.0-1.5. Within this ratio range, the composition has good taste masking effect, weak grittiness, and fast dissolution rate. In some more preferred embodiments, the weight ratio of the oseltamivir or pharmaceutically acceptable salt thereof to the taste masking agent is 1.0:0.3-1.0:0.8. Within this range, the composition has better taste masking effect, weaker grittiness, and faster dissolution rate.

[0021] The pharmaceutically acceptable excipient can include at least one selected from a filler, a binder, a disintegrant, a pH adjuster, a sweetener, a flavoring agent, a lubricant, a glidant, a suspending agent, a plasticizer, an anti-adherent, and a pore-forming agent.

[0022] The filler can include at least one selected from lactose, microcrystalline cellulose, mannitol, sorbitol, maltitol, xylitol, corn starch, pregelatinized starch, dextrin, maltodextrin, sucrose, gelatin, anhydrous dibasic calcium phosphate, and magnesium aluminum silicate.

[0023] The content of the filler can be 10.00wt%-85.00wt% with respect to the total weight of the composition. In some preferred embodiments, the content of the filler is 20.00wt%-40.00wt% with respect to the total weight of the composition.

[0024] The binder can include at least one selected from methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, povidone, pregelatinized starch, and corn starch.

[0025] The content of the binder can be 0-6.00wt% with respect to the total weight of the composition.

[0026] The disintegrant can include at least one selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and corn starch.

[0027] The content of the disintegrant can be 0-35.00 wt% with respect to the total weight of the composition. In some preferred embodiments, the content of the disintegrant is 5.00 wt%-15.00 wt% with respect to the total weight of the composition.

[0028] The pH adjuster can include at least one selected from the group consisting of citric acid, tartaric acid, and sodium dihydrogen citrate.

[0029] The content of the pH adjuster can be 0-12.00 wt% with respect to the total weight of the composition.

[0030] The sweetener can include at least one selected from the group consisting of sucralose, aspartame, and sodium saccharin.

[0031] The content of the sweetener can be 0.10 wt%-25.00 wt% with respect to the total weight of the composition. In some preferred embodiments, the content of the sweetener is 0.10 wt%-6.00 wt% with respect to the total weight of the composition, at which ratio the composition has a better mouthfeel.

[0032] The flavoring agent can include at least one selected from the group consisting of peach flavor, orange flavor, strawberry flavor, pineapple flavor, lemon flavor, mint flavor, apple flavor, lychee flavor, and mango flavor.

[0033] The content of the flavoring agent can be 0.10 wt%-5.00 wt% with respect to the total weight of the composition. In some preferred embodiments, the content of the flavoring agent is 0.10 wt%-3.00 wt% with respect to the total weight of the composition, at which ratio the composition has a better mouthfeel.

[0034] The lubricant can include at least one selected from the group consisting of magnesium stearate, sodium stearyl fumarate, hydrogenated castor oil, polyethylene glycol, microfine silica, and talc.

[0035] The glidant can include at least one selected from the group consisting of magnesium stearate, sodium stearyl fumarate, hydrogenated castor oil, polyethylene glycol, microfine silica, and talc.

[0036] The content of the lubricant can be 0-4.50 wt% with respect to the total weight of the composition. In some preferred embodiments, the content of the lubricant is 0.50 wt%-3.00 wt% with respect to the total weight of the composition.

[0037] The content of the glidant can be 0-15.00 wt% with respect to the total weight of the composition. In some preferred embodiments, the content of the glidant can be 0.50 wt%-8.00 wt% with respect to the total weight of the composition.

[0038] The suspending agent can include at least one selected from glycerin, sucrose, sodium alginate, xanthan gum, acacia, pectin, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, colloidal microcrystalline cellulose, povidone, polyvinyl alcohol, dextran, sodium acrylate, carbomer, aluminum silicate, and magnesium aluminum silicate.

[0039] The content of the suspending agent can be 0-15.00 wt% with respect to the total weight of the composition.

[0040] The plasticizer can include at least one selected from dibutyl adipate, diethyl phthalate, triethyl citrate, triacetin, mineral oil, castor oil, fatty acid, oleic acid, sperm, stearyl, and polyethylene glycol.

[0041] The content of the plasticizer can be 0-13.00 wt% with respect to the total weight of the composition. In some preferred embodiments, the content of the plasticizer can be 0.50 wt%-6.00 wt% with respect to the total weight of the composition.

[0042] The anti-adherent can include at least one selected from talc, glyceryl monostearate, and microfine silica.

[0043] The content of the anti-adherent can be 0-20.00 wt% with respect to the total weight of the composition. In some preferred embodiments, the content of the anti-adherent can be 0.50 wt%-8.00 wt% with respect to the total weight of the composition.

[0044] The pore-forming agent can include at least one selected from polyethylene glycol, povidone, hydroxypropylmethyl cellulose, a sugar, an inorganic salt, talc, magnesium stearate, and silicon dioxide.

[0045] The inorganic salt can include at least one selected from inorganic salts such as sodium chloride, sodium carbonate, sodium bicarbonate, sodium sulfate, potassium sulfate, sodium phosphate, potassium chloride, sodium tartrate, sodium citrate, calcium hydrogen phosphate, calcium sulfate, and calcium carbonate.

[0046] The content of the pore-forming agent can be 0-15.00 wt% with respect to the total weight of the composition.

[0047] The taste-masking agent is combined with oseltamivir or a pharmaceutically acceptable salt thereof through a coating process to form drug-containing taste-masked particles.

[0048] The content of the oseltamivir or the pharmaceutically acceptable salt thereof can be 2.00wt%-55.00wt% relative to the total weight of the composition. In some embodiments, the content of the oseltamivir or the pharmaceutically acceptable salt thereof is 5.00wt%-50.00wt%. In some embodiments, the content of the oseltamivir or the pharmaceutically acceptable salt thereof is 10.00wt%-45.00wt%. In some embodiments, the content of the oseltamivir or the pharmaceutically acceptable salt thereof is 15.00wt%-40.00wt%. In some embodiments, the content of the oseltamivir or the pharmaceutically acceptable salt thereof is 20.00wt%-35.00wt%. In some embodiments, the content of the oseltamivir or the pharmaceutically acceptable salt thereof is 25.00wt%-30.00wt%.

[0049] In some embodiments of the present application, comprising: oseltamivir or a pharmaceutically acceptable salt thereof, a taste masking agent selected from a water insoluble material or an enteric material, the water insoluble material comprising ethyl cellulose; the enteric material comprising methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer or hypromellose acetate succinate, and optionally other pharmaceutically acceptable excipients.

[0050] In some embodiments of the present application, comprising: oseltamivir or a pharmaceutically acceptable salt thereof, a taste masking agent selected from a water insoluble material or an enteric material, the water insoluble material comprising ethyl cellulose; the enteric material comprising methacrylic acid-ethyl acrylate copolymer L100-55, and optionally other pharmaceutically acceptable excipients.

[0051] In some embodiments of the present application, comprising: oseltamivir or a pharmaceutically acceptable salt thereof, a taste masking agent selected from a water insoluble material or an enteric material, the weight ratio of the oseltamivir or the pharmaceutically acceptable salt thereof to the taste masking agent is 1.0:0.3-1.0:3.0.

[0052] In some embodiments of the present application, comprising: oseltamivir or a pharmaceutically acceptable salt thereof, a taste masking agent selected from a water insoluble material or an enteric material, the weight ratio of the oseltamivir or the pharmaceutically acceptable salt thereof to the taste masking agent is 1.0:0.3-1.0:0.8.

[0053] In some embodiments of the present application, comprising: oseltamivir or a pharmaceutically acceptable salt thereof, a taste masking agent selected from a water insoluble material or an enteric material, the water insoluble material comprising ethyl cellulose; the enteric material comprising methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer or hypromellose acetate succinate, or the enteric material comprising methacrylic acid-ethyl acrylate copolymer L100-55; and optionally other pharmaceutically acceptable excipients; the weight ratio of the oseltamivir or a pharmaceutically acceptable salt thereof to the taste masking agent is 1.0:0.3-1.0:3.0.

[0054] In some embodiments of the present application, comprising: oseltamivir or a pharmaceutically acceptable salt thereof, a taste masking agent selected from a water insoluble material or an enteric material, the water insoluble material comprising ethyl cellulose; the enteric material comprising methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer or hypromellose acetate succinate, or the enteric material comprising methacrylic acid-ethyl acrylate copolymer L100-55; and optionally other pharmaceutically acceptable excipients; the weight ratio of the oseltamivir or a pharmaceutically acceptable salt thereof to the taste masking agent is 1.0:0.3-1.0:0.8.

[0055] In some embodiments of the present application, comprising: oseltamivir or a pharmaceutically acceptable salt thereof, a taste masking agent selected from a water insoluble material or an enteric material, the water insoluble material comprising ethyl cellulose; the enteric material comprising methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer or hypromellose acetate succinate, or the enteric material comprising methacrylic acid-ethyl acrylate copolymer L100-55; and optionally other pharmaceutically acceptable excipients; the weight ratio of the oseltamivir or a pharmaceutically acceptable salt thereof to the taste masking agent is 1.0:0.3-1.0:3.0; the taste masking agent is combined with the oseltamivir or a pharmaceutically acceptable salt thereof by a coating process to form taste masked drug particles.

[0056] In some embodiments of the present application, comprising: oseltamivir or its pharmaceutically acceptable salt, taste masking agent and optionally other pharmaceutically acceptable excipients, the taste masking agent is selected from a water insoluble material or an enteric material, the water insoluble material includes ethyl cellulose; the enteric material includes methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer or hydroxypropyl methyl cellulose acetate succinate, or the enteric material includes methacrylic acid-ethyl acrylate copolymer L100-55; the weight ratio of oseltamivir or its pharmaceutically acceptable salt to taste masking agent is 1.0:0.3-1.0:0.8; the taste masking agent is combined with oseltamivir or its pharmaceutically acceptable salt by coating process to form taste masked drug-containing particles.

[0057] In some embodiments of the present application, comprising: oseltamivir or its pharmaceutically acceptable salt, taste masking agent and optionally other pharmaceutically acceptable excipients, the taste masking agent is selected from a water insoluble material or an enteric material, the water insoluble material includes ethyl cellulose; the enteric material includes methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer or hydroxypropyl methyl cellulose acetate succinate, or the enteric material includes methacrylic acid-ethyl acrylate copolymer L100-55; the weight ratio of oseltamivir or its pharmaceutically acceptable salt to taste masking agent is 1.0:0.3-1.0:3.0 or 1.0:0.3-1.0:0.8; the taste masking agent is combined with oseltamivir or its pharmaceutically acceptable salt by coating process to form taste masked drug-containing particles; the content of oseltamivir or its pharmaceutically acceptable salt can be 2.00wt%-55.00wt% relative to the total weight of the composition.

[0058] In some embodiments of the present application, comprising: oseltamivir or a pharmaceutically acceptable salt thereof, a taste masking agent selected from a water insoluble material or an enteric material, the water insoluble material comprising ethyl cellulose; the enteric material comprising methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer or hypromellose acetate succinate, or the enteric material comprising methacrylic acid-ethyl acrylate copolymer L100-55, and optionally other pharmaceutically acceptable excipients, the weight ratio of the oseltamivir or a pharmaceutically acceptable salt thereof to the taste masking agent is 1.0:0.3-1.0:3.0 or 1.0:0.3-1.0:0.8; the taste masking agent is combined with the oseltamivir or a pharmaceutically acceptable salt thereof by a coating process to form taste masked particles containing drug; the other pharmaceutically acceptable excipients can include at least one selected from a filler, a binder, a disintegrant, a pH adjuster, a sweetener, a flavoring, a lubricant, a glidant, a suspending agent, a plasticizer, an anti-adherent and a pore former; the content of the sweetener can be 0.10wt%-25.00wt% and / or the content of the flavoring can be 0.10wt%-5.00wt% relative to the total weight of the composition.

[0059] In some preferred embodiments of the present application, a composition comprises: oseltamivir phosphate, a taste-masking agent selected from a water-insoluble material or an enteric material, the water-insoluble material being ethyl cellulose, the enteric material being methacrylic acid-ethyl acrylate copolymer L100-55, and optionally other pharmaceutically acceptable excipients, the weight ratio of oseltamivir phosphate to the taste-masking agent being 1.0:0.3-1.0:0.8, the taste-masking agent being combined with oseltamivir or a pharmaceutically acceptable salt thereof by a coating process to form taste-masked particles; the other pharmaceutically acceptable excipients include at least one selected from a filler, a binder, a disintegrant, a pH regulator, a sweetener, a flavoring, a lubricant, a glidant, a suspending agent, a plasticizer, an anti-adherent, and a pore-forming agent; the content of the filler is 45.00wt%-50.00wt% relative to the total weight of the composition, the content of the binder is 0.02wt%-0.05wt%, the content of the disintegrant is 5.00wt%-10.00wt%, the content of the sweetener is 1.00wt%-2.00wt%, the content of the flavoring is 1.00wt%-2.00wt%, the content of the lubricant is 1.00wt%-2.00wt%, the content of the glidant is 2.00wt%-5.00wt%, the content of the plasticizer is 0-1.50wt%, the content of the anti-adherent is 1.00wt%-3.00wt%, the content of the pore-forming agent is 0-15.00wt%, and the content of oseltamivir or a pharmaceutically acceptable salt thereof is 10.00wt%-20.00wt%, the content of the taste-masking agent is 8.00wt%-16.00wt%, and the composition is an orally disintegrating tablet; the prepared composition can achieve good taste-masking effect, fast release, good taste, high safety, and stability within the above ranges.

[0060] The coating process includes powder coating or granule coating. The powder coating refers to coating the powder containing oseltamivir or a salt thereof directly. The granule coating refers to pre-treating oseltamivir or a salt thereof to prepare drug-containing granules, and then coating the granules with the taste-masking agent, wherein the pre-treatment method includes wet granulation, fluidized bed granulation, or spray drying.

[0061] The single-dose specification of the composition can be 15mg-100mg in terms of oseltamivir.

[0062] The composition can be prepared into a common tablet, an orally disintegrating tablet, a chewable tablet, a dry suspension, or a granule, etc.

[0063] In the second aspect, the present application provides a preparation method of any of the above-mentioned compositions.

[0064] In some embodiments of the present application, a preparation method of any of the above-mentioned compositions comprises:

[0065] (1) mixing oseltamivir or a salt thereof, a filler and optionally other internal excipients as a substrate, spraying a solution or suspension containing a taste-masking agent and optionally other taste-masking layer excipients on the substrate using a fluidized bed to form taste-masked drug-containing particles;

[0066] (2) mixing the taste-masked drug-containing particles with external excipients, tabletting or packaging to obtain the composition.

[0067] In some embodiments of the present application, a method for preparing any of the above-mentioned compositions comprises:

[0068] (1) mixing oseltamivir or a salt thereof, a filler and optionally other internal excipients as a substrate, granulating and drying, and then crushing to form a substrate, spraying a solution or suspension containing a taste-masking agent and optionally other taste-masking layer excipients on the substrate using a fluidized bed to form taste-masked drug-containing particles;

[0069] (2) mixing the taste-masked drug-containing particles with external excipients, tabletting or packaging to obtain the composition.

[0070] In some embodiments of the present application, a method for preparing any of the above-mentioned compositions comprises:

[0071] (1) dissolving oseltamivir or a salt thereof, a filler and optionally other internal excipients in a solvent, removing the solvent by spray drying to obtain a drug-containing spray-dried product as a substrate, spraying a solution or suspension containing a taste-masking agent and optionally other taste-masking layer excipients on the substrate using a fluidized bed to form taste-masked drug-containing particles;

[0072] (2) mixing the taste-masked drug-containing particles with external excipients, tabletting or packaging to obtain the composition.

[0073] The solvent can comprise purified water.

[0074] The internal excipients can comprise at least one selected from the group consisting of sweeteners and flavorings.

[0075] The taste-masking layer excipients can comprise at least one selected from the group consisting of plasticizers, anti-adherents and pore-forming agents.

[0076] The external excipients can comprise at least one selected from the group consisting of fillers, disintegrants, suspending agents, sweeteners, flavorings, lubricants and glidants.

[0077] The plasticizers, anti-adherents, pore-forming agents, fillers, disintegrants, suspending agents, sweeteners, flavorings, lubricants or glidants can be selected from the excipients as described above.

[0078] Advantages

[0079] Compared with the prior art, the present application has the following advantages:

[0080] (1) The composition of the present application is convenient to take, has good taste masking property, good taste, fast release, and good stability.

[0081] (2) When the weight ratio of oseltamivir or its pharmaceutically acceptable salt to taste masking agent is 1.0:0.3-1.0:3.0, the composition prepared in this range can achieve good taste masking effect, good taste, and also ensure the stability of the composition, prolong the shelf life of the composition. When the weight ratio of oseltamivir or its pharmaceutically acceptable salt to taste masking agent is 1.0:0.3-1.0:0.8, the taste masking effect, taste and stability are the best.

[0082] (2) Compared with the prior art which needs two or more taste masking agents to achieve taste masking and fast release at the same time, the composition of the present application can achieve taste masking and fast release at the same time with only one taste masking agent. The present application reduces the number of auxiliary materials, improves the taste, reduces the preparation difficulty, and also reduces the complexity of auxiliary materials, which is also beneficial to the stability of the composition and the safety of the drug, and has significant progress.

[0083] (3) When the taste masking agent of the composition of the present application is selected from ethyl cellulose or methacrylic acid-ethyl acrylate copolymer L100-55, the compatibility of the taste masking agent with oseltamivir or its salt is good, the stability of the composition is good, the safety is high, the stability during the shelf life can be ensured, and even the shelf life of the composition can be prolonged.

[0084] (4) The preparation method of the present application has good reproducibility, simple preparation, and the composition prepared by the method has good uniformity, good taste masking property, fast release, and good stability.

[0085] (5) When the content of the sweetener is 0.10wt%-6.00wt% and / or the content of the flavoring is 0.10wt%-3.00wt%, the taste of the composition is better.

[0086] Term definition:

[0087] "Coating weight gain" refers to the percentage of the difference between the weight of the coated particles and the weight of the uncoated particles to the weight of the uncoated particles.

[0088] "pH" refers to "acidity or basicity"; "mg" means "milligram"; "min" means "minute"; "N" means the unit of hardness "Newton"; "rpm" means the rotation speed "revolutions per minute"; "μm" means "micrometer"; "s" means "second"; "ml" means "milliliter"; "mm" means "millimeter"; "HCl" means "hydrochloric acid"; "M" means molarity "moles per liter"; "°C" means "degrees Celsius"; "RRT" means "relative retention time"; "USP" means "United States Pharmacopeia"; "RH" means "relative humidity".

[0089] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur. For example, "optionally other pharmaceutically acceptable excipients" means that other pharmaceutically acceptable excipients can or can not be present.

[0090] In the foregoing of the present application, whether or not the words "about" or "approximately" are used, all numbers disclosed herein are meant to be approximate. Each numerical limitation disclosed herein can have a reasonable variation, understood by one of ordinary skill in the art to have a value that uses 10% under / over, or a reasonable margin of error, as understood by one of ordinary skill in the art to have a value that uses 1%, 2%, 3%, 4%, or 5% under / over the stated value.

[0091] "Pharmaceutically acceptable" means, in the context used herein, a substance or composition that is suitable for use with humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio as in extensive medical judgment, and effective for its intended use.

[0092] The term "percent by weight" or "percent by weight" or "wt%" is defined as the weight of an individual component in a formulation divided by the total weight of all components in the formulation multiplied by 100. In some cases, if the formulation has an outer coating, the total weight can or can not include the weight of the coating. DETAILED DESCRIPTION

[0093] In order to make the technical solution of the present application better understood by those skilled in the art, some non-limiting examples are further disclosed below to further illustrate the present application in detail.

[0094] The reagents used in the present application can be purchased from the market or can be prepared by the methods described in the present application.

[0095] Example 1: Preparation of taste-masked oseltamivir phosphate granules

[0096] Composition prescription:

[0097]

[0098]

[0099] Preparation process: each substrate component was weighed according to the prescription ratio, sieved and mixed, the taste masking layer coating liquid was prepared according to the prescription ratio, and was sprayed onto the substrate by using the fluidized bed, the spraying was stopped (the amount of the coating liquid used was the amount of the target coating weight gain (after drying)), dried for 3 min, discharged, and the oseltamivir phosphate taste masking granules were obtained.

[0100] Example 2: Preparation of oseltamivir phosphate taste masking granules

[0101] Composition prescription:

[0102]

[0103] Preparation process: oseltamivir phosphate and mannitol were weighed according to the prescription ratio, and were transferred to a granulator for pre-mixing, 2% (W / W) povidone aqueous solution was used as the granulation liquid for wet granulation (the final amount of povidone after drying was shown in the prescription), then wet massing, fluidized bed drying and pulverizer crushing were sequentially performed, and the drug-containing granules were prepared for use. The drug-containing granules, talc and micronized silica gel were weighed according to the prescription ratio, mixed, sieved and shaken to obtain the substrate; the taste masking layer coating liquid was prepared according to the prescription ratio, and was sprayed onto the substrate by using the fluidized bed, the spraying was stopped (the amount of the coating liquid used was the amount of the target coating weight gain (after drying)), dried for 3 min, discharged, and the oseltamivir phosphate taste masking granules were obtained.

[0104] Example 3: Preparation of oseltamivir phosphate taste masking granules

[0105] Composition prescription:

[0106]

[0107] Preparation process: same as example 2.

[0108] Example 4: Preparation of oseltamivir phosphate taste masking granules

[0109] Composition prescription:

[0110]

[0111]

[0112] Preparation process: same as example 2.

[0113] Example 5: Preparation of oseltamivir phosphate taste masking granules

[0114] Composition prescription:

[0115]

[0116]

[0117] Preparation process: Weigh oseltamivir phosphate and mannitol according to the prescription ratio, add them to purified water, stir until completely dissolved, and then spray dry to remove the purified water to obtain drug-containing granules for later use. Weigh the drug-containing granules, talc powder, and micronized silica gel according to the prescription ratio, mix and sieve, and shake well to obtain the substrate; prepare the flavor-masking coating solution according to the prescription ratio for later use. Spray the flavor-masking coating solution onto the substrate using a fluidized bed, stop spraying (the amount of sprayed solution is the amount of coating solution used for the target coating weight gain (after drying), dry for 3 minutes, and then discharge to obtain the final product.

[0118] Example 6: Preparation of Oseltamivir Phosphate Masked Granules

[0119] Composition formulation:

[0120]

[0121] Preparation process: Same as in Example 5.

[0122] Example 7: Preparation of Oseltamivir Phosphate Masked Granules

[0123] Composition formulation:

[0124]

[0125]

[0126] Preparation process: Same as in Example 2.

[0127] Example 8: Preparation of Oseltamivir Phosphate Orally Disintegrating Tablets

[0128] Composition formulation:

[0129]

[0130] Preparation process: Weigh all components except sodium stearate according to the prescription ratio, sieve and transfer to a mixing tank, mix at 10 rpm for 20 min, add sodium stearate according to the prescription ratio and mix for 5 min, compress into tablets to obtain oseltamivir phosphate orally disintegrating tablets with a hardness of 30N-55N. The single dose of oseltamivir is 15mg-75mg.

[0131] Comparative Example 1: Preparation of Oseltamivir Phosphate Masked Granules

[0132] Composition formulation:

[0133]

[0134] Preparation process: Same as in Example 1.

[0135] Comparative Example 2: Preparation of Oseltamivir Phosphate Masked Granules

[0136] Composition prescription:

[0137]

[0138]

[0139] Preparation process: same as Example 5.

[0140] Preparation of taste-masked oseltamivir phosphate granules

[0141] Composition prescription:

[0142]

[0143] Preparation process: same as Example 2.

[0144] Preparation of taste-masked oseltamivir phosphate granules (using Eudragit EPO as coating material)

[0145]

[0146]

[0147] Preparation process: same as Example 2.

[0148] Preparation of oseltamivir phosphate lyophilized mouth-disintegrating tablets

[0149] Composition prescription (reference CN201310355363.2):

[0150] Component Formulation ratio (wt%) Oseltamivir phosphate 17.72 Mannitol 40.46 Gelatin 33.72 Dextran 4.05 Aspartame 2.43 Milk flavor 1.62 Purified water 100.00

[0151] Preparation process: add the prescribed amount of gelatin to two-thirds of the prescribed amount of purified water, mix and heat to complete dissolution; add the mixture of uniformly mixed mannitol and oseltamivir phosphate, stir until uniform, continue to add dextran, aspartame and milk flavor, stir until uniform, add the remaining prescribed amount of purified water, stir and mix uniformly, transfer to a freeze dryer, freeze-dry to obtain oseltamivir phosphate lyophilized mouth-disintegrating tablets. The single-dose specifications of oseltamivir in Examples 5-7 are 10 mg, 30 mg and 75 mg, respectively.

[0152] Preparation of oseltamivir phosphate mouth-disintegrating tablets (using direct mixing and tabletting process)

[0153] Composition prescription:

[0154]

[0155]

[0156] Preparation process: the components except for sodium stearyl fumarate were weighed according to the prescription ratio, sieved and transferred into a mixing barrel, mixed at 10 rpm for 20 min, sodium stearyl fumarate was added according to the prescription ratio and mixed for 5 min, and then tableting was performed to obtain oseltamivir phosphate orally disintegrating tablets with a hardness of 30 N-55 N, and the single dose specifications of oseltamivir were 15 mg-75 mg.

[0157] Preparation of oseltamivir phosphate orally disintegrating tablets

[0158] Composition prescription:

[0159]

[0160] Preparation process: same as Example 8.

[0161] Example 9: taste masking effect test

[0162] Electronic tongue bitterness value determination method:

[0163] Electronic tongue manufacturer (model): INSENT (Tasting Sensing system SA402B), Japan.

[0164] Electronic tongue bitterness value determination of oseltamivir phosphate raw material: artificial saliva was used to prepare different series of concentrations (0.03 mg / ml, 0.06 mg / ml, 0.12 mg / ml, 0.25 mg / ml, 0.5 mg / ml, 1.0 mg / ml, 2.0 mg / ml, 4.0 mg / ml, 6.0 mg / ml) of oseltamivir phosphate solution, after complete dissolution, the bitterness value of oseltamivir phosphate at each concentration was detected, and the appropriate determination concentration was selected according to the response sensitivity, and the appropriate determination concentration was 0.5 mg / ml (calculated as oseltamivir).

[0165] Electronic tongue bitterness value determination of oseltamivir phosphate taste masking granules: artificial saliva was used to prepare the drug-containing taste masking granules into a concentration of 0.5 mg / ml (calculated as oseltamivir), and the bitterness value was determined after 20 s of residence and filtration through a 0.45 μm water filter membrane.

[0166] Electronic tongue bitterness value determination of oseltamivir phosphate orally disintegrating tablets: one 75 mg specification (calculated as oseltamivir) oseltamivir phosphate orally disintegrating tablet was placed in 150 ml artificial saliva, and after complete disintegration, the bitterness value was determined immediately after filtration through a 0.45 μm water membrane to obtain a filtrate.

[0167] The results are shown in Table 2.

[0168] Taste evaluation method:

[0169] Taste test of oseltamivir phosphate taste-masked granules: 1 to 3 healthy adults, without taking water, put the granules containing 75 mg of oseltamivir into the oral cavity and start timing, spit out after staying for about 25 s, record the bitterness degree, whether there is grit feeling, and the residual taste after rinsing.

[0170] Taste test of oseltamivir phosphate orally disintegrating tablets: 1 to 3 healthy adults, without taking water, put a piece of orally disintegrating tablet into the oral cavity and start timing, the tongue is slightly peristalsis, record the time of complete disintegration of the tablet, the bitterness degree, whether there is grit feeling, and record the residual taste after rinsing. The bitterness evaluation is scored according to Table 1 for bitterness, and the average value is calculated. The results are shown in Table 2.

[0171] Table 1: Correspondence table of bitterness score and bitterness evaluation

[0172] Total Bitterness score 0 Bitterness evaluation 1 No bitterness at all 1.5 Almost no bitterness 2 Very weak bitterness 2.5 Little bitterness 3 Moderate bitterness 3.5 Obvious bitterness 4 Strong bitterness

[0173] Table 2: Electronic tongue bitterness value determination value and population taste test results

[0174]

[0175]

[0176] Conclusion: When the weight ratio of raw material drug and taste masking agent is within 1.0:0.3-1.0:3.0, the taste masking effect can be achieved and the taste is good. When the weight ratio of raw material drug and taste masking agent is greater than 1.0:0.3, the taste masking effect is poor; when the weight ratio of raw material drug and taste masking agent is less than 1.0:3.0, the grit feeling is strong and the taste is poor. Simple direct mixing or freeze-drying process (as described in CN201310355363.2 patent) has obvious bitterness when the single dose specification is 30 mg or more, and cannot achieve the taste masking effect.

[0177] Example 10: In vitro dissolution data

[0178] The taste-masked granules, orally disintegrating tablets prepared in each example and comparative example, and oseltamivir phosphate capsules reference (Tamiflu, Roche) were determined for dissolution in 0.1M HC1 medium, the volume of the medium was 900±9ml, the temperature of the medium was 37.0±0.5℃, the paddle method, 50rpm / min was used for in vitro dissolution test. The dissolution sampling time point was 15min. The sampling position was at the midpoint of the paddle tip to the liquid surface, 10mm away from the inner wall of the dissolution cup. High performance liquid chromatography (HPLC) method was used for in vitro dissolution content determination. The test results are shown in Table 3.

[0179] Table 3: In vitro dissolution results (n=3)

[0180] Very strong bitterness Sample Content (%) 95±2.06 Example 1 94±1.13 Example 2 95±1.60 Example 4 96±1.22 Example 5 94±2.10 Example 7 94±1.05 Formulation 2 in Example 8 96±1.20 Formulation 3 in Example 8 94±1.94 Formulation 4 in Example 8 70±2.12 Comparative Example 3 94±1.60 Comparative Example 4 95±1.09 Formulation 5 in Comparative Example 9 72±0.09 Formulation 8 in Comparative Example 9 Oseltamivir phosphate capsule reference (TAMIFLU, Roche) 98±2.08

[0181] Results analysis: The samples of Examples 1, 2, 4, 5, 7 and 8 can all be dissolved by more than 90% in 0.1M HC1 medium within 15 minutes, while the samples of Comparative Examples 3 and 9 can only be dissolved by about 70% in 0.1M HC1 medium within 15 minutes.

[0182] Conclusion: When the weight ratio of the raw material drug and the taste masking agent is within 1.0:0.3-1.0:3.0, the drug can be quickly dissolved and the drug release is not affected. When the weight ratio of the raw material drug and the taste masking agent is less than 1.0:3.0, the dissolution is significantly slowed down.

[0183] Example 11: Compatibility detection

[0184] The oseltamivir phosphate and the taste masking agent were stored in a vial at 25℃ for 21 days, and then the related substances were detected according to the method of the United States Pharmacopoeia to investigate the compatibility of the raw and auxiliary materials, and the results are shown in Table 4 (n=3, recorded as the average value), wherein only the key impurities are listed, and the rest of the impurities or unknown impurities are within the limit, and therefore are not listed.

[0185] Table 4: Results of related substances of raw and auxiliary material compatibility after storage at 25℃ for 21 days

[0186]

[0187] Conclusion: The taste masking agent has good compatibility with oseltamivir phosphate, while the taste masking agent used in the patent CN201310290328.7 (i.e. Eudragit EPO) will cause the impurities to exceed the limit and has poor compatibility with oseltamivir phosphate.

[0188] Example 12: Stability data

[0189] The oseltamivir phosphate taste masking granules were stored in a vial at 50℃ high temperature for 21 days, and the orally disintegrating tablets were stored in double aluminum packaging at 40℃ / 75% RH for 6 months. The related substances were detected according to the method of the United States Pharmacopoeia, and the results are shown in Tables 5 and 6 (n=3, recorded as the average value), wherein only the key impurities are listed, and the rest of the impurities or unknown impurities are within the limit, and therefore are not listed.

[0190] Table 5: Results of related substances of taste masking granules at 50℃ high temperature for 21 days

[0191]

[0192]

[0193] Table 6: Results of related substances of orally disintegrating tablets at 40℃ / 75% RH for 6 months

[0194]

[0195] Conclusion: The taste-masking agents and the content range of the taste-masking agents described in Examples 1-8 have good stability, and the stability is poor when the weight ratio of the raw material and the taste-masking agent is greater than 1.0:0.3, and the taste-masking agent (i.e. Eudragit EPO) used in the patent CN201310290328.7 will cause the impurities to exceed the standard and the stability is poor.

[0196] Summary:

[0197] (1) The ethyl cellulose or methacrylic acid-ethyl acrylate copolymer L100-55 has good compatibility with oseltamivir or its salt, and the composition prepared by using them has good stability and good taste masking.

[0198] (2) The composition prepared by using the Eudragit EPO described in the prior art has poor compatibility and poor stability.

[0199] (3) The composition prepared by using the weight ratio of oseltamivir or its pharmaceutically acceptable salt and the taste-masking agent in the range of 1.0:0.3-1.0:3.0 has good taste masking effect, good taste, good dissolution effect and good stability; and the composition prepared by using the weight ratio outside this range has poor taste masking effect, poor taste, poor stability and poor dissolution effect.

[0200] (4) The composition prepared without using the taste-masking agent and without performing the coating process has poor taste and poor stability.

[0201] (5) When the content of the sweetening agent is 0.10wt%-6.00wt% and / or the content of the flavoring agent is 0.10wt%-3.00wt%, the composition has better taste.

[0202] The method of the present application has been described by preferred embodiments, and the related personnel can obviously modify or appropriately change and combine the method and application described herein to realize and apply the present application technology within the content, spirit and scope of the present application. The skilled in the art can refer to the content herein to appropriately improve the process parameters. It is particularly pointed out that all similar substitutions and modifications are obvious to the skilled in the art, and they are considered to be included in the present application.

Claims

1. A composition comprising: oseltamivir phosphate, a flavor masking agent, and optionally other pharmaceutically acceptable excipients, wherein the flavor masking agent is a water-insoluble material or an enteric material; the water-insoluble material is ethyl cellulose, the enteric material is methacrylate-ethyl acrylate copolymer L100-55, the weight ratio of oseltamivir phosphate to the flavor masking agent is 1.0:0.3-1.0:0.8, and the flavor masking agent is combined with oseltamivir phosphate via a coating process to form drug-containing flavor-masked particles; the other pharmaceutically acceptable excipients include at least one selected from fillers, binders, disintegrants, pH adjusters, sweeteners, flavorings, lubricants, flow aids, suspending agents, plasticizers, anti-adhesives, and pore-forming agents; the content of the filler is 45.00 wt%-50.00 wt% relative to the total weight of the composition, and the content of the binder is 0. The composition comprises 0.02wt%-0.05wt%, the disintegrant content is 5.00wt%-10.00wt%, the sweetener content is 1.00wt%-2.00wt%, the flavoring content is 1.00wt%-2.00wt%, the lubricant content is 1.00wt%-2.00wt%, the glidant content is 2.00wt%-5.00wt%, the plasticizer content is 0-1.50wt%, the anti-adhesive content is 1.00wt%-3.00wt%, the porogen content is 0-15.00wt%, the oseltamivir phosphate content is 10.00wt%-20.00wt%, and the flavor masking agent content is 8.00wt%-16.00wt%. The composition is an orally disintegrating tablet.

2. A method for preparing the composition of claim 1, comprising: (1) Oseltamivir phosphate, filler and optional other internal excipients are mixed as a substrate, and a solution or suspension containing masking agent and optional other masking layer excipients is sprayed onto the substrate in a fluidized bed to form drug-masked particles; (2) The drug-containing masking particles are mixed with excipients, and then tableted or packaged to obtain the composition; Or include: (1) Oseltamivir phosphate, filler and optional other internal excipients are mixed, granulated and dried and pulverized as substrate. The solution or suspension containing the masking agent and optional other masking layer excipients is sprayed onto the substrate in a fluidized bed to form drug-masked particles. (2) The drug-containing masking particles are mixed with excipients, and then tableted or packaged to obtain the composition; Or include (1) Dissolve oseltamivir phosphate, filler and optional other internal excipients in a solvent, remove the solvent by spray drying to obtain a drug-containing spray-dried material as a substrate, and use a fluidized bed to spray the solution or suspension containing the masking agent and optional other masking layer excipients onto the substrate to form drug-containing masking particles. (2) The drug-containing masking particles are mixed with excipients, and then tableted or packaged to obtain the composition.

3. The method according to claim 2, wherein the internal excipient comprises at least one selected from sweeteners and flavorings; and / or the flavor-masking layer excipient comprises at least one selected from plasticizers, anti-sticking agents and pore-forming agents; and / or the external excipient comprises at least one selected from fillers, disintegrants, suspending agents, sweeteners, flavorings, lubricants and flow aids; and / or the solvent comprises water.

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