WO2007112619A1 - Granule de phosphate d'oseltamivir et son procédé de préparation - Google Patents

Granule de phosphate d'oseltamivir et son procédé de préparation Download PDF

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WO2007112619A1
WO2007112619A1 PCT/CN2006/002043 CN2006002043W WO2007112619A1 WO 2007112619 A1 WO2007112619 A1 WO 2007112619A1 CN 2006002043 W CN2006002043 W CN 2006002043W WO 2007112619 A1 WO2007112619 A1 WO 2007112619A1
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Prior art keywords
oseltamivir
weight
granules
granule
phosphate
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PCT/CN2006/002043
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English (en)
French (fr)
Inventor
Song Li
Wu Zhong
Junhai Xiao
Yunde Xie
Xingzhou Li
Hao Cui
Zhibing Zheng
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Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
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Application filed by Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China filed Critical Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
Priority to JP2009503391A priority Critical patent/JP5222841B2/ja
Priority to EP06775361.6A priority patent/EP2005945B1/en
Priority to ES06775361.6T priority patent/ES2604778T3/es
Priority to KR1020087024836A priority patent/KR101303325B1/ko
Priority to US12/225,935 priority patent/US9034382B2/en
Publication of WO2007112619A1 publication Critical patent/WO2007112619A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals

Definitions

  • the invention relates to oseltamivir granules and a preparation method thereof. Background technique
  • Neuraminidase (NA) inhibitors are a class of anti-influenza drugs developed in recent years.
  • oseltamivir phosphate As a newly developed neuraminidase inhibitor, oseltamivir phosphate is effective against both influenza A and B viruses. It is not easy to resist, has good patient tolerance and high safety, and is clinically used for the prevention and treatment of influenza.
  • Oseltamivir phosphate is a therapeutic drug for the prevention and control of influenza pandemics in the World Health Organization and the Ministry of Health of China. It is also a national strategic reserve drug for preventing and controlling influenza pandemics in China and the rest of the world.
  • oseltamivir phosphate dosage form in China, which has a unit dose of 98.5 mg/granule (including oseltamivir 75 mg), according to the weight-dose form recommended for children over 1 year old. , taking the dose of oseltamizine phosphate is shown in the table below:
  • the plastic capsule is difficult to be accurately administered to children, especially young children, and the safety of administration cannot be ensured.
  • the dosage form is not suitable for these specific populations. Therefore, there is a need to develop new oseltamivir phosphate dosage forms suitable for the elderly, children, and severely flu patients. Summary of the invention The inventors have researched and developed oseltamivir granules with numerous advantages: for example, the granules are easily soluble in water, can be blunt, and are suitable for children and patients who have difficulty swallowing capsules, and the dosage can be based on the age of the patient. The weight and the weight are conveniently selected, and the preparation process is simple and easy, and the cost is low.
  • one aspect of the invention relates to oseltamivir granules comprising oseltamivir phosphate, at least one diluent, at least one binder, and optionally a food flavor, a sweetener, and / or food coloring.
  • the oseltamivir phosphate granules of the present invention comprises 1. 97-19.8% by weight of oseltamivir phosphate, 75. 0-97. 5 wt% diluent, 0. 1-5. 0 % by weight of binder, and optionally from 1.0 to 5.0% by weight of food flavor, sweetener and/or food coloring. The sum of the components is equal to or less than 100%.
  • Another aspect of the invention provides a process for the preparation of oseltamivir granules comprising oseltamivir phosphate, a diluent, a binder, and optionally a food flavor, a sweetener, and/or an edible
  • the pigment is mixed, and the steps of making soft materials, sieving granulation, and granulating are carried out.
  • oseltamivir granules per gram contains 0. 0197g-0. 198g of oseltamivir phosphate, and a diluent, a binder and optionally a food flavor, a sweetener And / or food coloring.
  • the oseltamivir granule of the present invention comprises:
  • Optional 1. 0-5. 0% by weight of food flavor, sweetener and/or food coloring. The sum of the above components is equal to or less than 100%.
  • the oseltamivir granules per unit dose contains from 15 mg to 150 mg of active ingredient based on oseltamivir, for example, per The unit dose contains 15 mg, 25 mg, 30 mg > 45 mg, 60 mg, 75 mg or 90 mg of oseltamivir, preferably 15 mg and 25 mg.
  • the granule of the invention adopts 30-55 v/v%, preferably 40 v/v% aqueous solution of ethanol as a wetting agent to make a soft material, so that the obtained granules have better elasticity, good fluidity, accurate loading, uniform content, and High release.
  • the diluent used in the oseltamivir granules is selected from the group consisting of: one or both of powdered sugar, dextrin, and sorbitol, including but not limited to sucrose, glucose, a sugar in the usual sense, such as aspartame or stevioside, which can have a flavoring effect at the same time;
  • the binder is selected from the group consisting of sodium carboxymethylcellulose, methylcellulose, povidone, and scutellaria One or more of gum arabic, the binder may have a suspending effect at the same time;
  • the sweetener is selected from the group consisting of sucrose, glucose, aspartame or stevioside.
  • the oseltamivir granules of the present invention can be prepared as follows:
  • the main drug content and water content of the granules are determined to determine the amount and packaging; or the dry granules are mixed with the food coloring and packaged to obtain oseltamivir granules.
  • the granules of the present invention may be in a unit dosage form, and may be packaged in a bottle or in a bag, and each bottle or bag may contain 0.6 to 6 g of granules.
  • the formulation is packaged in an aluminum-plastic composite film, each package containing 0.6 to 6 grams of granules.
  • the granule tightness is suitable, the fluidity is good, the loading is accurate, the content is uniform, and the release is high;
  • Example 1 Preparation of 15 mg of oseltamivir granules
  • the oseltamivir phosphate and its excipients were pulverized through a 100 il sieve, and the prescribed amount of oseltamivir phosphate, povidone k30 and sucrose were accurately weighed and mixed uniformly by equal addition; using 40v/v% ethanol aqueous solution
  • the soft material is sieved through a 14-mesh sieve.
  • the wet granules are placed in an oven at 45-60 ° C, dried, and sieved through a 14-mesh sieve. After the fine powder is sieved through a No. 5 sieve, the main drug content and moisture of the granule are determined.
  • the above granules were dispensed into a package of 0.6 g per unit dose containing 15 mg of oseltamivir and packaged in an aluminum-plastic composite film.
  • Example 2 Preparation of 15 mg of oseltamivir granules
  • the oseltamivir phosphate and the auxiliary materials were pulverized through a 100-mesh sieve, and the prescribed amount of oseltamivir phosphate, povidone k30 and sucrose were accurately weighed and uniformly mixed by the equal amount; 40v/v was used. /.
  • the soft material is made of ethanol aqueous solution, and the granules are sieved through 14 mesh. The wet granules are placed in an oven at 45-60 °C, and then sieved through a 14-mesh sieve. After the fine powder is sieved through a No. 5 sieve, the main drug content of the granules is determined. And moisture, determine the loading, the above particles are divided into 1.0 Og / per unit dose package, which contains oseltamivir 15rag, packaged with aluminum-plastic composite film.
  • the preparation method was the same as in Example 1.
  • the above granules were packaged into lg/package per unit dose containing 25 mg of oseltamivir, packaged in an aluminum-plastic composite film.
  • the preparation method was the same as in Example 1.
  • the above granules were packaged into a package of 1. 2 g per unit dose containing oseltamivir 25 mg in an aluminum-plastic composite film package.
  • Example 6 Preparation of 25 mg of oseltamivir granules
  • the preparation method was the same as in Example 1.
  • the above granules were packaged into lg per unit dose package containing oseltamivir 25 mg, packaged in an aluminum-plastic composite film.
  • Example 7 Preparation of 25 mg of oseltamivir granules
  • the preparation method was the same as in Example 1.
  • the above granules were packaged into lg/package per unit dose containing oseltamivir 25 mg in an aluminum-plastic composite film package.
  • Example 8 Preparation of 25 mg of oseltamivir granules Component weight
  • the preparation method was the same as in Example 1.
  • the above granules were packaged into lg/package per unit dose containing oseltamivir 25rag in aluminum-plastic composite film.
  • Example 9 Preparation of 25 mg of oseltamivir granules
  • the oseltamivir phosphate and its excipients were pulverized through a 100 mesh sieve, and the prescribed amount of oseltamivir phosphate, sodium carboxymethylcellulose and sucrose were accurately weighed and mixed uniformly by equal addition; 40% ethanol aqueous solution was used.
  • the soft material is made into a 14-mesh sieve.
  • the wet granules are placed in an oven at 45-60 °C, and then sieved through a 14-mesh sieve. After the fine powder is sieved through a No. 5 sieve, the amount of the main granules and the moisture are determined.
  • the above granules are packaged into lg/package per unit dose containing oseltamivir 25rag, aluminum-plastic composite film package.
  • Example 10 Preparation of 25 mg of oseltamivir granules
  • the oseltamivir phosphate and its excipients were pulverized through a 100 mesh sieve, and the prescribed amount of oseltamivir, methylcellulose and sucrose were accurately weighed and mixed uniformly by equal addition; using 40v/v% ethanol aqueous solution Soft material, after 14 mesh sieve granulation, wet granules are dried in an oven at 45-60 °C, sieved through a 14-mesh sieve, and sieved to a fine powder with a No. 5 sieve to determine the main drug content and moisture of the granules.
  • the above granules were packaged in lg/package per unit dose containing 25 mg of oseltamivir, packaged in an aluminum-plastic composite film.
  • Example 11 Preparation of 150 mg of oseltamivir granules
  • the preparation method was the same as in Example 1.
  • the above granules were packaged into lg/package per unit dose containing oseltamivir 150 mg in an aluminum-plastic composite film package.
  • Example 12 Solubility and dispersibility test of oseltamivir granules granules The above granules prepared in Example 1 were hydrolyzed to a solution having a concentration of 5 mg/ml in oseltamivir, and the pH was measured. About 5.4, the solution is a neutral to weakly acidic solution, which is non-irritating to the human body and has a good taste, which is beneficial to the patient.
  • the sum of the No. 1 sieve and the No. 5 sieve shall not exceed 15% of the test quantity.
  • the above granule sample inspection result All comply with the Pharmacopoeia regulations, so that the uniformity of the particle size of the granules can be fully ensured, and the particles are not affected by the moisture agglomeration or pulverization during transportation and storage.

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Description

磷酸奥司他韦颗粒剂及其制备方法 技术领域
本发明涉及碑酸奥司他韦颗粒剂及其制备方法。 背景技术
神经氨酸酶（NA)抑制剂是近年来开发的一类抗流感病毒药物， 磷酸奥司他韦作为一种最新研制的神经氨酸酶抑制剂， 具有对 A、 B 型流感病毒均有效、 不易耐药和患者耐受性好、 安全性高等优 点， 临床上用于预防和治疗流感。 磷酸奥司他韦是世界卫生組织 和我国卫生部防控流感大流行的治疗用药， 也是我国和世界各国 防控流感大流行的国家战略储备药品。
目前， 在我国有市售的磷酸奥司他韦剂型为胶嚢， 其单位剂 量为 98. 5mg/粒 （其中含奥司他韦 75mg ) , 按照对 1岁以上的儿 童推荐的体重-剂量表， 服用磷酸奥司他书剂量见下表：
Figure imgf000002_0001
可见， 胶嚢因剂量太大， 对于儿童患者尤其是低龄儿童患者不易 准确给药， 无法确保给药的安全性；另一方面， 由于老年人、 儿童 以及流感重症患者吞咽不便或吞咽困难， 胶袁剂型对于这些特定 人群而言并不适合。 因此， 需要开发适合老年人、 儿童以及流感 重症患者服用的磷酸奥司他韦新剂型。 发明内容 本发明人经过研究， 开发出具有众多优点的磷酸奥司他韦颗 粒剂：例如颗粒易溶于水， 可以冲服，适合于儿童和吞咽胶嚢有困 难的患者服用，用药剂量可以根据患者的年龄和体重方便地选择 使用，并且其制备工艺简便易行， 成本低廉。
因此，本发明的一个方面涉及磷酸奥司他韦颗粒剂，所述颗粒 剂包含磷酸奥司他韦、 至少一种稀释剂、 至少一种粘合剂以及任 选的食用香精、 甜味剂和 /或食用色素。
具体来说，本发明的磷酸奥司他韦颗粒剂包含 1. 97-19. 8 重 量％的磷酸奥司他韦， 75. 0-97. 5重量％稀释剂， 0. 1-5. 0重量％ 粘合剂，以及任选的 1. 0-5. 0重量％食用香精、 甜味剂和 /或食用 色素。 各組分之和等于或小于 100%。
本发明的另一个方面提供了磷酸奥司他韦颗粒剂的制备方法， 所述方法包括将磷酸奥司他韦、 稀释剂、 粘合剂以及任选的食用 香精、 甜味剂和 /或食用色素进行混合，制软材、 过筛制粒以及整 粒等步骤。
根据本发明的一个实施方案，每克磷酸奥司他韦颗粒剂中含 有 0. 0197g-0. 198g的磷酸奥司他韦， 以及稀释剂、粘合剂和任选 的食用香精、 甜味剂和 /或食用色素。
根据本发明的另一个实施方案，本发明的磷酸奥司他韦颗粒 剂包含：
磷酸奥司他韦 1. 97-19. 8重量％，
稀释剂 75. 0-97. 5重量％，
粘合剂 0. 1-5. 0重量％，和
任选的 1. 0-5. 0重量％的食用香精、 甜味剂和 /或食用色素。 上述各组分之和等于或小于 100%。
根据本发明进一步的实施方案，每单位剂量的磷酸奥司他韦 颗粒剂中含有以奥司他韦计的活性成分为 15mg-150mg， 例如，每 单位剂量含有 15mg、 25mg、 30mg > 45mg、 60mg、 75mg或 90mg的 奥司他韦，优选 15mg和 25mg。
本发明的颗粒剂采用 30-55v/v%、 优选 40v/v%的乙醇水溶液 作为润湿剂制软材， 因此得到的颗粒松紧度较适合， 流动性良好， 装量准确， 含量均一，并且释放度高。
根据本发明， 磷酸奥司他韦颗粒剂中所采用的稀释剂选自： 糖粉、糊精、 山梨醇中的一种或两种，所述的糖粉包括但不局限于 蔗糖、 葡萄糖、 阿斯巴甜或甜菊苷等通常意义上的糖，所述稀释剂 可以同时具有矫味作用； 粘合剂选自羧甲基纤维素钠、 甲基纤维 素、 聚维酮、 西黄耆胶、 阿拉伯胶的一种或多种，所述粘合剂可以 同时具有助悬作用；甜味剂选自蔗糖、葡萄糖、阿斯巴甜或甜菊苷。
本发明更加优选的配方示于实施例。
本发明的磷酸奥司他韦颗粒剂可按以下方法制备：
1 )将磷酸奥司他韦、稀释剂、 粘合剂置于 40 ~ 60 °C下干燥 4 小时， 粉碎过 100目筛备用；
2 )精确称取处方量的磷酸奥司他韦、 稀释剂、 粘合剂， 任选 加入食用香精， 按等量递加法混合均勾， 得到混合粉；
3 )用 30-55 / 的乙醇水溶液制软材， 过 14 目筛制粒；
4 )将湿颗粒置于 45- 60 °C下充分干燥， 经 14 目筛整粒， 得 到干颗粒；
5) 将干颗粒用 5 号筛筛去细粉后， 测定颗粒主药含量和水 分， 确定装量， 包装； 或者将干颗粒与食用色素混匀后包装， 即 得到磷酸奥司他韦颗粒。
本发明的颗粒剂为单位剂量形式， 可以包装成瓶， 也可以包 装成袋，每一瓶或袋中可含有 0. 6 ~ 6g颗粒剂。优选地，配方用铝 塑复合膜包装， 每包装含有 0. 6 ~ 6克颗粒剂。
对得到的颗粒进行测试发现，本发明的颗粒剂（尤其是使用优 选配方制备得到的颗粒剂）具有以下优点：
(1)颗粒松紧度较合适， 流动性良好， 装量准确， 含量均一， 释放度高；
(2)颗粒剂的稳定性好， 储藏时间长；
( 3)颗粒剂易溶于水， 水溶液清亮透明且口感良好，儿童用药 的依从性高， 同时可以提高磷酸奥司他韦的生物利用度；
(4)颗粒剂服用方便，入口即化，既可以含服也可以用水冲服;
(5)生产工艺简便易行， 成本低廉。
(6)容易确定儿童患者的给药剂量。 具体实施方式
实施例 1 : 规格为 15mg的磷酸奥司他韦颗粒剂的制备
Figure imgf000005_0001
将磷酸奥司他韦以及辅料均粉碎过 100 il筛， 精确称取处方 量的磷酸奥司他韦、聚维酮 k30和蔗糖，按等量递加法混合均匀； 用 40v/v%乙醇水溶液制软材，过 14目筛制粒，将湿颗粒置于 45-60 °C烘箱烘干后， 经 14 目筛整粒， 用 5号筛筛去细粉后， 测定颗粒 主药含量和水分， 确定装量， 将上述颗粒分装为 0. 6g/每单位剂 量的包装， 其中含有奥司他韦 15mg， 用铝塑复合膜包装。
也可以将其分装成含有以奥司他韦计 30mg或 45mg的单位包 实施例 2: 规格为 15mg的磷酸奥司他韦颗粒剂的制备
Figure imgf000006_0001
将磷酸奥司他韦以及辅料均粉碎过 100 目筛， 精确称取处方 量的磷酸奥司他韦、聚维酮 k30和蔗糖，按等量递加法混合均匀； 用 40v/v。/。乙醇水溶液制软材，过 14目筛制粒，将湿颗粒置于 45-60 °C烘箱烘干后， 经 14 目筛整粒， 用 5号筛筛去细粉后， 测定颗粒 主药含量和水分， 确定装量， 将上述颗粒分装为 l. Og/每单位剂 量的包装， 其中含有奥司他韦 15rag， 用铝塑复合膜包装。
也可以将其分装成含有以奥司他韦计 30mg或 45rag的单位包 装。 实施例 3: 规格为 25mg的磷酸奥司他韦颗粒剂的制备
成分 重
磷酸奥司他韦 32. 83 g
(按干品计） (含奥司他韦 25g) 蔗糖 947. 17 g
聚维酮 k30 20 g
总量 1000 g 制备方法同实施例 1。将上述颗粒分装为 lg/每单位剂量的包 装， 其中含有奥司他韦 25mg， 铝塑复合膜包装。
也可以分装成含有以奥司他韦计 15rag、 30mg或 45mg的单位 包装。 实施例 4: 规格为 25mg的磷酸奥司他韦颗粒剂的制备
Figure imgf000007_0001
制备方法同实施例 1。将上述颗粒分装为 1. 2g/每单位剂量的 包装， 其中含有奥司他韦 25mg， 铝塑复合膜包装。
也可以分装成含有以奥司他韦计 15mg、 30rag或 45mg的单位 包装。 实施例 5 : 规格为 25rag的磷酸奥司他韦颗粒剂的制备
Figure imgf000007_0002
制备方法同实施例 1。将上述颗粒分装为 l g/每单位剂量的包 装， 其中含有奥司他韦 25mg， 铝塑复合膜包装。 也可以分装成含有以奥司他韦计 15mg、 30mg、 45mg , 60mg 或 75mg的单位包装。 实施例 6: 规格为 25mg的磷酸奥司他韦颗粒剂的制备
Figure imgf000008_0001
制备方法同实施例 1。 将上述颗粒分装为 lg每单位剂量的包 装， 其中含有奥司他韦 25mg， 铝塑复合膜包装。
也可以分装成含有以奥司他韦计 15mg、 30mg、 45mg、 60mg、 75mg或 90mg的单位包装。 实施例 7: 规格为 25mg的磷酸奥司他韦颗粒剂的制备
Figure imgf000008_0002
制备方法同实施例 1。将上述颗粒分装为 lg/每单位剂量的包 装， 其中含有奥司他韦 25mg， 铝塑复合膜包装。
也可以分装成含有以奥司他韦计 15rag、 30mg、 45mg 60mg、 75mg、 90mg或 l 50mg的单位包装。 实施例 8: 规格为 25mg的磷酸奥司他韦颗粒剂的制备 成分 重量
磷酸奥司他韦 197. 2 g
(按干品计） (含奥司他韦 150 g) 蔗糖 5683. 6 g
聚维酮 k30 120 g
总量 6000 g
制备方法同实施例 1。将上述颗粒分装为 lg/每单位剂量的包 装， 其中含有奥司他韦 25rag , 铝塑复合膜包装。
也可以分装成含有以奥司他韦计 15mg、 30mg、 45mg、 60mg、 75mg、 90mg或 150mg的单位包装。 实施例 9: 规格为 25mg的磷酸奥司他韦颗粒剂的制备
Figure imgf000009_0001
将磷酸奥司他韦以及辅料均粉碎过 1 00 目筛， 精确称取处方 量的磷酸奥司他韦、 羧曱基纤维素钠和蔗糖， 按等量递加法混合 均匀；用 40%乙醇水溶液制软材，过 14目筛制粒，湿颗粒置于 45-60 °C烘箱烘干后， 经 14目筛整粒， 用 5号筛筛去细粉后， 测定颗粒 主药舍量和水分， 将上述颗粒分装为 lg/每单位剂量的包装， 其 中含有奥司他韦 25rag， 铝塑复合膜包装。
也可以分装成含有以奥司他韦计 15mg、 30mg、 45mg、 50rag 或 75mg的单位包装。 实施例 10: 规格为 25mg的磷酸奥司他韦颗粒剂的制备
Figure imgf000010_0002
将磷酸奥司他韦以及辅料均粉碎过 100 目筛， 精确称取处方 量的磷酸奥司他韦、 甲基纤维素和蔗糖，按等量递加法混合均匀； 用 40v/v%乙醇水溶液制软材， 过 14 目筛制粒， 湿颗粒置于 45-60 °C烘箱烘干后， 经 14 目筛整粒， 用 5号筛筛去细粉后， 测定颗粒 主药含量和水分， 将上述颗粒分装为 lg/每单位剂量的包装， 其 中含有奥司他韦 25mg， 铝塑复合膜包装。
也可以分装成含有以奥司他韦计 15mg、 30mg、 45mg、 50rag 或 75mg的单位包装。 实施例 11 : 规格为 150mg的磷酸奥司他韦颗粒剂的制备
Figure imgf000010_0001
Figure imgf000010_0003
制备方法同实施例 1。将上述颗粒分装为 lg/每单位剂量的包 装， 其中含有奥司他韦 150mg, 铝塑复合膜包装。
也可以分装成含有以奥司他韦计 15mg、 30mg、 45mg、 60mg、 75mg、 90mg的单位包装。 实施例 12. 磷酸奥司他韦颗粒剂的溶解性和分散性测试 将实施例 1制备得到的上述颗粒剂加水配成以奥司他韦计浓 度为 5mg/ml的溶液时， 测定其 pH值约为 5. 4， 溶液为中性至弱 酸性溶液， 对人体无刺激， 口感良好， 有利于患者的使用。
根据中国药典 2005年版二部附录 IX E第二法 （双筛分法） 的要求， 一号筛上物和五号筛下物的总和不得超过供试量的 15 % , 上述颗粒剂样品检查结果均符合药典规定， 从而可充分保证 颗粒剂粒径的均一性， 不使颗粒因受潮结块或在运输和贮存中粉 碎而影响质量。
取上述颗粒剂样品 10g， 加热水 200ml， 搅拌 5min， 观察本 品溶化性， 检查结果表明样品全部溶化， 未见异物。 符合中国药 典 2005年版二部附录 I N规定。 上述制备的可溶性磷酸奥司他韦 含糖颗粒能够完全分散或溶解在水中，从而可保证颗粒剂的生物 利用度， 方便患者服用。

Claims

权 利 要 求
1 · 磷酸奥司他韦颗粒剂，其中每克磷酸奥司他韦颗粒剂中含 有 0. 0197g-0. 198g的磷酸奥司他韦， 以及稀释剂、粘合剂和任选 的食用香精、 甜味剂和 /或食用色素。
2. 权利要求 1的磷酸奥司他韦颗粒剂，其包含：
磷酸奥司他韦 1. 97-19. 8重量％,
稀释剂 75. 0-97. 5重量％，
粘合剂 0. 1-5. 0重量％，和
任选的 1. 0-5. 0重量％食用香精、 甜味剂和 /或食用色素。
3. 权利要求 2的磷酸奥司他韦颗粒剂， 其中所述的稀释剂选 自糖粉、 糊精和山梨醇中的一种或两种； 所述的粘合剂选自羧甲 基纤维素钠、 甲基纤维素、 聚维酮、 西黄耆胶和阿拉伯胶中的一 种或多种；所述的甜味剂选自蔗糖、 葡萄糖、 阿斯巴甜和甜菊苷。
4. 权利要求 1-3任一项的磷酸奥司他韦颗粒剂， 其具有以下 组成：
磷酸奥司他韦 3. 28重量％,
蔗糖 94. 72重量％，
聚维酮 k3Q 2. 00重量％。
5. 权利要求 1-3任一项的磷酸奥司他韦颗粒剂， 其具有以下 组成：
磷酸奥司他韦 1. 97重量。 /。，
蔗糖 96. 83重量％，
聚维酮 k30 1. 20重量％。
6. 权利要求 1-3任一项的磷酸奥司他韦颗粒剂， 其具有以下 组成：
磷酸奥司他韦 3. 28重量％，
蔗糖 94. 72重量％，
羧甲基纤维素钠 2. 00重量％。
7. 根据权利要求 1-3任一项的颗粒剂， 各组分所占的重量百 分比为：
磷酸奥司他韦 3. 28重量％，
蔗糖 94. 72重量％，
甲基纤维素 2. 00重量％。
8. 根据权利要求 1或 2的磷酸奥司他韦颗粒剂， 每单位剂量 含有 15mg、 25rag、 30mg、 45mg、 60mg、 75mg或 150mg的奥司他 韦。
9. 根据权利要求 7的磷酸奥司他韦颗粒剂， 每单位剂量含有 15mg或 25mg的奥司他韦。
10. 权利要求 2 的磷酸奥司他韦颗粒剂的制备方法， 其包括 以下步骤：
1 )将磷酸奥司他韦、 稀释剂、 粘合剂置于 40 ~ 60°C下干燥 4 小时， 粉碎过 100目筛备用；
2 )精确称取处方量的磷酸奥司他韦、 稀释剂、 粘合剂， 任选 加入食用香精， 按等量递加法混合均勾， 得到混合粉；
3 ) 用 30- 55v/v%、 优选 4(^/^的乙醇水溶液制软材， 过 14 目筛制粒；
4 )将湿颗粒置于 45-60°C下充分千燥， 经 14 目筛整粒， 得 到干颗粒；
5) 将干颗粒用 5 号筛筛去细粉后， 测定颗粒主药含量和水 分， 确定装量， 包装； 或者将干颗粒与食用色素混匀后包装， 即 得到磷酸奥司他韦颗粒。
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