WO2021057881A1 - 一种奥司他韦制剂 - Google Patents

一种奥司他韦制剂 Download PDF

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WO2021057881A1
WO2021057881A1 PCT/CN2020/117625 CN2020117625W WO2021057881A1 WO 2021057881 A1 WO2021057881 A1 WO 2021057881A1 CN 2020117625 W CN2020117625 W CN 2020117625W WO 2021057881 A1 WO2021057881 A1 WO 2021057881A1
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oseltamivir
release
preparation
sustained
core
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PCT/CN2020/117625
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English (en)
French (fr)
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李雪
黄心
游劲松
黄芳芳
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广东东阳光药业有限公司
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Priority to CN202080057247.0A priority Critical patent/CN114340614B/zh
Priority to US17/764,322 priority patent/US20220354816A1/en
Publication of WO2021057881A1 publication Critical patent/WO2021057881A1/zh

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    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the invention relates to the field of pharmaceutical preparations, in particular to a preparation of oseltamivir or its salt.
  • Oseltamivir active metabolite chemical name: (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1- Formic acid, the structural formula is shown in the following formula 02:
  • Oseltamivir phosphate is mainly used for the treatment of influenza A and B in adults and children aged 1 and over, and the prevention of influenza A and B in adults and adolescents aged 13 and over.
  • the marketed dosage forms include capsules, dry suspensions, and granules. The specifications are based on oseltamivir. There are 15mg, 30mg, 45mg, 75mg capsules or granules, and 6mg/ml dry suspension.
  • the above dosage forms are all conventional
  • the immediate-release preparations dissolve in vitro and show complete release within 10 minutes, and are quickly absorbed after oral administration.
  • the dosage method for the treatment of influenza is to take twice a day.
  • the goal of the present invention is to develop an oseltamivir phosphate preparation that can take into account both rapid onset and long-term maintenance of effective blood concentration.
  • the first aspect of the present invention provides an oseltamivir preparation, which can be administered once a day to obtain a sustained release of at least 24 hours or longer, can reduce the number of administrations, avoid peak and valley fluctuations, and improve the treatment of patients Compliance and safety.
  • the second aspect of the present invention provides an oseltamivir preparation, which is administered once a day; the preparation includes a sustained-release part containing oseltamivir or its salt and an immediate-release part containing oseltamivir or its salt.
  • the design of the ratio of the immediate-release part and the sustained-release part will significantly affect the onset time and the maintenance time of the steady-state blood concentration, as well as the safety of medication.
  • the ratio of immediate-release part/slow-release part is low, which cannot reach the effective blood drug concentration quickly, resulting in slow onset; while the ratio of immediate-release part/slow-release part is high, although the effective blood concentration can be reached quickly, it may also cause the concentration to be too high , Increase the probability of adverse reactions (gastrointestinal mucosal irritation); in addition, the ratio of immediate-release part to sustained-release part is low, which can only maintain the effective blood concentration for a short time, resulting in the once-a-day medication frequency cannot be maintained throughout the day. There is no sustained-release effect. Therefore, the design of the ratio of immediate-release part/sustained-release part is very critical to the clinical effect.
  • the oseltamivir preparation provided by the present invention is administered once a day, and can be a two-phase release preparation, a three-phase release preparation, or a multi-phase release preparation with more than three phases.
  • the third aspect of the present invention provides a method for preparing an oseltamivir preparation.
  • the oseltamivir preparation prepared by the method has good in vivo and in vitro effect data, stable quality, and meets quality requirements; the method is relatively simple to operate, Good reproducibility, suitable for industrial production.
  • Cmax refers to the maximum blood concentration in the body after administration.
  • C2h refers to the corresponding blood drug concentration 2 hours after administration.
  • Tmax refers to the time corresponding to the maximum blood concentration in the body after administration.
  • AUC0-t refers to the area under the plasma concentration-time curve from 0 to the last selected time point after administration.
  • BA refers to bioavailability.
  • the concentration “ng/mL” refers to nanograms/ml, which is weight/volume, and the volume is plasma volume.
  • Ng ⁇ h/mL refers to nanogram ⁇ hour/ml, which is weight ⁇ time/volume.
  • Oleltamivir active metabolite refers to ((3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1- Formic acid), as shown in structural formula 02.
  • sustained release refers to the use of LC/MS/MS analytical equipment to detect samples. According to its detection limit, the active metabolite of oseltamivir ((3R,4R,5S)-4-acetamido-5-amino can be detected -3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid) blood concentration.
  • LC/MS/MS refers to liquid-mass spectrometry.
  • HPLC high performance liquid phase
  • peak-to-valley ratio of blood drug concentration refers to the ratio of the highest blood drug concentration in the body within 24 hours after administration to the corresponding blood drug concentration at 24 hours.
  • ng refers to nanograms
  • mg refers to milligrams
  • h refers to hours
  • mm refers to millimeters
  • °C refers to degrees Celsius
  • rpm refers to rotation speed.
  • SR 30D refers to a 30% dispersion system of polyvinyl acetate
  • SR refers to a mixture of polyvinyl acetate and povidone.
  • the present invention has undergone in-depth research and investigation to prepare a preparation containing oseltamivir or its salt.
  • the preparation is administered once a day to obtain a sustained release of at least 24 hours or more, which can reduce the dose.
  • the number of medications can avoid peak and valley fluctuations, thereby improving the patient's treatment compliance and safety;
  • the preparation can be a single-phase release preparation, a two-phase release preparation, a three-phase release preparation, or a multi-phase release preparation with more than three phases.
  • the preparation can maintain a high blood concentration in the body for a long time and has high bioavailability.
  • the first aspect of the present invention provides an oseltamivir preparation, including oseltamivir or a salt thereof, and the preparation is a once-a-day administration.
  • oseltamivir is included; in some embodiments, oseltamivir phosphate is included.
  • the active ingredient oseltamivir or its salt can be quickly released within a certain period of time ⁇ 4h. In some embodiments, in the oseltamivir preparation, the active ingredient oseltamivir or a salt thereof can be rapidly released within a certain 1 hour period of ⁇ 4 hours.
  • the active ingredient oseltamivir or its salt is released rapidly within a certain 1h period of ⁇ 4h, and the release amount is 25%-55%; in some embodiments, The release amount is 25%-35%; in some embodiments, the release amount is 25%-40%; in some embodiments, the release amount is 25%-45%; in some embodiments, the release amount is 35% -40%; in some embodiments, the release amount is 35%-45%; in some embodiments, the release amount is 35%-55%; in some embodiments, the release amount is 40%-45%; In some embodiments, the release amount is 40%-55%; in some embodiments, the release amount is 45%-55%. In some embodiments, the release amount of the active ingredient oseltamivir or its salt within a certain 1 hour period of ⁇ 4 hours is 25%, 35%, 40%, 45%, or 55%.
  • the active ingredient oseltamivir or its salt is released rapidly in the first hour, and the release amount is 25%-55%.
  • the release amount is 25%-35%; in some embodiments, the release amount is 25%-40%; in some embodiments, the release amount is 25%-45%; in some embodiments , The release is 35%-40%; in some embodiments, the release is 35%-45%; in some embodiments, the release is 35%-55%; in some embodiments, the release is 40 %-45%; in some embodiments, the release amount is 40%-55%; in some embodiments, the release amount is 45%-55%.
  • the release amount of the active ingredient oseltamivir or its salt in the first hour is 25%, 35%, 40%, 45%, or 55%.
  • the release amount of the active ingredient oseltamivir or its salt in 4 hours is 25%-90%, or the release amount is 25%-85%.
  • the release amount is 25%-53%; in some embodiments, the release amount is 25%-62%; in some embodiments, the release amount is 25%-78%; in some embodiments , The release amount is 53%-62%; in some embodiments, the release amount is 53%-78%; in some embodiments, the release amount is 53%-90%; in some embodiments, the release amount is 62% %-78%; in some embodiments, the release amount is 62%-90%; in some embodiments, the release amount is 78%-90%.
  • the release amount of the active ingredient oseltamivir or its salt within 4 hours is 25%, 53%, 62%, 63%, 78%, or 90%.
  • the release amount of the active ingredient oseltamivir or its salt in 10 hours is greater than 70%. In some embodiments, in the oseltamivir preparation, the 10h release amount of the active ingredient oseltamivir or its salt is 70%-99%. In some embodiments, in the oseltamivir preparation, the 10h release amount of the active ingredient oseltamivir or its salt is greater than 74%, or greater than 77%, or greater than 80%, or greater than 86%, or greater than 89%, Or greater than 93%, or greater than 95%, or greater than 98%.
  • the 10h release amount of the active ingredient oseltamivir or its salt is 93%, 94%, 95%, 96%, 97%, 98%, 77%, 86% , 74%, or 89%.
  • the weight of the active ingredient oseltamivir accounts for 3%-50% of the total weight of the preparation. In some embodiments, in the oseltamivir preparation, the weight ratio of the active ingredient oseltamivir is 3%-45%.
  • the weight ratio of oseltamivir is 3%-21%; in some embodiments, the weight ratio of oseltamivir is 3%-32%; in some embodiments, oseltamivir The weight ratio of oseltamivir is 21%-32%; in some embodiments, the weight ratio of oseltamivir is 21%-50%; in some embodiments, the weight ratio of oseltamivir or its salt is 32%- 50%. In some embodiments, the weight ratio of oseltamivir is 3%, 21%, 32%, or 50%.
  • the peak-to-valley ratio of the plasma concentration of the active metabolite of oseltamivir within 24 hours is less than 2.5:1.
  • the peak-to-valley ratio of blood drug concentration in the body of less than 2.5:1 can avoid peak-to-valley fluctuations, thereby improving the patient's treatment compliance and safety.
  • the peak-to-valley ratio of the plasma concentration of the active metabolite of oseltamivir within 24 hours is 2.14:1.
  • the peak-to-valley ratio of the plasma concentration of the active metabolite of oseltamivir within 24 hours is less than 2:1, which is more conducive to avoiding peak-to-valley fluctuations. Thereby improving the patient's treatment compliance and safety.
  • the peak-to-valley ratio of the plasma concentration of the active metabolite of oseltamivir within 24 hours is 1.21:1.
  • the oseltamivir preparation is based on the weight of oseltamivir, and the single-dose specification is 60mg-300mg.
  • the specification is 60mg-90mg; in some embodiments, the specification is 60mg-150mg; in some embodiments, the specification is 60mg-200mg; in some embodiments, the specification is 90mg-150mg; in some embodiments, the specification is 60mg-200mg; in some embodiments, the specification is 90mg-150mg; In an embodiment, the specification is 90mg-200mg; in some embodiments, the specification is 90mg-300mg; in some embodiments, the specification is 150mg-200mg; in some embodiments, the specification is 150mg-300mg; in some embodiments Among them, the specification is 200mg-300mg.
  • the single dose strength is 60 mg, 90 mg, 150 mg, 200 mg, or 300 mg.
  • the immediate release dosage form for children currently on the market, based on the weight of oseltamivir, has a minimum specification of 30 mg and is administered twice a day.
  • the minimum specification is 60 mg; the immediate release dosage form for adults currently on the market Dosage form, based on the weight of oseltamivir, the minimum specification is 75mg, twice a day, if it is prepared into a once-a-day sustained-release preparation, the minimum specification is 150mg, if the specification is increased to 300mg, it cannot be compared with the 75mg specification for one day administration
  • the two-time immediate-release dosage form is equivalent, indicating that the bioavailability is low. If it is released suddenly, the risk of toxic and side effects will increase, and the tablet will be heavy and cause difficulty in swallowing. Therefore, based on the weight of oseltamivir, it is more appropriate to choose 60mg-300mg. .
  • the oseltamivir preparation further comprises at least one sustained-release material, and the weight of the sustained-release material accounts for 3%-50% of the total weight of the preparation.
  • the weight ratio of the sustained-release material is 3%-50%, and a preparation capable of continuously releasing oseltamivir for at least 24 hours or longer can be prepared, and the number of administrations can be reduced.
  • the weight ratio of the sustained-release material is 3%-10%; in some embodiments, the weight ratio of the sustained-release material is 3%-20%; in some embodiments, the weight ratio of the sustained-release material is 3%-20%; The weight ratio of the sustained-release material is 3%-30%; in some embodiments, the weight ratio of the sustained-release material is 10%-20%; in some embodiments, the weight ratio of the sustained-release material is 10%. %-30%; in some embodiments, the weight ratio of the sustained-release material is 10%-50%; in some embodiments, the weight ratio of the sustained-release material is 20%-30%; in some embodiments In an example, the weight ratio of the sustained-release material is 20%-50%. In some embodiments, the weight ratio of the sustained-release material is 30%-50%. In some embodiments, the weight ratio of the sustained-release material is 3.3%, 10%, 20%, 29%, or 50%.
  • the oseltamivir preparation further comprises at least one sustained-release material, and the sustained-release material includes selected from the group consisting of ethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, and polyoxyethylene.
  • Ethylene polyvinyl alcohol, methacrylic acid-ethyl acrylate copolymer RL, methacrylic acid-ethyl acrylate copolymer RS, methacrylic acid-ethyl acrylate copolymer NE 30D, methacrylic acid-ethyl acrylate copolymer NE L100-55, hypromellose acetate succinate, glyceryl behenate, chitosan, carbomer, carnauba wax, SR 30D, SR, at least one of cellulose acetate titanate, sodium alginate, sodium carboxymethyl cellulose, carrageenan, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and paraffin wax.
  • the sustained-release material is cellulose acetate; in some embodiments, the sustained-release material is methacrylic acid-ethyl acrylate copolymer RL and methacrylic acid-ethyl acrylate copolymer RS; In some embodiments, the sustained-release material is ethyl cellulose; in some embodiments, the sustained-release material is hydroxypropyl methylcellulose; in some embodiments, the sustained-release material is poly Oxyethylene and ethyl cellulose.
  • the oseltamivir preparation further includes at least one sustained-release material
  • the sustained-release material includes a pH-independent polymer material, a pH-dependent polymer material or a waxy framework material.
  • the pH-independent polymer material includes selected from ethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, polyoxyethylene, polyvinyl alcohol, methacrylic acid-ethyl acrylate copolymer RL, methacrylic acid- Ethyl acrylate copolymer RS, methacrylic acid-ethyl acrylate copolymer NE 30D, SR 30D, At least one of SR;
  • the pH-dependent polymer material includes selected from the group consisting of methacrylic acid-ethyl acrylate copolymer L100-55, hypromellose acetate succinate, cellulose acetate titanate, chitosan At least one of sugar, carbomer, carrageenan, sodium al
  • the oseltamivir preparation includes at least one sustained-release material, and the weight of oseltamivir or its salt accounts for 3%-50% of the total weight of the preparation. In some embodiments, the oseltamivir preparation comprises at least one sustained-release material, and the 4h release amount of oseltamivir or its salt is 25%-90%. In some embodiments, the oseltamivir preparation includes at least one sustained-release material, and the release amount of oseltamivir or its salt in 10 hours is greater than 70%.
  • the oseltamivir preparation comprises at least one sustained-release material, the weight ratio of oseltamivir or its salt is 3%-50%, and the 4h release amount of oseltamivir or its salt is 25%-90%. In some embodiments, the oseltamivir preparation comprises at least one sustained-release material, the weight ratio of oseltamivir or its salt is 3%-50%, and the 10h release amount of oseltamivir or its salt is greater than 70%.
  • the release amount of oseltamivir or its salt in 4 hours is 25%-90%, and the release amount of setavir or its salt in 10 hours is greater than 70%.
  • the oseltamivir preparation comprises at least one sustained-release material, the 4h release amount of oseltamivir or its salt is 25%-90%, and the 10h release amount of setavir or its salt is greater than 70%. %.
  • the oseltamivir preparation comprises at least one sustained-release material; the weight ratio of oseltamivir or its salt is 3%-50%; the 4h release amount of oseltamivir or its salt is 25%-90%, 10h release of oseltamivir or its salt is greater than 70%.
  • the sustained-release material in the oseltamivir preparation is cellulose acetate, and the weight of oseltamivir or its salt accounts for 25%-35% of the total weight of the preparation. In some embodiments, the sustained-release material in the oseltamivir preparation is cellulose acetate, and the weight ratio of oseltamivir or its salt is 30%-35%. In some embodiments, the sustained-release material in the oseltamivir preparation is cellulose acetate, and the weight ratio of oseltamivir or its salt is 31.6%.
  • the sustained-release material in the oseltamivir preparation is cellulose acetate, and the 4h release amount of oseltamivir or its salt is 25%-90%. In some embodiments, the sustained-release material in the oseltamivir preparation is cellulose acetate, and the release amount of oseltamivir or its salt in 4 hours is greater than 70%. In some embodiments, the sustained-release material in the oseltamivir preparation is cellulose acetate, and the 10h release amount of oseltamivir or its salt is greater than 70% or 90% or 95%.
  • the sustained-release material in the oseltamivir formulation is cellulose acetate, the release amount of oseltamivir or its salt in 4 hours is greater than 70%, and the release amount of oseltamivir or its salt in 10 hours is greater than 70% or 90% or 95%.
  • the sustained-release material in the oseltamivir preparation is cellulose acetate, the weight ratio of oseltamivir or its salt is 30%-35%, and the 4h release amount of oseltamivir or its salt is 25%-90%, the 10h release amount of oseltamivir or its salt is greater than 70% or 80% or 90% or 95%.
  • the sustained-release material in the oseltamivir preparation is cellulose acetate, the weight ratio of oseltamivir or its salt is 30%-35%, and the release amount of oseltamivir or its salt in 4 hours is greater than 70%, the 10h release of oseltamivir or its salt is greater than 70% or 80% or 90% or 95%.
  • the sustained-release material in the oseltamivir preparation is cellulose acetate, the weight ratio of oseltamivir or its salt is 31.6%, the 4h release amount of oseltamivir is 78%, The release amount of Wei or its salt in 10 hours was 97%.
  • the sustained-release material in the oseltamivir preparation is hydroxypropyl methylcellulose
  • the weight ratio of oseltamivir or its salt is 32.0%
  • the 4h release amount of oseltamivir is 63%
  • Oseltamivir or its salt 10h release amount is 86%.
  • the oseltamivir formulation further comprises at least one sustained-release material, the weight of the sustained-release material accounts for 3%-50% of the total weight of the formulation, and the sustained-release material includes From ethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, polyoxyethylene, polyvinyl alcohol, methacrylic acid-ethyl acrylate copolymer RL, methacrylic acid-ethyl acrylate copolymer RS, methyl Acrylic acid-ethyl acrylate copolymer NE 30D, methacrylic acid-ethyl acrylate copolymer L100-55, hypromellose acetate succinate, glyceryl behenate, chitosan, carbomer, carnauba wax , SR 30D, SR, at least one of cellulose acetate titanate, sodium alginate, sodium carboxymethyl cellulose, carrageenan, cetyl alcohol, stearyl
  • the release amount of oseltamivir or its salt in 1 hour is 25%-55%, and the release amount of oseltamivir or its salt in 4 hours is 25%-90%.
  • the 10h release of Tamivir or its salt is greater than 70%; the weight ratio of oseltamivir or its salt is 3%-50%; based on the weight of oseltamivir, the specification is 60mg-300mg; after once a day, 24h
  • the peak-to-valley ratio of the plasma concentration of the active metabolite of intramedullary oseltamivir is less than 2.5:1; optionally, in some embodiments, the oseltamivir preparation further comprises at least one sustained-release material,
  • the weight ratio of the sustained-release material is 3%-50%, and the sustained-release material includes selected from the group consisting of ethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, polyoxyethylene, polyvinyl alcohol, and methacrylic acid.
  • an oseltamivir preparation comprising oseltamivir or a salt thereof, the preparation is a once-a-day dosing preparation, and the preparation includes a sustained-release preparation containing oseltamivir or a salt thereof Part and immediate-release part containing oseltamivir or its salt.
  • the formulation may be a biphasic release formulation, a three-phase release formulation, or a multiphase release formulation with more than three phases.
  • the formulation is a biphasic release formulation, in some embodiments, the formulation is a three-phase release formulation, and in some embodiments, the formulation is a multiphase release formulation.
  • the active ingredient is oseltamivir; in some embodiments, the active ingredient is oseltamivir phosphate.
  • the oseltamivir preparation comprising a sustained-release part containing oseltamivir or its salt and an immediate-release part containing oseltamivir or its salt, the active ingredient oseltamivir or its salt in a time period of ⁇ 4h It can be released quickly, and the release amount is 25%-55%.
  • the oseltamivir preparation comprising a sustained-release part containing oseltamivir or its salt and an immediate-release part containing oseltamivir or its salt, and the active ingredient oseltamivir or its salt in a certain 1h of ⁇ 4h Rapid release within a period of time, the release amount is 25%-55%; in some embodiments, the release amount is 25%-35%; in some embodiments, the release amount is 25%-40%; in some embodiments , The release amount is 25%-45%; in some embodiments, the release amount is 35%-40%; in some embodiments, the release amount is 35%-45%; in some embodiments, the release amount is 35 %-55%; in some embodiments, the release amount is 40%-45%; in some embodiments, the release amount is 40%-55%; in some embodiments, the release amount is 45%-55%. In some embodiments, the release amount of the active ingredient oseltamivir or its salt within a certain 1 hour period of ⁇ 4 hours is 25%
  • the active ingredient oseltamivir or its salt is released rapidly in the first hour, and the release amount is 25%-55%; in some embodiments, the release amount is 25%- 35%; in some embodiments, the release amount is 25%-40%; in some embodiments, the release amount is 25%-45%; in some embodiments, the release amount is 35%-40%; in some embodiments, the release amount is 35%-40%; In embodiments, the release amount is 35%-45%; in some embodiments, the release amount is 35%-55%; in some embodiments, the release amount is 40%-45%; in some embodiments, the release The amount is 40%-55%; in some embodiments, the amount released is 45%-55%. In some embodiments, the release amount of the active ingredient oseltamivir or its salt in the first hour is 25%, 35%, 40%, 45%, or 55%.
  • the release amount of the active ingredient oseltamivir or its salt within 4 hours is 25%-90%, or the release amount is 25%-85%; in some embodiments, the release The amount is 25%-53%; in some embodiments, the release amount is 25%-62%; in some embodiments, the release amount is 25%-78%; in some embodiments, the release amount is 53%- 62%; in some embodiments, the release amount is 53%-78%; in some embodiments, the release amount is 53%-90%; in some embodiments, the release amount is 62%-78%; in some embodiments, the release amount is 62%-90%; in some embodiments, the release amount is 78%-90%. In some embodiments, the release amount of the active ingredient oseltamivir or its salt within 4 hours is 25%, 53%, 62%, 63%, 78%, or 90%.
  • the release amount of the active ingredient oseltamivir or its salt in 10 hours is greater than 70%. In some embodiments, in the oseltamivir preparation, the 10h release amount of the active ingredient oseltamivir or its salt is 70%-99%. In some embodiments, in the oseltamivir preparation, the 10h release amount of the active ingredient oseltamivir or its salt is greater than 74%, or greater than 77%, or greater than 80%, or greater than 86%, or greater than 89%, Or greater than 93%, or greater than 95%, or greater than 98%.
  • the 10h release amount of the active ingredient oseltamivir or its salt is 93%, 94%, 95%, 96%, 97%, 98%, 77%, 86% , 74%, or 89%.
  • the ratio of the weight of the active ingredient oseltamivir to the total weight of the preparation is 3%-50%, or 3%-45%.
  • the weight ratio of oseltamivir is 3%-21%; in some embodiments, the weight ratio of oseltamivir is 3%-32%; in some embodiments, oseltamivir
  • the weight ratio of oseltamivir is 21%-32%; in some embodiments, the weight ratio of oseltamivir is 21%-50%; in some embodiments, the weight ratio of oseltamivir or its salt is 32%- 50%. In some embodiments, the weight ratio of oseltamivir is 3%, 21%, 32%, or 50%.
  • the peak-to-valley ratio of the plasma concentration of the active metabolite of oseltamivir within 24 hours is less than 2.5:1.
  • the peak-to-valley ratio of blood drug concentration in the body of less than 2.5:1 can avoid peak-to-valley fluctuations, thereby improving the patient's treatment compliance and safety.
  • the peak-to-valley ratio of the plasma concentration of the active metabolite of oseltamivir within 24 hours is 2.14:1.
  • the peak-to-valley ratio of the plasma concentration of the active metabolite of oseltamivir within 24 hours is less than 2:1, which is more conducive to avoiding peak-to-valley fluctuations. Thereby improving the patient's treatment compliance and safety.
  • the peak-to-valley ratio of the plasma concentration of the active metabolite of oseltamivir within 24 hours is 1.21:1.
  • the oseltamivir preparation based on the weight of oseltamivir, has a single-dose specification of 60mg-300mg; in some embodiments, the specification is 60mg-90mg; in some embodiments, the specification is 60mg-150mg; in some embodiments, In embodiments, the specification is 60mg-200mg; in some embodiments, the specification is 90mg-150mg; in some embodiments, the specification is 90mg-200mg; in some embodiments, the specification is 90mg-300mg; in some embodiments In some embodiments, the specification is 150mg-200mg; in some embodiments, the specification is 150mg-300mg; in some embodiments, the specification is 200mg-300mg.
  • the strength is 60 mg, 90 mg, 150 mg, 200 mg, or 300 mg.
  • the immediate release dosage form for children currently on the market based on the weight of oseltamivir, has a minimum specification of 30 mg and is administered twice a day. If it is prepared as a once-a-day sustained-release preparation, the minimum specification is 60 mg; the immediate release dosage form for adults currently on the market The dosage form is based on the weight of oseltamivir. The minimum specification is 75mg, which is administered twice a day. If it is prepared as a once-a-day sustained-release preparation, the minimum specification is 150mg. If the rule is increased to 300mg, it cannot be compared with the 75mg specification for one day.
  • the two-time immediate-release dosage form of the drug is equivalent, indicating that the bioavailability is low. If the drug is released suddenly, the risk of toxic and side effects will increase, and the tablet will be heavy, causing difficulty in swallowing. Therefore, based on the weight of oseltamivir, it is more appropriate to choose 60mg-300mg specification.
  • the oseltamivir preparation further comprises at least one sustained-release material, and the weight of the sustained-release material accounts for 3%-50% of the total weight of the preparation.
  • the weight ratio of the sustained-release material is 3%-10%; in some embodiments, the weight ratio of the sustained-release material is 3%-20%; in some embodiments, the weight ratio of the sustained-release material is 3%-20%; The weight ratio of the sustained-release material is 3%-30%; in some embodiments, the weight ratio of the sustained-release material is 10%-20%; in some embodiments, the weight ratio of the sustained-release material is 10%.
  • the weight ratio of the sustained-release material is 10%-50%; in some embodiments, the weight ratio of the sustained-release material is 20%-30%; in some embodiments In an example, the weight ratio of the sustained-release material is 20%-50%; in some embodiments, the weight ratio of the sustained-release material is 30%-50%. In some embodiments, the weight ratio of the sustained-release material is 3.3%, 10%, 20%, 29%, or 50%.
  • the weight ratio of the sustained-release material is 3%-50%, and a preparation capable of continuously releasing oseltamivir for at least 24 hours or longer can be prepared, and the number of administrations can be reduced.
  • the oseltamivir preparation further comprises at least one sustained-release material, and the sustained-release material includes selected from the group consisting of ethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, and polyoxyethylene.
  • Ethylene polyvinyl alcohol, methacrylic acid-ethyl acrylate copolymer RL, methacrylic acid-ethyl acrylate copolymer RS, methacrylic acid-ethyl acrylate copolymer NE 30D, methacrylic acid-ethyl acrylate copolymer L100 -55, hypromellose acetate succinate, glyceryl behenate, chitosan, carbomer, carnauba wax, SR 30D, SR, at least one of cellulose acetate titanate, sodium alginate, sodium carboxymethyl cellulose, carrageenan, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and paraffin wax.
  • the sustained-release material is cellulose acetate; in some embodiments, the sustained-release material is methacrylic acid-ethyl acrylate copolymer RL and methacrylic acid-ethyl acrylate copolymer RS; In some embodiments, the sustained-release material is ethyl cellulose; in some embodiments, the sustained-release material is hydroxypropyl methylcellulose; in some embodiments, the sustained-release material is poly Oxyethylene and ethyl cellulose.
  • the oseltamivir preparation further includes at least one sustained-release material
  • the sustained-release material includes a pH-independent polymer material, a pH-dependent polymer material or a waxy framework material.
  • the pH-independent polymer material includes selected from ethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, polyoxyethylene, polyvinyl alcohol, methacrylic acid-ethyl acrylate copolymer RL, methacrylic acid- Ethyl acrylate copolymer RS, methacrylic acid-ethyl acrylate copolymer NE 30D, SR 30D, At least one of SR;
  • the pH-dependent polymer material includes selected from the group consisting of methacrylic acid-ethyl acrylate copolymer L100-55, hypromellose acetate succinate, cellulose acetate titanate, chitosan At least one of sugar, carbomer, carrageenan, sodium al
  • the oseltamivir preparation includes at least one sustained-release material; the weight of oseltamivir accounts for 3%-50% of the total weight of the preparation; the oseltamivir or its salt is released in 4 hours The amount is 25%-90%, and the 10h release amount of oseltamivir or its salt is greater than 70%.
  • the sustained-release material in the oseltamivir preparation is methacrylic acid-ethyl acrylate copolymer RL and methacrylic acid-ethyl acrylate copolymer RS, and the weight ratio of oseltamivir is 22.4%
  • the release amount of oseltamivir in 4 hours is 78%, and the release amount of oseltamivir or its salt in 10 hours is 97%; in some embodiments, the sustained-release material in the oseltamivir preparation is ethyl cellulose.
  • the weight ratio of setavir is 3.3%, the release amount of oseltamivir in 4 hours is 75%, and the release amount of oseltamivir or its salt in 10 hours is 96%.
  • the oseltamivir formulation further comprises at least one sustained-release material, the weight of the sustained-release material accounts for 3%-50% of the total weight of the formulation, and the sustained-release material includes From ethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, polyoxyethylene, polyvinyl alcohol, methacrylic acid-ethyl acrylate copolymer RL, methacrylic acid-ethyl acrylate copolymer RS, methyl Acrylic acid-ethyl acrylate copolymer NE 30D, methacrylic acid-ethyl acrylate copolymer L100-55, hypromellose acetate succinate, glyceryl behenate, chitosan, carbomer, carnauba wax , SR 30D, SR, at least one of cellulose acetate titanate, sodium alginate, sodium carboxymethyl cellulose, carrageenan, cetyl alcohol, stearyl
  • the release amount of oseltamivir or its salt in 1 hour is 25%-55%, and the release amount of oseltamivir or its salt in 4 hours is 25%-90%.
  • the release amount of Tamivir or its salt in 10 hours is greater than 70%; the weight ratio of oseltamivir or its salt is 3%-50%; based on the weight of oseltamivir, the single-dose specification is 60mg-300mg; after once a day administration , The peak-to-valley ratio of the plasma concentration of the active metabolite of oseltamivir within 24h is less than 2.5:1.
  • the oseltamivir formulation further comprises at least one sustained-release material, the weight ratio of the sustained-release material is 3%-50%, and the sustained-release material includes Ethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, polyoxyethylene, polyvinyl alcohol, methacrylic acid-ethyl acrylate copolymer RL, methacrylic acid-ethyl acrylate copolymer RS, methacrylic acid -Ethyl acrylate copolymer NE 30D, methacrylic acid-ethyl acrylate copolymer L100-55, hypromellose acetate succinate, glyceryl behenate, chitosan, carbomer, carnauba wax, SR 30D, SR, at least one of cellulose acetate titanate, sodium alginate, sodium carboxymethyl cellulose, carrageenan, cetyl alcohol, stearyl alcohol, cetosteacetate
  • the oseltamivir specification in the immediate-release part is 10mg-75mg, or 15mg-75mg, or 15mg-30mg, or 15mg-50mg, or 30mg-50mg, or 30mg-75mg, Or 50mg-75mg; the specification of oseltamivir in the sustained-release part is 30mg-225mg, or 30mg-175mg, or 50mg-100mg, or 50mg-120mg, or 50mg-175mg, or 50mg-225mg, or 100mg- 120mg, or 100mg-150mg, or 100mg-225mg, or 120mg-150mg, or 120mg-175mg, or 120mg-225mg, or 150mg-175mg, or 150mg-225mg, or 175mg-225mg.
  • the specification of oseltamivir in the immediate-release part is 50 mg, and the specification of oseltamivir in the sustained-release part is 100 mg; in some embodiments, the specification of oseltamivir in the immediate-release part is 50 mg , The specification of oseltamivir in the sustained-release part is 130mg; in some embodiments, the specification of oseltamivir in the immediate-release part is 30mg, and the specification of oseltamivir in the sustained-release part is 60mg; in some embodiments Among them, the specification of oseltamivir in the immediate-release part is 50 mg, and the specification of oseltamivir in the sustained-release part is 150 mg; in some embodiments, the specification of oseltamivir in the immediate-release part is 10 mg, and the specification of oseltamivir in the sustained-release part is 10 mg.
  • the specification of oseltamivir is 50 mg; in some embodiments, the specification of oseltamivir in the immediate-release part is 75 mg, and the specification of oseltamivir in the sustained-release part is 225 mg; in some embodiments, the specification of oseltamivir in the immediate-release part is 225 mg; in some embodiments, the specification of oseltamivir in the immediate-release part is 225 mg; in some embodiments, the specification of oseltamivir in the immediate-release part is 225 mg; The specification of oseltamivir in the part is 30 mg, and the specification of oseltamivir in the sustained-release part is 120 mg.
  • the oseltamivir preparation provided in the first or second aspect of the present invention is used for the treatment of adult influenza A or adult influenza B.
  • the blood drug concentration in the active metabolite of oseltamivir is greater than 100ng/ml, or greater than 150ng/ml, or greater than 170ng/ml, or greater than 200ng/ml, or greater than 250ng/ml.
  • the blood concentration in the active metabolite of intravenous oseltamivir is greater than 172 ng/ml in 24 hours; in some embodiments, the blood concentration in the active metabolite of intraperitoneal oseltamivir is greater than 261 ng/ml in 24 hours.
  • the oseltamivir preparation provided by the first or second aspect of the present invention is used for the treatment of children with influenza A or children with influenza B.
  • the blood drug concentration in the active metabolite of oseltamivir is greater than 100ng/ml, or greater than 150ng/ml, or greater than 200ng/ml, or greater than 250ng/ml.
  • the oseltamivir preparation provided in the first or second aspect of the present invention is used for the treatment of influenza A or influenza B in adults or children, and the preparation is based on the weight of oseltamivir and has a specification of 60 mg-300 mg.
  • the formulation specification is 60 mg; in some embodiments, the formulation specification is 90 mg; in some embodiments, the formulation specification is 150 mg; in some embodiments, the formulation specification is 200mg; In some embodiments, the formulation strength is 300mg.
  • the oseltamivir preparation has a specification of 150 mg-300 mg based on the weight of oseltamivir. In some embodiments, the oseltamivir preparation is used to treat adult influenza A or adult influenza B, and the specification is 150 mg-300 mg based on the weight of oseltamivir.
  • the minimum specification is 75 mg, which is administered twice a day. If it is prepared as a once-a-day sustained-release preparation, the minimum specification is 150 mg.
  • the adult dosage form is based on the weight of oseltamivir. Choose 150mg-300mg is more appropriate specification.
  • the oseltamivir preparation has a specification of 60 mg-180 mg based on the weight of oseltamivir. In some embodiments, the oseltamivir preparation is used to treat children with influenza A or children with influenza B, and the specification is 60 mg-180 mg based on the weight of oseltamivir.
  • the immediate release dosage forms for children currently on the market have specifications of 30mg and 45mg. They are administered twice a day, and 30mg or 45mg is administered at a time.
  • the ideal specification is 60-90mg, but the biologically sustained-release preparation Utilization is generally lower than that of immediate-release preparations, and the specifications of sustained-release preparations need to be appropriately increased to be bioequivalent to immediate-release preparations administered twice a day, and the higher the dosage, the risk of general toxic and side effects will increase accordingly.
  • the specification is increased by 2 times within the acceptable range, therefore, 60-180mg is a more appropriate specification for children's dosage form.
  • the specification of children's sustained-release preparations exceeds 180mg, indicating that the bioavailability is low, and if it is released suddenly, the risk of side effects will increase.
  • the blood concentration of the active metabolite of oseltamivir is more than 20%, or more than 30%, or more than 40% of Cmax in 2 hours; the blood concentration in the body of 24 hours Above 30%, or above 40% of Cmax.
  • the blood concentration of the active metabolite of oseltamivir in 2 hours is 27% of Cmax; in some embodiments, the blood concentration of the active metabolite of oseltamivir in 2 hours is 25% of Cmax; In some embodiments, the blood concentration of the active metabolite of oseltamivir in 24 hours is 47% of Cmax; in some embodiments, the blood concentration of the active metabolite of oseltamivir in 24 hours is 82% of Cmax.
  • the oseltamivir preparation provided in the first aspect or the second aspect of the present invention continuously releases oseltamivir for a period of at least 24 hours.
  • the blood concentration in the active metabolite of oseltamivir is greater than 100ng/ml, or greater than 150ng/ml, and the maintenance time is greater than 16h, or greater than 20h.
  • the blood concentration in the active metabolite of oseltamivir is greater than or equal to 170 ng/ml, and the maintenance time is greater than 16 hours.
  • the blood concentration in the active metabolite of oseltamivir is greater than or equal to 250 ng/ml, and the maintenance time is greater than 12 hours.
  • the blood concentration in the active metabolite of oseltamivir is greater than or equal to 250ng/ml, and the maintenance time is greater than 16h.
  • the blood concentration in the active metabolite of oseltamivir is 261 ng/mL, and the maintenance time is 16 h; in some embodiments, the blood concentration in the active metabolite of oseltamivir is 172 ng/mL, which is maintained The time is 20h.
  • an oseltamivir preparation comprising oseltamivir or its salt
  • the preparation is a once-a-day dosing preparation
  • the preparation includes a sustained release containing oseltamivir or its salt
  • the weight ratio of oseltamivir in the immediate-release part is 20%-30%; in some embodiments, the weight ratio of oseltamivir in the immediate-release part is 20% -40%; in some embodiments, the weight ratio of oseltamivir in the immediate-release part is 30%-40%; in some embodiments, the weight of oseltamivir in the immediate-release part The ratio is 30%-50%; in some embodiments, the weight ratio of oseltamivir in the immediate-release part is 40%-50%.
  • the formulation may be a biphasic release formulation, a three-phase release formulation, or a multiphase release formulation with more than three phases.
  • the formulation is a biphasic release formulation, in some embodiments, the formulation is a three-phase release formulation, and in some embodiments, the formulation is a multiphase release formulation.
  • the active ingredient is oseltamivir; in some embodiments, the active ingredient is oseltamivir phosphate.
  • an oseltamivir preparation comprising oseltamivir or a salt thereof, the preparation is a once-a-day dosing preparation, and the preparation includes a sustained-release preparation containing oseltamivir or a salt thereof A part and an immediate-release part containing oseltamivir or its salt, and the weight ratio of oseltamivir in the immediate-release part to oseltamivir in the sustained-release part is 1:4-1:1.
  • the weight ratio of oseltamivir in the immediate-release part to oseltamivir in the sustained-release part is 1:4-1:3; in some embodiments, the fast-release part The weight ratio of oseltamivir in the release portion to oseltamivir in the sustained-release portion is 1:4-1:2; in some embodiments, the weight ratio of oseltamivir and oseltamivir in the immediate-release portion The weight ratio of oseltamivir in the sustained-release part is 1:3-1:2; in some embodiments, the oseltamivir in the immediate-release part and the oseltamivir in the sustained-release part The weight ratio of tamivir is 1:3-1:1; in some embodiments, the weight ratio of oseltamivir in the immediate-release part to oseltamivir in the sustained-release part is 1:2 -1:1; In some embodiments,
  • the formulation may be a biphasic release formulation, a three-phase release formulation, or a multiphase release formulation with more than three phases.
  • the formulation is a biphasic release formulation, in some embodiments, the formulation is a three-phase release formulation, and in some embodiments, the formulation is a multiphase release formulation.
  • the active ingredient is oseltamivir; in some embodiments, the active ingredient is oseltamivir phosphate.
  • an oseltamivir preparation comprising oseltamivir or a salt thereof, the preparation is a once-a-day administration preparation, and the preparation includes a sustained-release preparation containing oseltamivir or a salt thereof Part and the immediate-release part containing oseltamivir or its salt, based on the total weight of oseltamivir in the preparation, the weight ratio of oseltamivir in the immediate-release part is 20%-50%, so The weight ratio of oseltamivir in the immediate-release part to oseltamivir in the sustained-release part is 1:4-1:1.
  • the weight ratio of oseltamivir in the immediate-release part is 20%-30%; in some embodiments, the weight ratio of oseltamivir in the immediate-release part is 20% -40%; in some embodiments, the weight ratio of oseltamivir in the immediate-release part is 30%-40%; in some embodiments, the weight of oseltamivir in the immediate-release part The ratio is 30%-50%; in some embodiments, the weight ratio of oseltamivir in the immediate-release part is 40%-50%.
  • the weight ratio of oseltamivir in the immediate-release part to oseltamivir in the sustained-release part is 1:4-1:3; in some embodiments, the fast-release part The weight ratio of oseltamivir in the release portion to oseltamivir in the sustained-release portion is 1:4-1:2; in some embodiments, the weight ratio of oseltamivir and oseltamivir in the immediate-release portion The weight ratio of oseltamivir in the sustained-release part is 1:3-1:2; in some embodiments, the oseltamivir in the immediate-release part and the oseltamivir in the sustained-release part The weight ratio of tamivir is 1:3-1:1; in some embodiments, the weight ratio of oseltamivir in the immediate-release part to oseltamivir in the sustained-release part is 1:2 -1:1.
  • the formulation may be a biphasic release formulation, a three-phase release formulation, or a multiphase release formulation with more than three phases.
  • the formulation is a biphasic release formulation, in some embodiments, the formulation is a three-phase release formulation, and in some embodiments, the formulation is a multiphase release formulation.
  • the active ingredient is oseltamivir; in some embodiments, the active ingredient is oseltamivir phosphate.
  • the oseltamivir preparation includes at least one sustained-release material; the weight of oseltamivir accounts for 3%-50% of the total weight of the preparation; the oseltamivir or its salt is released in 4 hours The amount is 25%-90%, and the 10h release amount of oseltamivir or its salt is greater than 70%.
  • the sustained-release material in the oseltamivir preparation is methacrylic acid-ethyl acrylate copolymer RL and methacrylic acid-ethyl acrylate copolymer RS, and the weight ratio of oseltamivir is 22.4%
  • the release amount of oseltamivir in 4 hours is 78%, and the release amount of oseltamivir or its salt in 10 hours is 97%; in some embodiments, the sustained-release material in the oseltamivir preparation is ethyl cellulose.
  • the weight ratio of setavir is 3.3%, the release amount of oseltamivir in 4 hours is 75%, and the release amount of oseltamivir or its salt in 10 hours is 96%.
  • the release amount of oseltamivir or its salt in 1 hour is 25%-55%, and the release amount of oseltamivir or its salt in 4 hours is 25%-90%.
  • the release amount of Tamivir or its salt in 10 hours is greater than 70%; the weight ratio of oseltamivir or its salt is 3%-50%; based on the weight of oseltamivir, the single-dose specification is 60mg-300mg; after once a day administration , The peak-to-valley ratio of the plasma concentration of the active metabolite of oseltamivir within 24h is less than 2.5:1.
  • the oseltamivir formulation further comprises at least one sustained-release material, the weight ratio of the sustained-release material is 3%-50%, and the sustained-release material includes Ethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, polyoxyethylene, polyvinyl alcohol, methacrylic acid-ethyl acrylate copolymer RL, methacrylic acid-ethyl acrylate copolymer RS, methacrylic acid -Ethyl acrylate copolymer NE 30D, methacrylic acid-ethyl acrylate copolymer L100-55, hypromellose acetate succinate, glyceryl behenate, chitosan, carbomer, carnauba wax, SR 30D, SR, at least one of cellulose acetate titanate, sodium alginate, sodium carboxymethyl cellulose, carrageenan, cetyl alcohol, stearyl alcohol, cetosteacetate
  • an oseltamivir preparation comprising oseltamivir or a salt thereof, the preparation is a once-a-day dosing preparation, and the preparation includes a sustained-release preparation containing oseltamivir or a salt thereof Part and the immediate-release part containing oseltamivir or its salt, based on the total weight of oseltamivir in the preparation, the weight ratio of oseltamivir in the immediate-release part is 20%-50%, so
  • the formulation contains at least one sustained-release material, and the weight ratio of the sustained-release material is 3%-50%; the 1h release amount of oseltamivir is 25%-55%, and the 4h release amount is 25%-90% , 10h release is greater than 70%.
  • the weight ratio of oseltamivir in the immediate-release part to oseltamivir in the sustained-release part is 1:4-1:1. In some embodiments, the weight ratio of oseltamivir in the immediate-release part to oseltamivir in the sustained-release part is 1:4-1:3; in some embodiments, the fast-release part The weight ratio of oseltamivir in the release portion to oseltamivir in the sustained-release portion is 1:4-1:2; in some embodiments, the weight ratio of oseltamivir and oseltamivir in the immediate-release portion The weight ratio of oseltamivir in the sustained-release part is 1:3-1:2; in some embodiments, the oseltamivir in the immediate-release part and the oseltamivir in the sustained-release part The weight ratio of tamivir is 1:3-1:2; in some embodiments, the os
  • the oseltamivir preparation based on the weight of oseltamivir, has a single-dose specification of 60mg-300mg; in some embodiments, the specification is 60mg-90mg; in some embodiments, the specification is 60mg-150mg; in some embodiments, In embodiments, the specification is 60mg-200mg; in some embodiments, the specification is 90mg-150mg; in some embodiments, the specification is 90mg-200mg; in some embodiments, the specification is 90mg-300mg; in some embodiments In some embodiments, the specification is 150mg-200mg; in some embodiments, the specification is 150mg-300mg; in some embodiments, the specification is 200mg-300mg.
  • the strength is 60 mg, 90 mg, 150 mg, 200 mg, or 300 mg.
  • the immediate release dosage form for children currently on the market, based on the weight of oseltamivir, has a minimum specification of 30 mg and is administered twice a day.
  • the minimum specification is 60 mg; the immediate release dosage form for adults currently on the market Dosage form, based on the weight of oseltamivir, the minimum specification is 75mg, twice a day, if it is prepared into a once-a-day sustained-release preparation, the minimum specification is 150mg, if the rule is increased to 300mg, it cannot be combined with the 75mg specification for one day administration
  • the two-time immediate-release dosage form is equivalent, indicating that the bioavailability is low. If it is released suddenly, the risk of toxic and side effects will increase, and the tablet will be heavy and cause difficulty in swallowing. Therefore, based on the weight of oseltamivir, it is more appropriate to choose 60mg-300mg. .
  • the sustained-release material includes selected from ethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, polyoxyethylene, polyvinyl alcohol, methacrylic acid-ethyl acrylate copolymer RL, Methacrylic acid-ethyl acrylate copolymer RS, methacrylic acid-ethyl acrylate copolymer NE 30D, methacrylic acid-ethyl acrylate copolymer L100-55, hypromellose acetate succinate, glycerin behenate Ester, chitosan, carbomer, carnauba wax, SR 30D, SR, at least one of cellulose acetate titanate, sodium alginate, sodium carboxymethyl cellulose, carrageenan, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and paraffin wax.
  • the oseltamivir preparation is used for the treatment of influenza A in adults or influenza B in adults, and influenza A in children or influenza B in children.
  • oseltamivir active metabolite internal blood drug will be administered within 24 hours
  • the concentration is greater than 100ng/ml, or greater than 150ng/ml.
  • the blood concentration in the active metabolite of intravenous oseltamivir is greater than 172 ng/ml in 24 hours; in some embodiments, the blood concentration in the active metabolite of intraperitoneal oseltamivir is greater than 261 ng/ml in 24 hours.
  • the peak-to-valley ratio of the plasma concentration of the active metabolite of oseltamivir within 24 hours is less than 2.5:1.
  • the peak-to-valley ratio of blood drug concentration in the body of less than 2.5:1 can avoid peak-to-valley fluctuations, thereby improving the patient's treatment compliance and safety.
  • the peak-to-valley ratio of the plasma concentration of the active metabolite of oseltamivir within 24 hours is 2.14:1.
  • the peak-to-valley ratio of the plasma concentration of the active metabolite of oseltamivir within 24 hours is less than 2:1, which is more conducive to avoiding peak-to-valley fluctuations. Thereby improving the patient's treatment compliance and safety.
  • the peak-to-valley ratio of the plasma concentration of the active metabolite of oseltamivir within 24 hours is 1.21:1.
  • the blood concentration of the active metabolite of oseltamivir is more than 20%, or more than 30%, or more than 40% of Cmax in 2 hours; the blood concentration in the body of 24 hours Above 30%, or above 40% of Cmax.
  • the blood concentration of the active metabolite of oseltamivir in 2 hours is 27% of Cmax; in some embodiments, the blood concentration of the active metabolite of oseltamivir in 2 hours is 25% of Cmax; In some embodiments, the blood concentration of the active metabolite of oseltamivir in 24 hours is 47% of Cmax; in some embodiments, the blood concentration of the active metabolite of oseltamivir in 24 hours is 82% of Cmax.
  • the oseltamivir preparation continuously releases oseltamivir for a period of at least 24 hours.
  • the blood concentration in the active metabolite of oseltamivir is greater than or equal to 100ng/ml, and the maintenance time is greater than 16h, or greater than 20h. In some embodiments, in the oseltamivir preparation, the blood concentration in the active metabolite of oseltamivir is greater than or equal to 170 ng/ml, and the maintenance time is greater than 16 hours. In some embodiments, in the oseltamivir preparation, the blood concentration in the active metabolite of oseltamivir is greater than or equal to 250 ng/ml, and the maintenance time is greater than 12 hours.
  • the blood concentration in the active metabolite of oseltamivir is greater than or equal to 250ng/ml, and the maintenance time is greater than 16h.
  • the blood concentration in the active metabolite of oseltamivir is 261 ng/mL, and the maintenance time is 16 h; in some embodiments, the blood concentration in the active metabolite of oseltamivir is 172 ng/mL, which is maintained The time is 20h.
  • an oseltamivir preparation further comprising a sustained-release material
  • the sustained-release material includes hydroxypropyl methylcellulose and/or methacrylic acid-ethyl acrylate copolymer.
  • the sustained-release material includes hydroxypropyl methylcellulose; in some embodiments, the sustained-release material includes methacrylic acid-ethyl acrylate copolymer; in some embodiments, the Sustained release materials include hydroxypropyl methyl cellulose and methacrylic acid-ethyl acrylate copolymer.
  • the methacrylic acid-ethyl acrylate copolymer includes selected from the group consisting of methacrylic acid-ethyl acrylate copolymer RL, methacrylic acid-ethyl acrylate copolymer RS, methacrylic acid-ethyl acrylate copolymer NE 30D, A At least one of acrylic acid-ethyl acrylate copolymer L100-55.
  • the methacrylic acid-ethyl acrylate copolymer includes methacrylic acid-ethyl acrylate copolymer RL; in some embodiments, the methacrylic acid-ethyl acrylate copolymer includes methacrylic acid -Ethyl acrylate copolymer RS; in some embodiments, the methacrylic acid-ethyl acrylate copolymer includes methacrylic acid-ethyl acrylate copolymer NE 30D; in some embodiments, the methacrylic acid- The ethyl acrylate copolymer includes methacrylic acid-ethyl acrylate copolymer L100-55.
  • the hydroxypropyl methyl cellulose includes selected from hydroxypropyl methyl cellulose K15M, hydroxypropyl methyl cellulose K4M, hydroxypropyl methyl cellulose K100M, hydroxypropyl methyl cellulose K100LV At least one.
  • the hydroxypropyl methyl cellulose includes hydroxypropyl methyl cellulose K15M; in some embodiments, the hydroxypropyl methyl cellulose includes hydroxypropyl methyl cellulose K4M; In some embodiments, the hydroxypropyl methyl cellulose includes hydroxypropyl methyl cellulose K100M; in some embodiments, the hydroxypropyl methyl cellulose includes hydroxypropyl methyl cellulose K100LV.
  • the weight of the sustained-release material accounts for 3%-50% of the total weight of the formulation.
  • the weight ratio of the sustained-release material is 3%-10%; in some embodiments, the weight ratio of the sustained-release material is 3%-20%; in some embodiments, the weight ratio of the sustained-release material is 3%-20%; The weight ratio of the sustained-release material is 3%-30%; in some embodiments, the weight ratio of the sustained-release material is 10%-20%; in some embodiments, the weight ratio of the sustained-release material is 10%.
  • the weight ratio of the sustained-release material is 10%-50%; in some embodiments, the weight ratio of the sustained-release material is 20%-30%; in some embodiments In an example, the weight ratio of the sustained-release material is 20%-50%; in some embodiments, the weight ratio of the sustained-release material is 30%-50%. In some embodiments, the weight ratio of the sustained-release material is 37%, 29%, 25%, 50%, 21%, or 34%.
  • the weight of the hydroxypropyl methylcellulose accounts for 4%-30% of the total weight of the formulation, and the weight of the methacrylic acid-ethyl acrylate copolymer accounts for 0% of the total weight of the formulation. -35%.
  • the weight ratio of hypromellose is 4%-10%. In some embodiments, the weight ratio of hypromellose is 4%-15%. In some embodiments, The weight ratio of the hypromellose is 4%-20%. In some embodiments, the weight ratio of the hypromellose is 4%-25%. In some embodiments, the weight ratio of the hypromellose is 4%-25%. The weight ratio of hypromellose is 10%-15%.
  • the weight ratio of hypromellose is 10%-20%. In some embodiments, the hypromellose The weight ratio of the element is 10%-25%. In some embodiments, the weight ratio of the hypromellose is 10%-30%. In some embodiments, the weight ratio of the hypromellose It is 15%-20%. In some embodiments, the weight ratio of the hypromellose is 15%-25%.
  • the weight ratio of the hypromellose is 15%- 30%, in some embodiments, the weight ratio of the hypromellose is 20%-25%, and in some embodiments, the weight ratio of the hypromellose is 20%-30%; In some embodiments, the weight ratio of the methacrylic acid-ethyl acrylate copolymer is 5%-10%, and in some embodiments, the weight ratio of the methacrylic acid-ethyl acrylate copolymer is 5%- 20%. In some embodiments, the weight ratio of the methacrylic acid-ethyl acrylate copolymer is 5%-25%.
  • the weight ratio of the methacrylic acid-ethyl acrylate copolymer is In some embodiments, the weight ratio of the methacrylic acid-ethyl acrylate copolymer is 10%-20%. In some embodiments, the methacrylic acid-ethyl acrylate copolymer is The weight ratio of the methacrylic acid-ethyl acrylate copolymer is 10%-25%. In some embodiments, the weight ratio of the methacrylic acid-ethyl acrylate copolymer is 10%-35%. In some embodiments, the methacrylic acid-ethyl acrylate copolymer has a weight ratio of 10% to 35%.
  • the weight ratio of the ethyl acrylate copolymer is 20%-25%. In some embodiments, the weight ratio of the methacrylic acid-ethyl acrylate copolymer is 20%-35%. In some embodiments, the The weight ratio of the methacrylic acid-ethyl acrylate copolymer is 25%-35%.
  • the weight ratio of the hypromellose is 12%, and the weight ratio of the methacrylic acid-ethyl acrylate copolymer is 25%; in some embodiments, the hypromellose The weight ratio of the methacrylic acid-ethyl acrylate copolymer is 4%, and the weight ratio of the methacrylic acid-ethyl acrylate copolymer is 25%; in some embodiments, the weight ratio of the hypromellose is 12%, and the methyl The weight ratio of the acrylic acid-ethyl acrylate copolymer is 12%; in some embodiments, the weight ratio of the hypromellose is 17%, and the weight ratio of the methacrylic acid-ethyl acrylate copolymer is 33%.
  • the weight ratio of the hypromellose is 8%, and the weight ratio of the methacrylic acid-ethyl acrylate copolymer is 12%; in some embodiments, the hypromellose The weight ratio of methyl cellulose is 25%, and the weight ratio of the methacrylic acid-ethyl acrylate copolymer is 4%; in some embodiments, the weight ratio of hypromellose is 11%. The weight ratio of the methacrylic acid-ethyl acrylate copolymer is 23%.
  • the oseltamivir preparation further comprises a sustained-release material, and the sustained-release material is hydroxypropyl methylcellulose and a methacrylic acid-ethyl acrylate copolymer.
  • the proportion of weight to the total weight of the preparation is 3%-50%, or 20%-50%, or 30%-50%, or 10%-30%; the weight of the hydroxypropyl methylcellulose accounts for The proportion of the total weight of the preparation is 4%-30%, or 4%-15%, or 10%-20%, or 15%-30%; the amount of the methacrylic acid-ethyl acrylate copolymer accounts for the total weight of the preparation
  • the weight ratio is 0-35%, or 5%-25%, or 10%-30%, or 20%-35%.
  • the release amount of oseltamivir in 1 hour is 25%-55%; the release amount of oseltamivir in 4 hours is 25%-90%; the release amount of oseltamivir in 10 hours is greater than 70%; the weight of oseltamivir accounts for 3%-50% of the total weight of the preparation; it also contains at least one sustained-release material whose weight accounts for 3%-50% of the total weight of the preparation
  • the peak-to-valley ratio of the blood drug concentration in the active metabolite of oseltamivir within 24 hours is less than 2.5:1; the oseltamivir preparation is used for the treatment of influenza A in adults, influenza B in adults, and children For influenza A or children with influenza B, the blood concentration in the active metabolite of oseltamivir is greater than 100 ng/mL within 24 hours after being administered once a day; after the o
  • the oseltamivir preparations provided in the first to seventh aspects of the present invention can be prepared into tablets, capsules, and suspensions.
  • the oseltamivir formulation is a tablet; in some embodiments, the oseltamivir formulation is a capsule; in some embodiments, the oseltamivir formulation is a suspension .
  • the oseltamivir preparations provided by the first aspect to the seventh aspect of the present invention can be prepared into a double-layer tablet, wherein one layer of the double-layer tablet contains an immediate-release part and the other layer contains a sustained-release part.
  • the oseltamivir preparations provided in the first aspect to the seventh aspect of the present invention use a sustained-release part as a tablet core, and the immediate-release part is wrapped outside the tablet core.
  • the oseltamivir preparations provided in the first to seventh aspects of the present invention contain a sustained-release part and an immediate-release part, the sustained-release part contains a core 1, and the immediate-release part contains a core 2 that contains core 2.
  • the core 1 can be prepared by uniformly mixing oseltamivir and the framework sustained-release material, and the core 2 can be prepared by uniformly mixing oseltamivir and the framework material.
  • the core 1 may contain oseltamivir and is wrapped with a slow-release coating layer formed by high molecular polymers and other pharmaceutical excipients, and the core 2 may contain oseltamivir and be wrapped with water-soluble materials.
  • a quick-release coating layer formed by a polymer film-forming material and a plasticizer.
  • the core 1 can be prepared by the extrusion spheronization method, and the core 1 can be prepared by the extrusion spheronization method after mixing oseltamivir with pharmaceutical excipients.
  • Core 2
  • the core 1 can be prepared by spraying oseltamivir and the sustained-release film-forming material on the blank pellet core, and the core 1 can be prepared by mixing oseltamivir and the immediate-release coating material and spraying on the blank pellet core.
  • Core 2
  • the core 1 and the core 2 are mixed and then compressed into a double-layer tablet or a multi-layer tablet, or the core 1 and the core 2 are mixed and directly filled in a capsule, or The core 1 and the core 2 are mixed and then bagged.
  • the eighth aspect of the present invention provides a method for preparing the aforementioned oseltamivir preparation.
  • the quick-release coating layer formed by the water-soluble polymer film-forming material, plasticizer and oseltamivir is wrapped outside the blank core to obtain the quick-release part.
  • sustained-release coating layer formed by high molecular polymer and other pharmaceutical excipients is wrapped in the immediate-release part obtained in (1) to obtain the sustained-release part
  • the immediate-release part obtained in (1) and the sustained-release part obtained in (2) are filled in a capsule, or compressed into a tablet, or bagged to obtain the oseltamivir preparation.
  • sustained-release coating layer formed by high molecular polymer and other pharmaceutical excipients is wrapped outside the core containing oseltamivir to obtain the sustained-release part
  • a quick-release coating layer formed by a water-soluble polymer film-forming material, a plasticizer, and oseltamivir is wrapped outside the sustained-release part obtained in (1) to obtain the oseltamivir preparation.
  • sustained-release coating layer formed by oseltamivir, high molecular polymer and other pharmaceutical excipients is wrapped outside the blank core to obtain the sustained-release part.
  • a quick-release coating layer formed by a water-soluble polymer film-forming material, a plasticizer, and oseltamivir is wrapped outside the sustained-release part obtained in (1) to obtain the oseltamivir preparation.
  • the sustained-release part is a core containing oseltamivir and a matrix sustained-release material
  • the core may include particles, tablet cores or pellet cores.
  • the core may further include, optionally, a filler, a binder, a penetration enhancer or a lubricant.
  • the method for preparing the core includes wet granulation, dry granulation or direct powder compression.
  • the high molecular polymer may include selected from ethyl cellulose, cellulose acetate, methacrylic acid-ethyl acrylate copolymer RL, methacrylic acid-ethyl acrylate copolymer RS, In the methacrylic acid-ethyl acrylate copolymer NE 30D, SR 30D, SR, methacrylic acid-ethyl acrylate copolymer L100-55, at least one of hypromellose acetate succinate and cellulose acetate titanate.
  • the high-molecular polymer includes a pH-independent high-molecular material or a pH-dependent high-molecular material.
  • the pH-independent polymer material includes selected from ethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, polyoxyethylene, polyvinyl alcohol, methacrylic acid-ethyl acrylate copolymer RL, methyl Acrylic acid-ethyl acrylate copolymer RS, methacrylic acid-ethyl acrylate copolymer NE 30D, SR 30D, At least one of SR;
  • the pH-dependent polymer material includes selected from the group consisting of methacrylic acid-ethyl acrylate copolymer L100-55, hypromellose acetate succinate, cellulose acetate titanate, chitosan At least one of sugar, carbomer, carrageenan, sodium alginate, and sodium carboxymethyl cellulose.
  • the other pharmaceutical excipients may include plasticizers, anti-sticking agents, emulsifiers, or porogens.
  • the water-soluble polymer film-forming material may include selected from the group consisting of hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl At least one of methyl cellulose and copovidone.
  • the matrix sustained-release material may include selected from hypromellose, polyoxyethylene, polyvinyl alcohol, ethyl cellulose, glyceryl behenate, chitosan, carbohydrate At least one of carnauba wax, sodium alginate, sodium carboxymethyl cellulose, carrageenan, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and paraffin wax.
  • the framework sustained-release material includes a pH-independent polymer material, a pH-dependent polymer material or a waxy framework material.
  • the pH-independent polymer material includes at least one selected from ethyl cellulose, hydroxypropyl methylcellulose, polyoxyethylene, and polyvinyl alcohol;
  • the pH-dependent polymer material includes a shell At least one of glycan, carbomer, carrageenan, sodium alginate, sodium carboxymethyl cellulose;
  • the waxy skeleton material includes selected from the group consisting of glyceryl behenate, carnauba wax, cetyl alcohol, ten At least one of octaol, cetostearyl alcohol, and paraffin wax.
  • the immediate release coating layer is externally wrapped with an isolation layer.
  • the isolation layer contains a water-soluble polymer film-forming material, or a plasticizer, and optionally, an anti-sticking agent or a sunscreen agent.
  • Fig. 1 is a graph showing the drug-time curve of the active metabolite of oseltamivir in the body after oral administration of the oseltamivir preparation prepared in Example 12 of the present invention in an adult fasting state.
  • Fig. 2 is a graph showing the drug-time curve of the active metabolite of oseltamivir in the body after oral administration of the oseltamivir preparation prepared in Example 12 of the present invention in an adult eating state.
  • Fig. 3 is a graph showing the drug-time curve of the active metabolite of oseltamivir in the body after oral administration of the oseltamivir preparation prepared in Example 18 of the present invention in an adult eating state.
  • Tablet core preparation Weigh oseltamivir phosphate and microcrystalline cellulose according to the prescription, transfer them to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (the final dried polyvinylpyrrolidone The amount is as indicated in the prescription), then wet granulation, fluidized bed drying, dry granulation, adding fillers, penetration enhancers and lubricants, and then compressing tablets to obtain 100 mg oseltamivir tablet cores.
  • Controlled release film A controlled release film coating solution is prepared according to the prescription, and the above-mentioned tablet core is coated. The weight gain of the coating accounts for 8% of the tablet core.
  • Immediate-release layer prepare the coating solution for the immediate-release layer according to the prescription, and coat the above-mentioned controlled-release coated tablets, and the coating film contains 50 mg of oseltamivir.
  • Isolation layer Prepare the isolation layer coating solution according to the prescription, and coat the above-mentioned immediate-release coated tablets. The weight gain of the coating accounts for 2% of the immediate-release coated tablets.
  • Tablet core preparation Weigh oseltamivir phosphate and microcrystalline cellulose 101QD according to the prescription, transfer to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (finally dried polyethylene The amount of pyrrolidone is as indicated in the prescription), followed by wet sizing, fluidized bed drying, dry sizing, adding fillers, penetration enhancers and lubricants, and then compressing tablets to obtain 40 mg oseltamivir tablet cores.
  • Controlled release film 1 Prepare a controlled release film coating solution according to the prescription, and coat the above-mentioned tablet core, and the weight gain of the coating accounts for 10% of the tablet core.
  • Immediate-release layer prepare a coating solution for the immediate-release layer according to the prescription, and coat the above-mentioned controlled-release coated tablets, and the coating film contains 20 mg of oseltamivir.
  • Isolation layer Prepare the isolation layer coating solution according to the prescription, and coat the above-mentioned immediate-release coated tablets. The weight gain of the coating accounts for 2% of the immediate-release coated tablets.
  • Tablet core preparation Weigh oseltamivir phosphate and mannitol according to the prescription, transfer to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (the final amount of polyvinylpyrrolidone after drying is as prescribed (Shown), followed by wet sizing, fluidized bed drying, dry sizing, adding fillers, penetration enhancers and lubricants, and then compressing tablets to obtain 130 mg oseltamivir tablet cores.
  • Controlled release film A controlled release film coating solution is prepared according to the prescription, and the above-mentioned tablet core is coated. The weight gain of the coating accounts for 8% of the tablet core.
  • Immediate-release layer prepare the coating solution for the immediate-release layer according to the prescription, and coat the above-mentioned controlled-release coated tablets, and the coating film contains 50 mg of oseltamivir.
  • Isolation layer Prepare the isolation layer coating solution according to the prescription, and coat the above-mentioned immediate-release coated tablets. The weight gain of the coating accounts for 2% of the immediate-release coated tablets.
  • Tablet core preparation Weigh oseltamivir phosphate and hydroxypropyl methylcellulose K100LV according to the prescription, transfer to a granulator for pre-mixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (finally dried The amount of polyvinylpyrrolidone is as indicated in the prescription), followed by wet sizing, fluidized bed drying, dry sizing, adding a lubricant, and then compressing to obtain a 60 mg oseltamivir sustained-release tablet core.
  • Immediate-release layer prepare the coating solution for the immediate-release layer according to the prescription, and coat the above-mentioned sustained-release tablet core, and the coating film contains 30 mg of oseltamivir.
  • Isolation layer Prepare the isolation layer coating solution according to the prescription, and coat the above-mentioned immediate-release coated tablets. The weight gain of the coating accounts for 2% of the immediate-release coated tablets.
  • Preparation of the total mixed granules of the sustained-release layer Weigh oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methyl fiber according to the prescription, transfer to a granulator for pre-mixing, and use polyvinylpyrrolidone-water as a granulating liquid. Wet granulation (the final amount of polyvinylpyrrolidone after drying is as indicated in the prescription), followed by wet granulation, fluidized bed drying, dry granulation, and lubricant addition to obtain the total mixed granules of the sustained release layer.
  • Preparation of total mixed granules for immediate release layer Weigh oseltamivir phosphate and microcrystalline cellulose according to the prescription, transfer them to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (after final drying) The amount of polyvinylpyrrolidone is as indicated in the prescription), followed by wet sizing, fluidized bed drying, dry sizing, and adding lubricant to obtain the total mixed particles of the immediate release layer.
  • Preparation of double-layer tablets use a double-layer tableting machine to fill 100mg or 150mg of the total mixed particles of the sustained-release layer, pre-press to obtain the core of the sustained-release layer; then fill with 50mg of the immediate-release layer particles, press the tablet to obtain Speedy double layer core.
  • Isolation layer Prepare the isolation layer coating solution according to the prescription, and coat the above-mentioned fast-releasing double-layer tablet core.
  • the weight gain of the coating accounts for 2% of the tablet core.
  • Preparation of immediate-release granules Weigh oseltamivir phosphate and sucrose according to the prescription, transfer them to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (the amount of polyvinylpyrrolidone after final drying is as follows: As indicated in the prescription), then wet granulation, fluidized bed drying, and dry granulation to obtain immediate-release granules.
  • sustained-release granules Preparation of sustained-release granules: a sustained-release coating solution is prepared according to the prescription, and the immediate-release granules are taken and sustained-release coated. The weight gain of the coating accounts for 35% of the granules.
  • Preparation of blank granules Weigh each component (except polyvinylpyrrolidone) according to the prescription, transfer to a granulator for premixing, use polyvinylpyrrolidone-water as a granulating liquid for wet granulation (finally dried polyvinylpyrrolidone) The amount is shown in the prescription), then wet granulation, fluidized bed drying, and dry granulation to obtain blank granules.
  • Preparation of total mixed granules Weigh 10mg quick-release granules, 50mg slow-release granules and blank granules according to the prescription, add correctives and glidants, and mix to obtain the final total mixed granules, which are bagged to obtain a slow-release dry suspension.
  • Preparation of immediate-release pellets prepare the immediate-release layer coating solution according to the prescription, use the microcrystalline pellet core as the substrate to coat, after the immediate-release layer coating is finished; then wrap the pellet core with a 2% weight gain isolation layer to obtain Immediate release pellets;
  • sustained-release pellets formulate a sustained-release coating solution according to the prescription, and use the immediate-release pellets as the substrate for sustained-release coating.
  • the weight gain of the coating accounts for 10% of the immediate-release pellets.
  • the coating of the sustained-release layer is finished.
  • the pill core is wrapped with a 2% weight gain isolation layer to obtain sustained-release pellets;
  • Capsule filling Fill 50mg specification immediate release pellets and 100mg specification sustained release pellets into capsules to obtain oseltamivir phosphate biphasic release capsules.
  • Preparation of immediate-release pellets Weigh all components (except polyvinylpyrrolidone) according to the prescription of the immediate-release pellets, transfer them to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating liquid for wet granulation (final The amount of polyvinylpyrrolidone after drying is as indicated in the prescription), and then sequentially wet and granulate, extrude spheronization, drying, and sieving; prepare the isolation layer coating solution according to the prescription, take the sieved pellets, and coat them. The weight gain of the coating accounts for 2% of the pellets, resulting in immediate-release pellets;
  • sustained-release pellets a coating solution was prepared according to the sustained-release coating prescription, and the immediate-release pellets were used as the substrate for coating. The weight gain of the coating accounted for 12% of the immediate-release pellets to obtain sustained-release pellets; Prepare the coating solution for the isolation layer according to the prescription, take the sustained-release pellets, and coat them. The weight gain of the coating accounts for 2% of the sustained-release pellets to obtain the final sustained-release pellets;
  • Capsule filling Fill 50mg specification immediate release pellets and 100mg specification sustained release pellets into capsules to obtain oseltamivir phosphate biphasic release capsules.
  • Preparation of immediate-release pellets Weigh the components (except polyvinylpyrrolidone) according to the prescription of the immediate-release pellets, transfer them to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating liquid for wet granulation (final The amount of polyvinylpyrrolidone after drying is as indicated in the prescription), and then extruded, spheronized, dried, and sieved in sequence;
  • Preparation of pulse-release pellets prepare sustained-release coating solution according to the prescription, take the immediate-release pellets, and coat them. The weight gain of the coating accounts for 8% of the immediate-release pellets to obtain sustained-release pellets; The isolation layer coating solution is prepared, the sustained-release pellets are taken, and the sustained-release pellets are coated, and the weight gain of the coating accounts for 2% of the sustained-release pellets to obtain the final pulse-release pellets.
  • Preparation of sustained-release pellets Weigh each component (except polyvinylpyrrolidone) according to the prescription of drug-containing pellets, transfer to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating liquid for wet granulation (final The amount of polyvinylpyrrolidone after drying is as indicated in the prescription), and then extruded, spheronized, dried, and sieved in sequence to obtain medicated pellets;
  • Preparation of pulse sustained-release pellets Prepare sustained-release coating solution according to the prescription, take the drug-containing pellets, and coat them, the weight gain of the coating accounts for 10% of the sustained-release pellets; prepare the isolation layer coating according to the prescription Solution, take the pulse sustained-release pellets, coat them, and the weight gain of the coating accounts for 2% of the pulse sustained-release pellets to obtain delayed sustained-release pellets.
  • Capsule filling Fill the capsules with 75 mg pulse-release pellets and 225 mg delayed-release pellets to obtain oseltamivir phosphate delayed-release capsules.
  • Preparation of the total mixed granules of the sustained-release layer Weigh oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methyl fiber according to the prescription of the sustained-release layer, transfer to a granulator for pre-mixing, and prepare with polyvinylpyrrolidone-water The granules are subjected to wet granulation (the final amount of polyvinylpyrrolidone after drying is as indicated in the prescription), and then wet granulation, fluidized bed drying, dry granulation, and lactose and lubricant are added to obtain the total mixed granules of the sustained release layer.
  • Preparation of total mixed granules for immediate release layer Weigh oseltamivir phosphate and microcrystalline cellulose according to the prescription, transfer them to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (after final drying) The amount of polyvinylpyrrolidone is as indicated in the prescription), then wet sizing, fluidized bed drying, dry sizing, and disintegrating agent and lubricant are added to obtain the total mixed particles of the immediate release layer.
  • Preparation of double-layer tablets use a double-layer tableting machine to first fill with 100mg of total mixed particles for the sustained-release layer, pre-compress to obtain the core of the sustained-release layer; then fill with 50mg-size immediate-release particles, and compress to obtain a fast-release double layer Tablet core.
  • Isolation layer Prepare the isolation layer coating solution according to the prescription, and coat the above-mentioned fast-releasing double-layer tablet core.
  • the weight gain of the coating accounts for 2% of the tablet core.
  • Tablet core preparation Weigh oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methyl fiber according to the prescription and transfer to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (final The amount of polyvinylpyrrolidone after drying is as indicated in the prescription), followed by wet sizing, fluidized bed drying, dry sizing, adding lubricant, and compressing to obtain 120 mg oseltamivir sustained-release tablet cores.
  • Controlled release film A controlled release film coating solution is prepared according to the prescription, and the above-mentioned sustained release tablet core is coated, and the weight gain of the coating accounts for 2% of the tablet core.
  • Immediate-release layer Prepare the coating solution for the immediate-release layer according to the prescription, and coat the above-mentioned controlled-release coated tablets, and the coating film contains 30 mg of oseltamivir.
  • Isolation layer Prepare the isolation layer coating solution according to the prescription, and coat the above-mentioned immediate-release coated tablets. The weight gain of the coating accounts for 3% of the immediate-release coated tablets.
  • Tablet core preparation Weigh oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methylcellulose according to the prescription, transfer to a granulator for pre-mixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (The final amount of polyvinylpyrrolidone after drying is shown in the prescription), then wet granulation, fluidized bed drying, dry granulation, and lubricant to obtain the total mixed granules of the sustained-release layer, and tableting to obtain 300mg osstat Wei sustained-release tablet core.
  • Isolation layer Prepare the isolation layer coating solution according to the prescription, and coat the above-mentioned sustained-release tablet core. The weight gain of the coating accounts for 2% of the tablet core.
  • Preparation of immediate-release pellets Weigh all components (except polyvinylpyrrolidone) according to the prescription of the immediate-release pellets, transfer them to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating liquid for wet granulation (final The amount of polyvinylpyrrolidone after drying is as shown in the prescription), and then extruded, spheronized, dried, and sieved in sequence; the isolation layer coating liquid is prepared according to the prescription, and the sieved pellets are taken and coated to increase the weight of the coating. The percentage of the immediate-release pellets is 2%; the final immediate-release pellets are obtained.
  • Preparation of pulse-release pellets prepare a sustained-release coating solution according to the prescription, take the immediate-release pellets, coat them, and coat them with two different weight gains. The weight gain of the coating accounts for 8% or 30% of the pellets respectively. , Obtain sustained-release pellets; Prepare the isolation layer coating solution according to the prescription, take the sustained-release pellets with different coating weight gains, and coat them separately, the weight gain of the coating accounts for 2% of the sustained-release pellets; Get 2-4h and 7-9h pulse release pellets.
  • Capsule filling Fill the 50mg specification immediate release pellets, 50mg specification pulse release pellets (2-4h release) and 50mg specification pulse release pellets (7-9h release) into capsules to obtain oseltamivir phosphate slow release capsules.
  • Preparation of sustained-release pellets First, prepare the penetration enhancing layer coating solution according to the prescription, and use the microcrystalline pellet core as the substrate for coating, and the weight gain of the coating accounts for 7% of the weight of the pellet core. Then, the upper drug layer is configured according to the prescription, and the permeation-enhancing layer pellet core is used as a substrate for drug coating, and the weight gain of the coating accounts for 150% of the weight of the permeation-enhancing layer pellet core. Then, a sustained-release coating solution is prepared according to the prescription configuration, the above pill core is used as a substrate for sustained-release coating, and the weight gain of the coating accounts for 25% of the weight of the upper pill core.
  • a coating solution for the isolation layer is configured according to the prescription, and a release coating is applied to the sustained-release layer, and the weight gain of the coating accounts for 2% of the weight of the sustained-release pellet core.
  • 150 mg oseltamivir sustained-release pellets were filled into capsules to obtain oseltamivir phosphate sustained-release capsules.
  • Preparation of immediate-release pellets prepare the coating solution for the top drug layer according to the prescription of the rapid-release pellets, and use the microcrystalline pellet core as the substrate for coating.
  • the coating weight of the top drug layer accounts for 150% of the weight of the pellet core; After the coating is finished, the upper pill core is wrapped with a 2% weight gain isolation layer to obtain immediate-release pellets;
  • the permeation-enhancing layer coating liquid was prepared according to the formulation of sustained-release pellets, and the microcrystalline pellet core was used as the substrate for coating, and the weight gain of the coating accounted for 7% of the weight of the pellet core.
  • the upper drug layer is configured according to the prescription, and the permeation-enhancing layer pellet core is used as a substrate for drug coating, and the weight gain of the coating accounts for 150% of the weight of the permeation-enhancing layer pellet core.
  • a sustained-release coating solution is prepared according to the prescription configuration, the above pill core is used as a substrate for sustained-release coating, and the weight gain of the coating accounts for 25% of the weight of the upper pill core.
  • the isolation layer coating solution is configured according to the prescription, and the sustained-release layer is wrapped with an isolation coating, and the weight gain of the coating accounts for 2% of the weight of the sustained-release pellet core to obtain sustained-release pellets.
  • Capsule filling Fill the 30mg specification immediate release pellets and 120mg specification sustained release pellets into the capsules to obtain oseltamivir phosphate biphasic release capsules.
  • Preparation of immediate-release pellets prepare the coating solution for the top drug layer according to the prescription of the rapid-release pellets, and use the microcrystalline pellet core as the substrate for coating.
  • the coating weight of the top drug layer accounts for 150% of the weight of the pellet core; After the coating is finished, the upper pill core is wrapped with a 2% weight gain isolation layer to obtain immediate-release pellets;
  • the permeation-enhancing layer coating liquid was prepared according to the formulation of sustained-release pellets, and the microcrystalline pellet core was used as the substrate for coating, and the weight gain of the coating accounted for 7% of the weight of the pellet core.
  • the upper drug layer is configured according to the prescription, and the permeation-enhancing layer pellet core is used as a substrate for drug coating, and the weight gain of the coating accounts for 150% of the weight of the permeation-enhancing layer pellet core.
  • a sustained-release coating solution is prepared according to the prescription configuration, the above pill core is used as a substrate for sustained-release coating, and the weight gain of the coating accounts for 30% of the weight of the upper pill core.
  • the isolation layer coating solution is configured according to the prescription, and the sustained-release layer is wrapped with an isolation coating, and the weight gain of the coating accounts for 2% of the weight of the sustained-release pellet core to obtain sustained-release pellets.
  • Capsule filling fill 75mg specification immediate release pellets and 75mg specification sustained release pellets into capsules to obtain oseltamivir phosphate biphasic release capsules.
  • Comparative example 1 Oseltamivir weight ratio is 2%, and the content uniformity is poor (compared with Example 7)
  • Preparation of immediate-release granules Weigh oseltamivir phosphate and sucrose according to the prescription, transfer them to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (the amount of polyvinylpyrrolidone after final drying is as follows: As indicated in the prescription), then wet granulation, fluidized bed drying, and dry granulation to obtain immediate-release granules.
  • sustained-release granules Preparation of sustained-release granules: a sustained-release coating solution is prepared according to the prescription, and the immediate-release granules are taken and sustained-release coated. The weight gain of the coating accounts for 35% of the granules.
  • Preparation of blank granules Weigh all components (except polyvinylpyrrolidone) according to the prescription of blank granules, transfer them to a granulator for premixing, and use polyvinylpyrrolidone-water as granulating liquid for wet granulation (the final dried polyvinylpyrrolidone). The amount of vinylpyrrolidone is shown in the prescription), and then wet sizing, fluidized bed drying, and dry sizing to obtain blank particles.
  • Preparation of total mixed granules Weigh 10 mg quick-release granules, 50 mg slow-release granules, and blank granules according to the prescription, add flavors and glidants, and mix to obtain the final total mixed granules.
  • Tablet core preparation Weigh oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methylcellulose according to the prescription, transfer to a granulator for pre-mixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (The final amount of polyvinylpyrrolidone after drying is as indicated in the prescription), then sequentially wet sizing, fluidized bed drying, dry sizing, and adding lubricant to obtain the total mixed particles of the sustained release layer, and then press the tablet.
  • Tablet core preparation Weigh oseltamivir phosphate and mannitol according to the prescription, transfer to a granulator for pre-mixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (the final amount of polyvinylpyrrolidone after drying is as follows: (As indicated in the prescription), followed by wet sizing, fluidized bed drying, dry sizing, adding fillers, penetration enhancers and lubricants, and then compressing tablets to obtain 130 mg oseltamivir tablet cores.
  • Controlled release film A controlled release coating solution is prepared according to the prescription, and the tablet core is coated. The weight gain of the coating accounts for 6% of the tablet core.
  • Immediate-release layer prepare the coating solution for the immediate-release layer according to the prescription, and coat the above-mentioned controlled-release coated tablets, and the coating film contains 50 mg of oseltamivir.
  • Isolation layer Prepare the isolation layer coating solution according to the prescription, and coat the above-mentioned immediate-release coated tablets. The weight gain of the coating accounts for 2% of the immediate-release coated tablets.
  • Tablet core preparation Weigh oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methylcellulose according to the prescription, transfer to a granulator for pre-mixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (The final amount of polyvinylpyrrolidone after drying is shown in the prescription), then wet granulation, fluidized bed drying, dry granulation, adding lubricant and then compressing to obtain 60mg oseltamivir sustained-release tablet core.
  • Immediate-release layer prepare the coating solution for the immediate-release layer according to the prescription, and coat the above-mentioned sustained-release tablet core, and the coating film contains 30 mg of oseltamivir.
  • Isolation layer Prepare the isolation layer coating solution according to the prescription, and coat the above-mentioned immediate-release coated tablets. The weight gain of the coating accounts for 2% of the immediate-release coated tablets.
  • Comparative Example 4 has a slow dissolution rate, with a 10h dissolution rate of ⁇ 70%.
  • Preparation of the total mixed granules for the sustained-release layer According to the prescription, weigh oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methylcellulose, transfer to a granulator for pre-mixing, and use polyvinylpyrrolidone-water as a granulating liquid. Wet granulation (the final amount of polyvinylpyrrolidone after drying is as indicated in the prescription), followed by wet granulation, fluidized bed drying, dry granulation, and lactose and lubricant to obtain the total mixed granules of the sustained release layer.
  • Preparation of total mixed granules for immediate release layer Weigh oseltamivir phosphate and microcrystalline cellulose according to the prescription, transfer them to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (after final drying) The amount of polyvinylpyrrolidone is as indicated in the prescription), then wet sizing, fluidized bed drying, dry sizing, adding, disintegrating agent, and lubricant to obtain the total mixed particles of the immediate release layer.
  • Preparation of double-layer tablets use a double-layer tableting machine to first fill 90mg of the total mixed particles of the sustained-release layer, pre-compress to obtain the core of the sustained-release layer; then fill with 60mg of the immediate-release layer particles, press the tablet to obtain the fast-release double layer Tablet core.
  • Isolation layer Prepare the isolation layer coating solution according to the prescription, and coat the above-mentioned fast-releasing double-layer tablet core.
  • the weight gain of the coating accounts for 2% of the tablet core.
  • Tablet core preparation Weigh oseltamivir phosphate and microcrystalline cellulose according to the prescription, transfer them to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (the final dried polyvinylpyrrolidone The amount is shown in the prescription), then wet granulation, fluidized bed drying, dry granulation, adding fillers, penetration enhancers and lubricants, and then compressing tablets to obtain 150 mg oseltamivir tablet cores.
  • Controlled release film A controlled release coating solution is prepared according to the prescription, and the above-mentioned tablet core is coated. The weight gain of the coating accounts for 12% of the tablet core.
  • the oseltamivir preparations prepared in Examples 1-14 are dissolved in a pH 6.8 medium, the volume of the medium is 900 ⁇ 9 mL, the temperature of the medium is 37.0 ⁇ 0.5° C., the paddle method, 50 rpm/min.
  • Dissolution sampling time points in pH 6.8 0.25h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h.
  • Sampling position from the tip of the blade to the midpoint of the liquid surface, 10mm away from the inner wall of the dissolution cup.
  • High performance liquid phase (HPLC) method was used to determine the in vitro dissolution content. The test results are shown in the following table:
  • Remarks: "Release in 1h within 4h” and “Released in 4h” in Examples 18 to 26 are the dissolution data of acid resistance in 0.1M HCl for 1 hour and then transferred to pH 6.8 medium. Other examples or comparative examples in the table are dissolution data in Ph6.8 medium.
  • Dosing program Four-preparation four-cycle four-cross test (24 healthy beagle dogs, half male and half, divided into 4 groups, 6 in each group, administered on an empty stomach). Three groups were given a self-developed oseltamivir sustained-release preparation (150mg) once a day; the other group was given a reference preparation, which was a 75mg quick-release preparation (trade name: ), twice a day.
  • Table 6 lists the pharmacokinetic data of the product of Example 11, the product of Comparative Example 5, the product of Comparative Example 6 and the reference preparation in beagle dogs (detecting the concentration of the active metabolite of oseltamivir).
  • Comparative Example 5 has a fast release rate and fast absorption, resulting in the Cmax in the beagle dog being much higher than that of the reference preparation, and the risk of toxic and side effects is increased; in addition, due to the concentrated absorption in a short time and the rapid elimination, it cannot maintain a stable effective blood concentration for a long time; Comparative Example 6 has a slow release rate and slow absorption.
  • the Cmax in the beagle dog's body is much lower than that of the reference formulation, which may not have a rapid onset effect, and the bioavailability is only 47% of that of the reference formulation twice a day; and The best absorption position may be missed; the release rate of Example 12 is moderate, the Cmax in the beagle dog is 80% of the reference formulation twice a day, and the bioavailability is 81% of the reference formulation twice a day. ideal. Therefore, the product of Example 12 was selected for the first human clinical pre-test.
  • Dosage regimen double preparation double crossover experiment (12 healthy beagle dogs, half male and half, divided into 2 groups, 6 in each group, administered on an empty stomach), both groups were given self-developed oseltamivir sustained-release preparation (150mg ), once a day.
  • Table 7 lists the pharmacokinetic data of the product of Example 5 and the product of Example 12 in Beagle dogs (detecting the concentration of the active metabolite of oseltamivir).
  • the AUC 0-t of the product of Example 5 and the product of Example 12 in Beagle dogs is similar, but the Cmax of the product of Example 5 is much higher than that of the product of Example 12. Considering the high blood concentration, it may increase the risk of toxic and side effects. Therefore, the product of Example 12 was selected for the second human clinical pre-test.
  • Dosage regimen double preparation double crossover experiment (12 healthy beagle dogs, half male and half, divided into 2 groups, 6 in each group, administered on an empty stomach), both groups were given self-developed oseltamivir sustained-release preparation (150mg ), once a day.
  • Table 8 lists the pharmacokinetic data of the product of Example 18 and the product of Example 5 in Beagle dogs (detecting the concentration of the active metabolite of oseltamivir).
  • the AUC 0-t of the product of Example 18 in Beagle dogs was 1.17 times that of the product of Example 5, and the Cmax of the product of Example 18 was slightly higher than that of the product of Example 5. Therefore, the product of Example 18 was selected for the third human clinical pre-test.
  • Dosage regimen the oseltamivir biphasic release formulation (150 mg) prepared in Example 12 was administered on an empty stomach, once a day.
  • Table 9 lists the pharmacokinetic data in humans of the oseltamivir biphasic release preparation prepared in Example 12 (detecting the concentration of the active metabolite of oseltamivir).
  • the product of the present invention has good pharmacokinetic properties, Tmax is 6h, Tmax for food and administration is 14h, and Cmax is greater than 300ng/mL.
  • the drug-time curve is shown in Figure 1.
  • Dosing regimen double-preparation double-crossover experiment, in which one group was given the oseltamivir biphasic release formulation (150 mg) prepared in Example 12, and the drug was administered once a day in the fed state; the other was given to the ginseng Comparative preparation, the reference preparation is a 75mg quick-release preparation (trade name: ), administered twice a day.
  • Table 10 lists the pharmacokinetic data of Example 12 and the reference preparation in humans (detecting the concentration of the active metabolite of oseltamivir).
  • the product of the present invention has good pharmacokinetic properties, Tmax is 14h, and Cmax is greater than 300ng/mL.
  • the drug-time curve is shown in Figure 2.
  • Dosage regimen dual-preparation double-crossover experiment, in which one group was given the oseltamivir biphasic release formulation (180 mg) prepared in Example 18, and the drug was administered once a day in a fed state; the other was given to ginseng Comparative preparation, the reference preparation is a 75mg quick-release preparation (trade name: ), administered twice a day.
  • Table 11 lists the pharmacokinetic data of Example 18 and the reference preparation in humans (detecting the concentration of the active metabolite of oseltamivir).
  • the product of the present invention has good pharmacokinetic properties, Tmax is 8h, and Cmax is greater than 300ng/mL.
  • the drug-time curve is shown in Figure 3.
  • Preparation of the total mixed granules for the sustained-release layer Weigh oseltamivir phosphate, microcrystalline cellulose and hydroxypropyl methyl fiber according to the prescription, transfer to a granulator for pre-mixing, and use purified water as a granulating solution for wet granulation , And then wet sizing, fluidized bed drying, dry sizing, and adding lubricant to obtain the total mixed particles of the slow-release layer.
  • Preparation of total mixed granules for immediate release layer Weigh oseltamivir phosphate and microcrystalline cellulose according to the prescription, transfer them to a granulator for premixing, and use polyvinylpyrrolidone-water as a granulating solution for wet granulation (after final drying) The amount of polyvinylpyrrolidone is as indicated in the prescription), followed by wet sizing, fluidized bed drying, dry sizing, and adding lubricant to obtain the total mixed particles of the immediate release layer.
  • Preparation of double-layer tablets use a double-layer tableting machine to first fill with 150mg of total mixed particles of sustained-release layer, pre-compress to obtain the core of sustained-release layer; then fill with 30mg of immediate-release layer particles, press to get a fast slow Double layer core.
  • Isolation layer Prepare the isolation layer coating solution according to the prescription, and coat the above-mentioned fast-releasing double-layer tablet core.
  • the weight gain of the coating accounts for 2% of the tablet core.
  • Table 12 The ratio of the weight of the sustained-release material to the total weight of the formulation in Example 18-Example 26
  • the oseltamivir preparations prepared in Examples 18 to 26 are dissolved in a pH 6.8 medium, the volume of the medium is 900 ⁇ 9 mL, the temperature of the medium is 37.0 ⁇ 0.5° C., the paddle method, 100 rpm/min
  • the in vitro dissolution test was carried out under the following conditions. Dissolution sampling time points in pH 6.8: 0.25h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 14h and 16h. Sampling position: from the tip of the blade to the midpoint of the liquid surface, 10mm away from the inner wall of the dissolution cup. High performance liquid phase (HPLC) method was used to determine the in vitro dissolution content. The test results are shown in the following table:
  • the oseltamivir preparations prepared in Examples 18 to 26 were first acid-resistant in 0.1M HCl for 1 hour and then transferred to a pH 6.8 medium for dissolution.
  • the volume of the medium was 900 ⁇ 9 mL, and the temperature of the medium was 37.0. ⁇ 0.5°C, paddle method, in vitro dissolution test at 75rpm/min.
  • Dissolution sampling time points in 0.1M HCl 0.25h, 1h
  • dissolution sampling time points in pH 6.8 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 14h, 16h.
  • Sampling position from the tip of the blade to the midpoint of the liquid surface, 10mm away from the inner wall of the dissolution cup.
  • High performance liquid phase (HPLC) method was used to determine the in vitro dissolution content. The test results are shown in the following table:

Abstract

一种奥司他韦制剂及其制备方法。所述制剂包含奥司他韦或其盐、缓释材料，所述制剂可以是单相释放制剂，双相释放制剂，三相释放制剂，或者三相以上的多相释放制剂。所述制剂一天给药一次，可获得至少24h或更长时间的持续释放，可减少给药次数，避免峰谷波动。

Description

一种奥司他韦制剂 技术领域
本发明涉及医药制剂领域，具体涉及一种奥司他韦或其盐的制剂。
背景技术
奥司他韦的分子式为C 16H 28N 2O 4，化学名为：(3R,4R,5S)-4-乙酰胺基-5-氨基-3-(1-乙基丙氧基)-1-环己烯-1-甲酸乙酯，结构式如下式01所示：
Figure PCTCN2020117625-appb-000001
奥司他韦活性代谢物，化学名为：(3R,4R,5S)-4-乙酰胺基-5-氨基-3-(1-乙基丙氧基)-1-环己烯-1-甲酸，结构式如下式02所示：
Figure PCTCN2020117625-appb-000002
磷酸奥司他韦主要用于成人和1岁及1岁以上儿童的甲型和乙型流感的治疗，成人和13岁及13岁以上青少年的甲型和乙型流感的预防。上市剂型有胶囊、干混悬剂、颗粒剂，规格以奥司他韦计，有15mg、30mg、45mg、75mg的胶囊或颗粒剂，和6mg/ml的干混悬剂，上述剂型均为常规速释制剂，体外溶出显示10min内即释放完全，口服给药后快速吸收，用于治疗流感的服用方法为一天服用两次。经调查研究发现，磷酸奥司他韦抗流感的能力与其在体内有效血药浓度的维持时间有关。速释制剂，为了维持有效的血药浓度，一天需多次服药，服药频繁，病人的顺应性差，且易发生服用不及时或经常漏服的情况，而导致疗效不佳。同时，对于儿童给药，一天一次的缓释制剂，减少服药次数，可以极大的增加儿童服药的顺应性。所以开发一种奥司他韦缓释制剂具有很大的临床意义。
现有技术研究可知，对于常规的缓释制剂通常存在吸收时滞、生物利用度降低的问题。磷酸奥司他韦要求流感症状出现后的48h内服药，且越早服用越好，对于存在吸收时滞的缓释制剂可能会导致错过最佳 治疗时间窗口，从而导致临床疗效不佳。同时，奥司他韦在小肠上端、小肠下端、结肠的吸收率存在差异，结肠的吸收率明显低于小肠，不合适的释放速率会导致生物利用度的降低，同时也达不到长时间的治疗效果，而为了达到迅速起效，通常会导致缓释制剂突释，从而无法达到长时间的治疗效果。所以临床上急需开发一种能在短时间内起效并且能维持长时间疗效的缓释制剂，但这类制剂都需要特殊的释放速度才能达到预期的临床效果，而这种特殊的释放速率是非显而易见的，需要大量的试验探索。
本发明的的目标是开发一种能兼顾快速起效和长时间维持有效血药浓度的磷酸奥司他韦制剂。
发明内容
发明概述
本发明第一方面，提供一种奥司他韦制剂，该制剂一天给药一次，可获得至少24h或更长时间的持续释放，可减少给药次数，避免峰谷波动，从而提高患者的治疗依从性和安全性。
本发明第二方面，提供一种奥司他韦制剂，一天给药一次；该制剂包括含有奥司他韦或其盐的缓释部分和含有奥司他韦或其盐的速释部分。所述制剂中，速释部分和缓释部分比例的设计，会显著影响起效时间和稳态血药浓度的维持时间，以及服药安全性问题。速释部分/缓释部分比例低，不能快速达到有效血药浓度，导致起效慢；而速释部分/缓释部分比例高，虽然能快速达到有效血药浓度，但也可能导致浓度过高，增加不良反应(胃肠道黏膜刺激)发生的概率；另外，速释部分/缓释部分比例低，只能短时间维持有效血药浓度，导致一天一次的服药频率不能维持全天有效，达不到缓释的效果。因此速释部分/缓释部分比例的设计对临床效果是非常关键的。
本发明提供的奥司他韦制剂，一天给药一次，可以是双相释放制剂，三相释放制剂，或者三相以上的多相释放制剂。
本发明第三方面，提供一种奥司他韦制剂的制备方法，所述方法制备得到的奥司他韦制剂，体内外效果数据好，质量稳定，符合质量要求；所述方法操作比较简单，重现性好，适合工业大生产。
术语定义
本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
在本发明的上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值。每一个数字的数值有可能会出现10％以下的差异或者本领域人员认为的合理的差异，如1％、2％、3％、4％或5％的差异。
术语“Cmax”是指给药后体内最大血药浓度。
术语“C2h”是指给药后2小时对应的血药浓度。
术语“Tmax”是指给药后体内最大血药浓度对应的时间。
术语“AUC0-t”是指给药后0到选择的最后一个时间点血药浓度时间曲线下面积。
术语“BA”是指生物利用度。
浓度“ng/mL”指纳克/毫升，为重量/体积，所述体积为血浆体积。
“ng·h/mL”指纳克·每小时/毫升，为重量·时间/体积。
“奥司他韦活性代谢物”是指((3R,4R,5S)-4-乙酰胺基-5-氨基-3-(1-乙基丙氧基)-1-环己烯-1-甲酸)，如结构式02所示。
“持续释放”是指采用LC/MS/MS分析仪器检测样品，根据其检测限，能检测到奥司他韦活性代谢物((3R,4R,5S)-4-乙酰胺基-5-氨基-3-(1-乙基丙氧基)-1-环己烯-1-甲酸)的血药浓度。
LC/MS/MS指液质联用。
“HPLC”指高效液相。
“血药浓度的峰谷比”是指给药后的24h内体内最高血药浓度与24h对应的血药浓度的比值。
ng指纳克，mg指毫克，h指小时，mm指毫米，℃指摄氏度，rpm指转速。
Figure PCTCN2020117625-appb-000003
SR 30D指聚乙酸乙烯酯的30％分散体系，
Figure PCTCN2020117625-appb-000004
SR指聚醋酸乙烯聚维酮混合物。
发明详述
基于现有技术的不足，本发明经过深入研究和考察，制备了含奥司他韦或其盐的制剂，该制剂一天给药一次，可获得至少24h或更长时间的持续释放，可减少给药次数，避免峰谷波动，从而提高患者的治疗依从性和安全性；该制剂可以是单相释放制剂，双相释放制剂，三相释放制剂，或者三相以上的多相释放制剂。该制剂在体内能够较长时间维持较高的血药浓度，生物利用度高。
本发明第一方面，提供一种奥司他韦制剂，包括奥司他韦或其盐，所述制剂为一天一次给药的制剂。在一些实施例中，包括奥司他韦；在一些实施例中，包括磷酸奥司他韦。
所述奥司他韦制剂，活性成分奥司他韦或其盐在≤4h的某时间段内能够快速释放。在一些实施例中， 所述奥司他韦制剂，活性成分奥司他韦或其盐在≤4h的某1h时间段内能够快速释放。在一些实施例中，所述奥司他韦制剂，活性成分奥司他韦或其盐在≤4h的某1h时间段内快速释放，释放量为25％-55％；在一些实施例中，释放量为25％-35％；在一些实施例中，释放量为25％-40％；在一些实施例中，释放量为25％-45％；在一些实施例中，释放量为35％-40％；在一些实施例中，释放量为35％-45％；在一些实施例中，释放量为35％-55％；在一些实施例中，释放量为40％-45％；在一些实施例中，释放量为40％-55％；在一些实施例中，释放量为45％-55％。在一些实施例中，活性成分奥司他韦或其盐在≤4h的某1h时间段内释放量为25％，35％，40％，45％，或者55％。
在一些实施方式中，所述奥司他韦制剂，活性成分奥司他韦或其盐在第1h快速释放，释放量为25％-55％。在一些实施例中，释放量为25％-35％；在一些实施例中，释放量为25％-40％；在一些实施例中，释放量为25％-45％；在一些实施例中，释放量为35％-40％；在一些实施例中，释放量为35％-45％；在一些实施例中，释放量为35％-55％；在一些实施例中，释放量为40％-45％；在一些实施例中，释放量为40％-55％；在一些实施例中，释放量为45％-55％。在一些实施例中，活性成分奥司他韦或其盐在第1h释放量为25％，35％，40％，45％，或者55％。
在一些实施方式中，所述奥司他韦制剂，活性成分奥司他韦或其盐4h释放量为25％-90％，或者释放量为25％-85％。在一些实施例中，释放量为25％-53％；在一些实施例中，释放量为25％-62％；在一些实施例中，释放量为25％-78％；在一些实施例中，释放量为53％-62％；在一些实施例中，释放量为53％-78％；在一些实施例中，释放量为53％-90％；在一些实施例中，释放量为62％-78％；在一些实施例中，释放量为62％-90％；在一些实施例中，释放量为78％-90％。在一些实施例中，活性成分奥司他韦或其盐在4h释放量为25％，53％，62％，63％，78％，或者90％。
在一些实施方式中，所述奥司他韦制剂，活性成分奥司他韦或其盐10h释放量大于70％。在一些实施方式中，所述奥司他韦制剂，活性成分奥司他韦或其盐10h释放量为70％-99％。在一些实施方式中，所述奥司他韦制剂，活性成分奥司他韦或其盐10h释放量大于74％，或大于77％，或大于80％，或大于86％，或大于89％，或大于93％，或大于95％，或大于98％。在一些实施例中，所述奥司他韦制剂，活性成分奥司他韦或其盐10h释放量为93％，94％，95％，96％，97％，98％，77％，86％，74％，或者89％。
所述奥司他韦制剂，活性成分奥司他韦的重量占制剂总重量的比例为3％-50％。在一些实施例中，所述奥司他韦制剂，活性成分奥司他韦的重量比例为3％-45％。在一些实施例中，奥司他韦的重量比例为3％-21％；在一些实施例中，奥司他韦的重量比例为3％-32％；在一些实施例中，奥司他韦的重量比例为21％-32％；在一些实施例中，奥司他韦的重量比例为21％-50％；在一些实施例中，奥司他韦或其盐的重量比例为32％-50％。在一些实施例中，奥司他韦的重量比例为3％，21％，32％，或者50％。
所述奥司他韦制剂，一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度的峰谷比小于2.5:1。 小于2.5:1的体内血药浓度峰谷比，能够避免峰谷波动，从而提高患者的治疗依从性和安全性。在一些实施例中，24h内奥司他韦活性代谢物体内血药浓度的峰谷比为2.14:1。在一些实施例中，所述奥司他韦制剂，一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度的峰谷比小于2:1，更有利于避免峰谷波动，从而提高患者的治疗依从性和安全性。在一些实施例中，24h内奥司他韦活性代谢物体内血药浓度的峰谷比为1.21:1。
所述奥司他韦制剂，按照奥司他韦重量计，单剂量规格为60mg-300mg。在一些实施例中，规格为60mg-90mg；在一些实施例中，规格为60mg-150mg；在一些实施例中，规格为60mg-200mg；在一些实施例中，规格为90mg-150mg；在一些实施例中，规格为90mg-200mg；在一些实施例中，规格为90mg-300mg；在一些实施例中，规格为150mg-200mg；在一些实施例中，规格为150mg-300mg；在一些实施例中，规格为200mg-300mg。在一些实施例中，单剂量规格为60mg，90mg，150mg，200mg，或者300mg。目前已上市的儿童速释剂型，按照奥司他韦重量计，最小规格为30mg，一天给药2次，若制备成一天一次的缓释制剂，最小规格为60mg；目前已上市的成人速释剂型，按照奥司他韦重量计，最小规格为75mg，一天给药2次，若制备成一天一次的缓释制剂，最小规格为150mg，如果规格增加至300mg还不能与75mg规格、一天给药2次的速释剂型等效，说明生物利用度低，如果突释，毒副作用风险增加，且片重大，造成吞咽困难，所以按照奥司他韦重量计，选择60mg-300mg是比较合适的规格。
所述奥司他韦制剂，还包含至少一种缓释材料，所述缓释材料的重量占制剂总重量的比为3％-50％。缓释材料的重量比为3％-50％，可制备得到至少24h或更长时间持续释放奥司他韦的制剂，减少给药次数。在一些实施例中，所述缓释材料的重量比为3％-10％；在一些实施例中，所述缓释材料的重量比为3％-20％；在一些实施例中，所述缓释材料的重量比为3％-30％；在一些实施例中，所述缓释材料的重量比为10％-20％；在一些实施例中，所述缓释材料的重量比为10％-30％；在一些实施例中，所述缓释材料的重量比为10％-50％；在一些实施例中，所述缓释材料的重量比为20％-30％；在一些实施例中，所述缓释材料的重量比为20％-50％。在一些实施例中，所述缓释材料的重量比为30％-50％。在一些实施例中，所述缓释材料的重量比为3.3％，10％，20％，29％，或者50％。
在一些实施方式中，所述奥司他韦制剂，还包含至少一种缓释材料，所述缓释材料包括选自乙基纤维素，羟丙基甲基纤维素，醋酸纤维素，聚氧乙烯，聚乙烯醇，甲基丙烯酸-丙烯酸乙酯共聚物RL，甲基丙烯酸-丙烯酸乙酯共聚物RS，甲基丙烯酸-丙烯酸乙酯共聚物NE 30D，甲基丙烯酸-丙烯酸乙酯共聚物NE L100-55，醋酸羟丙甲纤维素琥珀酸酯，山嵛酸甘油酯，壳聚糖，卡波姆，巴西棕榈蜡，
Figure PCTCN2020117625-appb-000005
SR 30D，
Figure PCTCN2020117625-appb-000006
SR，醋酸纤维素钛酸酯，海藻酸钠，羧甲基纤维素钠，卡拉胶，十六醇，十八醇，十六十八醇，石蜡中的至少一种。在一些实施例中，所述缓释材料为醋酸纤维素；在一些实施例中，所述缓释材料为甲基丙烯酸-丙烯酸乙酯共聚物RL和甲基丙烯酸-丙烯酸乙酯共聚物RS；在一些实施例中，所述缓释材料为乙基纤维素；在一些实施例中，所述缓释材料为羟丙基甲基纤维素；在一些实施例中，所述缓释材料为聚 氧乙烯和乙基纤维素。
在一些实施方式中，所述奥司他韦制剂，还包含至少一种缓释材料，所述缓释材料包括非pH依赖性高分子材料，pH依赖性高分子材料或者蜡质骨架材料。非pH依赖性高分子材料包括选自乙基纤维素，羟丙基甲基纤维素，醋酸纤维素，聚氧乙烯，聚乙烯醇，甲基丙烯酸-丙烯酸乙酯共聚物RL，甲基丙烯酸-丙烯酸乙酯共聚物RS，甲基丙烯酸-丙烯酸乙酯共聚物NE 30D，
Figure PCTCN2020117625-appb-000007
SR 30D，
Figure PCTCN2020117625-appb-000008
SR中的至少一种；所述pH依赖性高分子材料包括选自甲基丙烯酸-丙烯酸乙酯共聚物L100-55，醋酸羟丙甲纤维素琥珀酸酯，醋酸纤维素钛酸酯，壳聚糖，卡波姆，卡拉胶，海藻酸钠，羧甲基纤维素钠中的至少一种；所述蜡质骨架材料包括选自山嵛酸甘油酯，巴西棕榈蜡，十六醇，十八醇，十六十八醇，石蜡的至少一种。
在一些实施方式中，所述奥司他韦制剂，包含至少一种缓释材料，奥司他韦或其盐的重量占制剂总重量的比例为3％-50％。在一些实施方式中，所述奥司他韦制剂，包含至少一种缓释材料，奥司他韦或其盐4h释放量为25％-90％。在一些实施方式中，所述奥司他韦制剂，包含至少一种缓释材料，奥司他韦或其盐10h释放量大于70％。在一些实施方式中，所述奥司他韦制剂，包含至少一种缓释材料，奥司他韦或其盐的重量比例为3％-50％，奥司他韦或其盐4h释放量为25％-90％。在一些实施方式中，所述奥司他韦制剂，包含至少一种缓释材料，奥司他韦或其盐的重量比例为3％-50％，奥司他韦或其盐10h释放量大于70％。在一些实施方式中，所述奥司他韦制剂，奥司他韦或其盐4h释放量为25％-90％，司他韦或其盐10h释放量大于70％。在一些实施方式中，所述奥司他韦制剂，包含至少一种缓释材料，奥司他韦或其盐4h释放量为25％-90％，司他韦或其盐10h释放量大于70％。在一些实施方式中，所述奥司他韦制剂，包含至少一种缓释材料；奥司他韦或其盐的重量比例为3％-50％；奥司他韦或其盐4h释放量为25％-90％，奥司他韦或其盐10h释放量大于70％。
在一些实施例中，所述奥司他韦制剂中缓释材料为醋酸纤维素，奥司他韦或其盐的重量占制剂总重量的比例为25％-35％。在一些实施例中，所述奥司他韦制剂中缓释材料为醋酸纤维素，奥司他韦或其盐的重量比例为30％-35％。在一些实施例中，所述奥司他韦制剂中缓释材料为醋酸纤维素，奥司他韦或其盐的重量比例为31.6％。在一些实施例中，所述奥司他韦制剂中缓释材料为醋酸纤维素，奥司他韦或其盐4h释放量为25％-90％。在一些实施例中，所述奥司他韦制剂中缓释材料为醋酸纤维素，奥司他韦或其盐4h释放量大于70％。在一些实施例中，所述奥司他韦制剂中缓释材料为醋酸纤维素，奥司他韦或其盐10h释放量大于70％或90％或95％。在一些实施例中，所述奥司他韦制剂中缓释材料为醋酸纤维素，奥司他韦或其盐4h释放量大于70％，奥司他韦或其盐10h释放量大于70％或90％或95％。在一些实施例中，所述奥司他韦制剂中缓释材料为醋酸纤维素，奥司他韦或其盐的重量比例为30％-35％，奥司他韦或其盐4h释放量为25％-90％，奥司他韦或其盐10h释放量大于70％或80％或90％或95％。在一些实施例中，所述奥司他韦制剂中缓释材料为醋酸纤维素，奥司他韦或其盐的重量比例为30％-35％，奥司他韦或其盐4h释放量大于70％，奥司他韦或其盐10h释放量大于70％或80％或90％或95％。在一些实施例中，所 述奥司他韦制剂中缓释材料为醋酸纤维素，奥司他韦或其盐的重量比例为31.6％，奥司他韦4h释放量为78％，奥司他韦或其盐10h释放量为97％。在一些实施例中，所述奥司他韦制剂中缓释材料为羟丙基甲基纤维素，奥司他韦或其盐的重量比例为32.0％，奥司他韦4h释放量为63％，奥司他韦或其盐10h释放量为86％。
在一些实施方式中，所述奥司他韦制剂，还包含至少一种缓释材料，所述缓释材料的重量占制剂总重量的比为3％-50％，所述缓释材料包括选自乙基纤维素，羟丙基甲基纤维素，醋酸纤维素，聚氧乙烯，聚乙烯醇，甲基丙烯酸-丙烯酸乙酯共聚物RL，甲基丙烯酸-丙烯酸乙酯共聚物RS，甲基丙烯酸-丙烯酸乙酯共聚物NE 30D，甲基丙烯酸-丙烯酸乙酯共聚物L100-55，醋酸羟丙甲纤维素琥珀酸酯，山嵛酸甘油酯，壳聚糖，卡波姆，巴西棕榈蜡，
Figure PCTCN2020117625-appb-000009
SR 30D，
Figure PCTCN2020117625-appb-000010
SR，醋酸纤维素钛酸酯，海藻酸钠，羧甲基纤维素钠，卡拉胶，十六醇，十八醇，十六十八醇，石蜡中的至少一种。
在一些实施方式中，所述奥司他韦制剂，奥司他韦或其盐1h释放量为25％-55％，奥司他韦或其盐4h释放量为25％-90％，奥司他韦或其盐10h释放量大于70％；奥司他韦或其盐的重量比例为3％-50％；按照奥司他韦重量计，规格为60mg-300mg；一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度的峰谷比小于2.5:1；任选的，在一些实施方式中，所述奥司他韦制剂，还包含至少一种缓释材料，所述缓释材料的重量比为3％-50％，所述缓释材料包括选自乙基纤维素，羟丙基甲基纤维素，醋酸纤维素，聚氧乙烯，聚乙烯醇，甲基丙烯酸-丙烯酸乙酯共聚物RL，甲基丙烯酸-丙烯酸乙酯共聚物RS，甲基丙烯酸-丙烯酸乙酯共聚物NE 30D，甲基丙烯酸-丙烯酸乙酯共聚物NE L100-55，醋酸羟丙甲纤维素琥珀酸酯，山嵛酸甘油酯，壳聚糖，卡波姆，巴西棕榈蜡，
Figure PCTCN2020117625-appb-000011
SR 30D，
Figure PCTCN2020117625-appb-000012
SR，醋酸纤维素钛酸酯，海藻酸钠，羧甲基纤维素钠，卡拉胶，十六醇，十八醇，十六十八醇，石蜡中的至少一种。
本发明第二方面，提供一种奥司他韦制剂，包括奥司他韦或其盐，所述制剂为一天一次给药的制剂，所述制剂包括含有奥司他韦或其盐的缓释部分和含有奥司他韦或其盐的速释部分。该制剂可以是双相释放制剂，三相释放制剂，或者三相以上的多相释放制剂。在一些实施例中，所述制剂为双相释放制剂，在一些实施例中，所述制剂为三相释放制剂，在一些实施例中，所述制剂为多相释放制剂。在一些实施例中，活性成分为奥司他韦；在一些实施例中，活性成分为磷酸奥司他韦。
所述包括含有奥司他韦或其盐的缓释部分和含有奥司他韦或其盐的速释部分的奥司他韦制剂，活性成分奥司他韦或其盐在≤4h的时间段内能够快速释放，释放量为25％-55％。所述包括含有奥司他韦或其盐的缓释部分和含有奥司他韦或其盐的速释部分的奥司他韦制剂，活性成分奥司他韦或其盐在≤4h的某1h时间段内快速释放，释放量为25％-55％；在一些实施例中，释放量为25％-35％；在一些实施例中，释放量为25％-40％；在一些实施例中，释放量为25％-45％；在一些实施例中，释放量为35％-40％；在一些实施例中，释放量为35％-45％；在一些实施例中，释放量为35％-55％；在一些实施例中，释放量为 40％-45％；在一些实施例中，释放量为40％-55％；在一些实施例中，释放量为45％-55％。在一些实施例中，活性成分奥司他韦或其盐在≤4h的某1h时间段内释放量为25％，35％，40％，45％，或者55％。
在一些实施方式中，所述奥司他韦制剂，活性成分奥司他韦或其盐在第1h快速释放，释放量为25％-55％；在一些实施例中，释放量为25％-35％；在一些实施例中，释放量为25％-40％；在一些实施例中，释放量为25％-45％；在一些实施例中，释放量为35％-40％；在一些实施例中，释放量为35％-45％；在一些实施例中，释放量为35％-55％；在一些实施例中，释放量为40％-45％；在一些实施例中，释放量为40％-55％；在一些实施例中，释放量为45％-55％。在一些实施例中，活性成分奥司他韦或其盐在第1h释放量为25％，35％，40％，45％，或者55％。
在一些实施方式中，所述奥司他韦制剂，活性成分奥司他韦或其盐4h释放量为25％-90％，或者释放量为25％-85％；在一些实施例中，释放量为25％-53％；在一些实施例中，释放量为25％-62％；在一些实施例中，释放量为25％-78％；在一些实施例中，释放量为53％-62％；在一些实施例中，释放量为53％-78％；在一些实施例中，释放量为53％-90％；在一些实施例中，释放量为62％-78％；在一些实施例中，释放量为62％-90％；在一些实施例中，释放量为78％-90％。在一些实施例中，活性成分奥司他韦或其盐在4h释放量为25％，53％，62％，63％，78％，或者90％。
在一些实施方式中，所述奥司他韦制剂，活性成分奥司他韦或其盐10h释放量大于70％。在一些实施方式中，所述奥司他韦制剂，活性成分奥司他韦或其盐10h释放量为70％-99％。在一些实施方式中，所述奥司他韦制剂，活性成分奥司他韦或其盐10h释放量大于74％，或大于77％，或大于80％，或大于86％，或大于89％，或大于93％，或大于95％，或大于98％。在一些实施例中，所述奥司他韦制剂，活性成分奥司他韦或其盐10h释放量为93％，94％，95％，96％，97％，98％，77％，86％，74％，或者89％。
所述奥司他韦制剂，活性成分奥司他韦的重量占制剂总重量的比例为3％-50％，或者3％-45％。在一些实施例中，奥司他韦的重量比例为3％-21％；在一些实施例中，奥司他韦的重量比例为3％-32％；在一些实施例中，奥司他韦的重量比例为21％-32％；在一些实施例中，奥司他韦的重量比例为21％-50％；在一些实施例中，奥司他韦或其盐的重量比例为32％-50％。在一些实施例中，奥司他韦的重量比例为3％，21％，32％，或者50％。
所述奥司他韦制剂，一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度的峰谷比小于2.5:1。小于2.5:1的体内血药浓度峰谷比，能够避免峰谷波动，从而提高患者的治疗依从性和安全性。在一些实施例中，24h内奥司他韦活性代谢物体内血药浓度的峰谷比为2.14:1。在一些实施例中，所述奥司他韦制剂，一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度的峰谷比小于2:1，更有利于避免峰谷波动，从而提高患者的治疗依从性和安全性。在一些实施例中，24h内奥司他韦活性代谢物体内血药浓度的峰谷比为1.21:1。
所述奥司他韦制剂，按照奥司他韦重量计，单剂量规格为60mg-300mg；在一些实施例中，规格为60mg-90mg；在一些实施例中，规格为60mg-150mg；在一些实施例中，规格为60mg-200mg；在一些实施例中，规格为90mg-150mg；在一些实施例中，规格为90mg-200mg；在一些实施例中，规格为90mg-300mg；在一些实施例中，规格为150mg-200mg；在一些实施例中，规格为150mg-300mg；在一些实施例中，规格为200mg-300mg。在一些实施例中，规格为60mg，90mg，150mg，200mg，或者300mg。目前已上市的儿童速释剂型，按照奥司他韦重量计，最小规格为30mg，一天给药2次，若制备成一天一次的缓释制剂，最小规格为60mg；目前已上市的成人速释剂型，按照奥司他韦重量计，最小规格为75mg，一天给药2次，若制备成一天一次的缓释制剂，，最小规格为150mg，如果规则增加至300mg还不能与75mg规格、一天给药2次的速释剂型等效，说明生物利用度低，如果突释，毒副作用风险增加，且片重大，造成吞咽困难，所以按照奥司他韦重量计，选择60mg-300mg是比较合适的规格。
所述奥司他韦制剂，还包含至少一种缓释材料，所述缓释材料的重量占制剂总重量的比为3％-50％。在一些实施例中，所述缓释材料的重量比为3％-10％；在一些实施例中，所述缓释材料的重量比为3％-20％；在一些实施例中，所述缓释材料的重量比为3％-30％；在一些实施例中，所述缓释材料的重量比为10％-20％；在一些实施例中，所述缓释材料的重量比为10％-30％；在一些实施例中，所述缓释材料的重量比为10％-50％；在一些实施例中，所述缓释材料的重量比为20％-30％；在一些实施例中，所述缓释材料的重量比为20％-50％；在一些实施例中，所述缓释材料的重量比为30％-50％。在一些实施例中，所述缓释材料的重量比为3.3％，10％，20％，29％，或者50％。缓释材料的重量比为3％-50％，可制备得到至少24h或更长时间持续释放奥司他韦的制剂，减少给药次数。
在一些实施方式中，所述奥司他韦制剂，还包含至少一种缓释材料，所述缓释材料包括选自乙基纤维素，羟丙基甲基纤维素，醋酸纤维素，聚氧乙烯，聚乙烯醇，甲基丙烯酸-丙烯酸乙酯共聚物RL，甲基丙烯酸-丙烯酸乙酯共聚物RS，甲基丙烯酸-丙烯酸乙酯共聚物NE 30D，甲基丙烯酸-丙烯酸乙酯共聚物L100-55，醋酸羟丙甲纤维素琥珀酸酯，山嵛酸甘油酯，壳聚糖，卡波姆，巴西棕榈蜡，
Figure PCTCN2020117625-appb-000013
SR 30D，
Figure PCTCN2020117625-appb-000014
SR，醋酸纤维素钛酸酯，海藻酸钠，羧甲基纤维素钠，卡拉胶，十六醇，十八醇，十六十八醇，石蜡中的至少一种。在一些实施例中，所述缓释材料为醋酸纤维素；在一些实施例中，所述缓释材料为甲基丙烯酸-丙烯酸乙酯共聚物RL和甲基丙烯酸-丙烯酸乙酯共聚物RS；在一些实施例中，所述缓释材料为乙基纤维素；在一些实施例中，所述缓释材料为羟丙基甲基纤维素；在一些实施例中，所述缓释材料为聚氧乙烯和乙基纤维素。
在一些实施方式中，所述奥司他韦制剂，还包含至少一种缓释材料，所述缓释材料包括非pH依赖性高分子材料，pH依赖性高分子材料或者蜡质骨架材料。非pH依赖性高分子材料包括选自乙基纤维素，羟丙基甲基纤维素，醋酸纤维素，聚氧乙烯，聚乙烯醇，甲基丙烯酸-丙烯酸乙酯共聚物RL，甲基丙烯酸- 丙烯酸乙酯共聚物RS，甲基丙烯酸-丙烯酸乙酯共聚物NE 30D，
Figure PCTCN2020117625-appb-000015
SR 30D，
Figure PCTCN2020117625-appb-000016
SR中的至少一种；所述pH依赖性高分子材料包括选自甲基丙烯酸-丙烯酸乙酯共聚物L100-55，醋酸羟丙甲纤维素琥珀酸酯，醋酸纤维素钛酸酯，壳聚糖，卡波姆，卡拉胶，海藻酸钠，羧甲基纤维素钠中的至少一种；所述蜡质骨架材料包括选自山嵛酸甘油酯，巴西棕榈蜡，十六醇，十八醇，十六十八醇，石蜡的至少一种。
在一些实施方式中，所述奥司他韦制剂，包含至少一种缓释材料；奥司他韦的重量占制剂总重量的比例为3％-50％；奥司他韦或其盐4h释放量为25％-90％，奥司他韦或其盐10h释放量大于70％。在一些实施例中，所述奥司他韦制剂中缓释材料为甲基丙烯酸-丙烯酸乙酯共聚物RL和甲基丙烯酸-丙烯酸乙酯共聚物RS，奥司他韦的重量比例为22.4％，奥司他韦4h释放量为78％，奥司他韦或其盐10h释放量为97％；在一些实施例中，所述奥司他韦制剂中缓释材料为乙基纤维素，奥司他韦的重量比例为3.3％，奥司他韦4h释放量为75％，奥司他韦或其盐10h释放量为96％。
在一些实施方式中，所述奥司他韦制剂，还包含至少一种缓释材料，所述缓释材料的重量占制剂总重量的比为3％-50％，所述缓释材料包括选自乙基纤维素，羟丙基甲基纤维素，醋酸纤维素，聚氧乙烯，聚乙烯醇，甲基丙烯酸-丙烯酸乙酯共聚物RL，甲基丙烯酸-丙烯酸乙酯共聚物RS，甲基丙烯酸-丙烯酸乙酯共聚物NE 30D，甲基丙烯酸-丙烯酸乙酯共聚物L100-55，醋酸羟丙甲纤维素琥珀酸酯，山嵛酸甘油酯，壳聚糖，卡波姆，巴西棕榈蜡，
Figure PCTCN2020117625-appb-000017
SR 30D，
Figure PCTCN2020117625-appb-000018
SR，醋酸纤维素钛酸酯，海藻酸钠，羧甲基纤维素钠，卡拉胶，十六醇，十八醇，十六十八醇，石蜡中的至少一种。
在一些实施方式中，所述奥司他韦制剂，奥司他韦或其盐1h释放量为25％-55％，奥司他韦或其盐4h释放量为25％-90％，奥司他韦或其盐10h释放量大于70％；奥司他韦或其盐的重量比例为3％-50％；按照奥司他韦重量计，单剂量规格为60mg-300mg；一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度的峰谷比小于2.5:1。任选的，在一些实施方式中，所述奥司他韦制剂，还包含至少一种缓释材料，所述缓释材料的重量比为3％-50％，所述缓释材料包括选自乙基纤维素，羟丙基甲基纤维素，醋酸纤维素，聚氧乙烯，聚乙烯醇，甲基丙烯酸-丙烯酸乙酯共聚物RL，甲基丙烯酸-丙烯酸乙酯共聚物RS，甲基丙烯酸-丙烯酸乙酯共聚物NE 30D，甲基丙烯酸-丙烯酸乙酯共聚物L100-55，醋酸羟丙甲纤维素琥珀酸酯，山嵛酸甘油酯，壳聚糖，卡波姆，巴西棕榈蜡，
Figure PCTCN2020117625-appb-000019
SR 30D，
Figure PCTCN2020117625-appb-000020
SR，醋酸纤维素钛酸酯，海藻酸钠，羧甲基纤维素钠，卡拉胶，十六醇，十八醇，十六十八醇，石蜡中的至少一种。
所述奥司他韦制剂，所述速释部分中的奥司他韦规格为10mg-75mg，或者15mg-75mg，或者15mg-30mg，或者15mg-50mg，或者30mg-50mg，或者30mg-75mg，或者50mg-75mg；所述缓释部分中的奥司他韦规格为30mg-225mg，或者30mg-175mg，或者50mg-100mg，或者50mg-120mg，或者50mg-175mg，或者50mg-225mg，或者100mg-120mg，或者100mg-150mg，或者100mg-225mg，或者120mg-150mg，或者120mg-175mg，或者120mg-225mg，或者150mg-175mg，或者150mg-225mg，或者175mg-225mg。在一些实施例中，速释部分中的奥司他韦规格为50mg，缓释部分中 的奥司他韦规格为100mg；在一些实施例中，速释部分中的奥司他韦规格为50mg，缓释部分中的奥司他韦规格为130mg；在一些实施例中，速释部分中的奥司他韦规格为30mg，缓释部分中的奥司他韦规格为60mg；在一些实施例中，速释部分中的奥司他韦规格为50mg，缓释部分中的奥司他韦规格为150mg；在一些实施例中，速释部分中的奥司他韦规格为10mg，缓释部分中的奥司他韦规格为50mg；在一些实施例中，速释部分中的奥司他韦规格为75mg，缓释部分中的奥司他韦规格为225mg；在一些实施例中，速释部分中的奥司他韦规格为30mg，缓释部分中的奥司他韦规格为120mg。
本发明第一方面或第二方面提供的奥司他韦制剂，用于治疗成人甲型流感或成人乙型流感，一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度大于100ng/ml，或大于150ng/ml，或大于170ng/ml，或者大于200ng/ml，或者大于250ng/ml。在一些实施例中，24h内奥司他韦活性代谢物体内血药浓度大于172ng/ml；在一些实施例中，24h内奥司他韦活性代谢物体内血药浓度大于261ng/ml。
本发明第一方面或第二方面提供的奥司他韦制剂，用于治疗儿童甲型流感或儿童乙型流感，一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度大于100ng/ml，或大于150ng/ml，或者大于200ng/ml，或者大于250ng/ml。
本发明第一方面或第二方面提供的奥司他韦制剂，用于治疗成人或儿童甲型流感或乙型流感，所述制剂按照奥司他韦重量计，规格为60mg-300mg。在一些实施例中，所述制剂规格为60mg；在一些实施例中，所述制剂规格为90mg；在一些实施例中，所述制剂规格为150mg；在一些实施例中，所述制剂规格为200mg；在一些实施例中，所述制剂规格为300mg。
在一些实施方式中，所述奥司他韦制剂，按照奥司他韦重量计，规格为150mg-300mg。在一些实施方式中，所述奥司他韦制剂，用于治疗成人甲型流感或成人乙型流感，按照奥司他韦重量计，规格为150mg-300mg。目前已上市的成人速释剂型，按照奥司他韦重量计，最小规格为75mg，一天给药2次，若制备成一天一次的缓释制剂，最小规格为150mg，如果规则增加至300mg还不能与75mg规格、一天给药2次的速释制剂等效，说明生物利用度低，如果突释，毒副作用风险增加，且片重大，造成吞咽困难，所以按照奥司他韦重量计，成人剂型选择150mg-300mg是比较合适的规格。
在一些实施方式中，所述奥司他韦制剂，按照奥司他韦重量计，规格为60mg-180mg。在一些实施方式中，所述奥司他韦制剂，用于治疗儿童甲型流感或儿童乙型流感，按照奥司他韦重量计，规格为60mg-180mg。目前已上市的儿童速释剂型，规格为30mg和45mg，一天给药2次，一次给药30mg或45mg，若制备成一天一次的缓释制剂，理想规格为60-90mg，但缓释制剂生物利用度一般比速释制剂低，需适当提高缓释制剂规格才能与一天给药2次的速释制剂生物等效，而剂量越高，一般毒副作用的风险也相应增加，综合原研审评报告，规格提高2倍在可接受的范围内，因此，儿童剂型选择60-180mg是比较合适的规格。儿童缓释制剂规格超过180mg，说明生物利用度低，如果突释，毒副作用的风险也会增加。
所述奥司他韦制剂，一天一次给药后，奥司他韦活性代谢物2h的体内血药浓度在Cmax的20％以上，或30％以上，或40％以上；24h的体内血药浓度在Cmax的30％以上，或40％以上。在一些实施例中，奥司他韦活性代谢物2h的体内血药浓度为Cmax的27％；在一些实施例中，奥司他韦活性代谢物2h的体内血药浓度为Cmax的25％；在一些实施例中，奥司他韦活性代谢物24h的体内血药浓度为Cmax的47％；在一些实施例中，奥司他韦活性代谢物24h的体内血药浓度为Cmax的82％。
本发明第一方面或第二方面提供的奥司他韦制剂，在至少24h时间期间持续释放奥司他韦。
所述奥司他韦制剂，奥司他韦活性代谢物体内血药浓度大于100ng/ml，或大于150ng/ml，维持时间大于16h，或者大于20h。在一些实施例中，所述奥司他韦制剂，奥司他韦活性代谢物体内血药浓度大于或者等于170ng/ml，维持时间大于16h。在一些实施例中，所述奥司他韦制剂，奥司他韦活性代谢物体内血药浓度大于或者等于250ng/ml，维持时间大于12h。在一些实施例中，所述奥司他韦制剂，奥司他韦活性代谢物体内血药浓度大于或者等于250ng/ml，维持时间大于16h。在一些实施例中，奥司他韦活性代谢物体内血药浓度为261ng/mL，维持时间为16h；在一些实施例中，奥司他韦活性代谢物体内血药浓度为172ng/mL，维持时间为20h。
本发明第三方面，提供一种奥司他韦制剂，包括奥司他韦或其盐，所述制剂为一天一次给药的制剂，所述制剂包括含有奥司他韦或其盐的缓释部分和含有奥司他韦或其盐的速释部分，基于所述制剂中奥司他韦的总重，所述速释部分中的奥司他韦的重量比例为20％-50％。在一些实施例中，所述速释部分中的奥司他韦的重量比例为20％-30％；在一些实施例中，所述速释部分中的奥司他韦的重量比例为20％-40％；在一些实施例中，所述速释部分中的奥司他韦的重量比例为30％-40％；在一些实施例中，所述速释部分中的奥司他韦的重量比例为30％-50％；在一些实施例中，所述速释部分中的奥司他韦的重量比例为40％-50％。该制剂可以是双相释放制剂，三相释放制剂，或者三相以上的多相释放制剂。在一些实施例中，所述制剂为双相释放制剂，在一些实施例中，所述制剂为三相释放制剂，在一些实施例中，所述制剂为多相释放制剂。在一些实施例中，活性成分为奥司他韦；在一些实施例中，活性成分为磷酸奥司他韦。
本发明第四方面，提供一种奥司他韦制剂，包括奥司他韦或其盐，所述制剂为一天一次给药的制剂，所述制剂包括含有奥司他韦或其盐的缓释部分和含有奥司他韦或其盐的速释部分，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:4-1:1。在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:4-1:3；在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:4-1:2；在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:3-1:2；在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:3-1:1；在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:2-1:1；在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:4，1:3， 1:2，或者1:1。该制剂可以是双相释放制剂，三相释放制剂，或者三相以上的多相释放制剂。在一些实施例中，所述制剂为双相释放制剂，在一些实施例中，所述制剂为三相释放制剂，在一些实施例中，所述制剂为多相释放制剂。在一些实施例中，活性成分为奥司他韦；在一些实施例中，活性成分为磷酸奥司他韦。
本发明第五方面，提供一种奥司他韦制剂，包括奥司他韦或其盐，所述制剂为一天一次给药的制剂，所述制剂包括含有奥司他韦或其盐的缓释部分和含有奥司他韦或其盐的速释部分，基于所述制剂中奥司他韦的总重，所述速释部分中的奥司他韦的重量比例为20％-50％，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:4-1:1。在一些实施例中，所述速释部分中的奥司他韦的重量比例为20％-30％；在一些实施例中，所述速释部分中的奥司他韦的重量比例为20％-40％；在一些实施例中，所述速释部分中的奥司他韦的重量比例为30％-40％；在一些实施例中，所述速释部分中的奥司他韦的重量比例为30％-50％；在一些实施例中，所述速释部分中的奥司他韦的重量比例为40％-50％。在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:4-1:3；在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:4-1:2；在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:3-1:2；在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:3-1:1；在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:2-1:1。该制剂可以是双相释放制剂，三相释放制剂，或者三相以上的多相释放制剂。在一些实施例中，所述制剂为双相释放制剂，在一些实施例中，所述制剂为三相释放制剂，在一些实施例中，所述制剂为多相释放制剂。在一些实施例中，活性成分为奥司他韦；在一些实施例中，活性成分为磷酸奥司他韦。
在一些实施方式中，所述奥司他韦制剂，包含至少一种缓释材料；奥司他韦的重量占制剂总重量的比例为3％-50％；奥司他韦或其盐4h释放量为25％-90％，奥司他韦或其盐10h释放量大于70％。在一些实施例中，所述奥司他韦制剂中缓释材料为甲基丙烯酸-丙烯酸乙酯共聚物RL和甲基丙烯酸-丙烯酸乙酯共聚物RS，奥司他韦的重量比例为22.4％，奥司他韦4h释放量为78％，奥司他韦或其盐10h释放量为97％；在一些实施例中，所述奥司他韦制剂中缓释材料为乙基纤维素，奥司他韦的重量比例为3.3％，奥司他韦4h释放量为75％，奥司他韦或其盐10h释放量为96％。
在一些实施方式中，所述奥司他韦制剂，奥司他韦或其盐1h释放量为25％-55％，奥司他韦或其盐4h释放量为25％-90％，奥司他韦或其盐10h释放量大于70％；奥司他韦或其盐的重量比例为3％-50％；按照奥司他韦重量计，单剂量规格为60mg-300mg；一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度的峰谷比小于2.5:1。任选的，在一些实施方式中，所述奥司他韦制剂，还包含至少一种缓释材料，所述缓释材料的重量比为3％-50％，所述缓释材料包括选自乙基纤维素，羟丙基甲基纤维素，醋酸纤维素，聚氧乙烯，聚乙烯醇，甲基丙烯酸-丙烯酸乙酯共聚物RL，甲基丙烯酸-丙烯酸乙酯共聚物RS，甲基丙烯酸-丙烯酸乙酯共聚物NE 30D，甲基丙烯酸-丙烯酸乙酯共聚物L100-55，醋酸羟丙甲纤维素琥珀酸酯，山 嵛酸甘油酯，壳聚糖，卡波姆，巴西棕榈蜡，
Figure PCTCN2020117625-appb-000021
SR 30D，
Figure PCTCN2020117625-appb-000022
SR，醋酸纤维素钛酸酯，海藻酸钠，羧甲基纤维素钠，卡拉胶，十六醇，十八醇，十六十八醇，石蜡中的至少一种。
本发明第六方面，提供一种奥司他韦制剂，包括奥司他韦或其盐，所述制剂为一天一次给药的制剂，所述制剂包括含有奥司他韦或其盐的缓释部分和含有奥司他韦或其盐的速释部分，基于所述制剂中奥司他韦的总重，所述速释部分中的奥司他韦的重量比例为20％-50％，所述制剂至少包含一种缓释材料，所述缓释材料的重量比例为3％-50％；所述奥司他韦1h释放量为25％-55％，4h释放量为25％-90％，10h释放量大于70％。
在一些实施方式中，所述奥司他韦制剂，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:4-1:1。在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:4-1:3；在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:4-1:2；在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:3-1:2；在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:3-1:1；在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:2-1:1；在一些实施例中，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:4，1:3，1:2，或者1:1。
所述奥司他韦制剂，按照奥司他韦重量计，单剂量规格为60mg-300mg；在一些实施例中，规格为60mg-90mg；在一些实施例中，规格为60mg-150mg；在一些实施例中，规格为60mg-200mg；在一些实施例中，规格为90mg-150mg；在一些实施例中，规格为90mg-200mg；在一些实施例中，规格为90mg-300mg；在一些实施例中，规格为150mg-200mg；在一些实施例中，规格为150mg-300mg；在一些实施例中，规格为200mg-300mg。在一些实施例中，规格为60mg，90mg，150mg，200mg，或者300mg。目前已上市的儿童速释剂型，按照奥司他韦重量计，最小规格为30mg，一天给药2次，若制备成一天一次的缓释制剂，最小规格为60mg；目前已上市的成人速释剂型，按照奥司他韦重量计，最小规格为75mg，一天给药2次，若制备成一天一次的缓释制剂，最小规格为150mg，如果规则增加至300mg还不能与75mg规格、一天给药2次的速释剂型等效，说明生物利用度低，如果突释，毒副作用风险增加，且片重大，造成吞咽困难，所以按照奥司他韦重量计，选择60mg-300mg是比较合适的规格。
在一些实施方式中，所述缓释材料包括选自乙基纤维素，羟丙基甲基纤维素，醋酸纤维素，聚氧乙烯，聚乙烯醇，甲基丙烯酸-丙烯酸乙酯共聚物RL，甲基丙烯酸-丙烯酸乙酯共聚物RS，甲基丙烯酸-丙烯酸乙酯共聚物NE 30D，甲基丙烯酸-丙烯酸乙酯共聚物L100-55，醋酸羟丙甲纤维素琥珀酸酯，山嵛酸甘油酯，壳聚糖，卡波姆，巴西棕榈蜡，
Figure PCTCN2020117625-appb-000023
SR 30D，
Figure PCTCN2020117625-appb-000024
SR，醋酸纤维素钛酸酯，海藻酸钠，羧甲基纤维素钠，卡拉胶，十六醇，十八醇，十六十八醇，石蜡中的至少一种。
所述奥司他韦制剂，用于治疗成人甲型流感或成人乙型流感，以及儿童甲型流感或儿童乙型流感，一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度大于100ng/ml，或大于150ng/ml。在一些实施例中，24h内奥司他韦活性代谢物体内血药浓度大于172ng/ml；在一些实施例中，24h内奥司他韦活性代谢物体内血药浓度大于261ng/ml。
所述奥司他韦制剂，一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度的峰谷比小于2.5:1。小于2.5:1的体内血药浓度峰谷比，能够避免峰谷波动，从而提高患者的治疗依从性和安全性。在一些实施例中，24h内奥司他韦活性代谢物体内血药浓度的峰谷比为2.14:1。在一些实施例中，所述奥司他韦制剂，一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度的峰谷比小于2:1，更有利于避免峰谷波动，从而提高患者的治疗依从性和安全性。在一些实施例中，24h内奥司他韦活性代谢物体内血药浓度的峰谷比为1.21:1。
所述奥司他韦制剂，一天一次给药后，奥司他韦活性代谢物2h的体内血药浓度在Cmax的20％以上，或30％以上，或40％以上；24h的体内血药浓度在Cmax的30％以上，或40％以上。在一些实施例中，奥司他韦活性代谢物2h的体内血药浓度为Cmax的27％；在一些实施例中，奥司他韦活性代谢物2h的体内血药浓度为Cmax的25％；在一些实施例中，奥司他韦活性代谢物24h的体内血药浓度为Cmax的47％；在一些实施例中，奥司他韦活性代谢物24h的体内血药浓度为Cmax的82％。
所述奥司他韦制剂，在至少24h时间期间持续释放奥司他韦。
所述奥司他韦制剂，奥司他韦活性代谢物体内血药浓度大于或者等于100ng/ml，维持时间大于16h，或者大于20h。在一些实施例中，所述奥司他韦制剂，奥司他韦活性代谢物体内血药浓度大于或者等于170ng/ml，维持时间大于16h。在一些实施例中，所述奥司他韦制剂，奥司他韦活性代谢物体内血药浓度大于或者等于250ng/ml，维持时间大于12h。在一些实施例中，所述奥司他韦制剂，奥司他韦活性代谢物体内血药浓度大于或者等于250ng/ml，维持时间大于16h。在一些实施例中，奥司他韦活性代谢物体内血药浓度为261ng/mL，维持时间为16h；在一些实施例中，奥司他韦活性代谢物体内血药浓度为172ng/mL，维持时间为20h。
本发明第七方面，提供一种奥司他韦制剂，还包含缓释材料，所述缓释材料包括羟丙基甲基纤维素和/或甲基丙烯酸-丙烯酸乙酯共聚物。在一些实施例中，所述缓释材料包括羟丙基甲基纤维素；在一些实施例中，所述缓释材料包括甲基丙烯酸-丙烯酸乙酯共聚物；在一些实施方式中，所述缓释材料包括羟丙基甲基纤维素和甲基丙烯酸-丙烯酸乙酯共聚物。
所述甲基丙烯酸-丙烯酸乙酯共聚物，包括选自甲基丙烯酸-丙烯酸乙酯共聚物RL，甲基丙烯酸-丙烯酸乙酯共聚物RS，甲基丙烯酸-丙烯酸乙酯共聚物NE 30D，甲基丙烯酸-丙烯酸乙酯共聚物L100-55中的 至少一种。在一些实施例中，所述甲基丙烯酸-丙烯酸乙酯共聚物包括甲基丙烯酸-丙烯酸乙酯共聚物RL；在一些实施例中，所述甲基丙烯酸-丙烯酸乙酯共聚物包括甲基丙烯酸-丙烯酸乙酯共聚物RS；在一些实施例中，所述甲基丙烯酸-丙烯酸乙酯共聚物包括甲基丙烯酸-丙烯酸乙酯共聚物NE 30D；在一些实施例中，所述甲基丙烯酸-丙烯酸乙酯共聚物包括甲基丙烯酸-丙烯酸乙酯共聚物L100-55。
所述羟丙基甲基纤维素，包括选自羟丙基甲基纤维素K15M，羟丙基甲基纤维素K4M，羟丙基甲基纤维素K100M，羟丙基甲基纤维素K100LV中的至少一种。在一些实施例中，所述羟丙基甲基纤维素包括羟丙基甲基纤维素K15M；在一些实施例中，所述羟丙基甲基纤维素包括羟丙基甲基纤维素K4M；在一些实施例中，所述羟丙基甲基纤维素包括羟丙基甲基纤维素K100M；在一些实施例中，所述羟丙基甲基纤维素包括羟丙基甲基纤维素K100LV。
在一些实施方式中，所述缓释材料的重量占制剂总重量的比例为3％-50％。在一些实施例中，所述缓释材料的重量比为3％-10％；在一些实施例中，所述缓释材料的重量比为3％-20％；在一些实施例中，所述缓释材料的重量比为3％-30％；在一些实施例中，所述缓释材料的重量比为10％-20％；在一些实施例中，所述缓释材料的重量比为10％-30％；在一些实施例中，所述缓释材料的重量比为10％-50％；在一些实施例中，所述缓释材料的重量比为20％-30％；在一些实施例中，所述缓释材料的重量比为20％-50％；在一些实施例中，所述缓释材料的重量比为30％-50％。在一些实施例中，所述缓释材料的重量比为37％，29％，25％，50％，21％，或者34％。
在一些实施方式中，所述的羟丙基甲基纤维素重量占制剂总重量的比例为4％-30％，所述甲基丙烯酸-丙烯酸乙酯共聚物重量占制剂总重量的比例为0-35％。在一些实施例中，所述羟丙甲纤维素的重量比为4％-10％，在一些实施例中，所述羟丙甲纤维素的重量比为4％-15％，在一些实施例中，所述羟丙甲纤维素的重量比为4％-20％，在一些实施例中，所述羟丙甲纤维素的重量比为4％-25％，在一些实施例中，所述羟丙甲纤维素的重量比为10％-15％，在一些实施例中，所述羟丙甲纤维素的重量比为10％-20％，在一些实施例中，所述羟丙甲纤维素的重量比为10％-25％，在一些实施例中，所述羟丙甲纤维素的重量比为10％-30％，在一些实施例中，所述羟丙甲纤维素的重量比为15％-20％，在一些实施例中，所述羟丙甲纤维素的重量比为15％-25％，在一些实施例中，所述羟丙甲纤维素的重量比为15％-30％，在一些实施例中，所述羟丙甲纤维素的重量比为20％-25％，在一些实施例中，所述羟丙甲纤维素的重量比为20％-30％；在一些实施例中，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为5％-10％，在一些实施例中，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为5％-20％，在一些实施例中，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为5％-25％，在一些实施例中，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为5％-35％，在一些实施例中，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为10％-20％，在一些实施例中，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为10％-25％，在一些实施例中，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为 10％-35％，在一些实施例中，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为20％-25％，在一些实施例中，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为20％-35％，在一些实施例中，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为25％-35％。在一些实施例中，所述羟丙甲纤维素的重量比为12％，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为25％；在一些实施例中，所述羟丙甲纤维素的重量比为4％，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为25％；在一些实施例中，所述羟丙甲纤维素的重量比为12％，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为12％；在一些实施例中，所述羟丙甲纤维素的重量比为17％，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为33％；在一些实施例中，所述羟丙甲纤维素的重量比为8％，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为12％；在一些实施例中，所述羟丙甲纤维素的重量比为25％，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为4％；在一些实施例中，所述羟丙甲纤维素的重量比为11％，所述甲基丙烯酸-丙烯酸乙酯共聚物的重量比为23％。
在一些实施方式中，所述奥司他韦制剂，还包含缓释材料，所述缓释材料为羟丙基甲基纤维素和甲基丙烯酸-丙烯酸乙酯共聚物，所述缓释材料的重量占制剂总重量的比例为3％-50％，或者为20％-50％，或者为30％-50％，或者为10％-30％；所述的羟丙基甲基纤维素重量占制剂总重量的比例为4％-30％，或者为4％-15％，或者为10％-20％，或者为15％-30％；所述甲基丙烯酸-丙烯酸乙酯共聚物量占制剂总重量的比例为0-35％，或者为5％-25％，或者为10％-30％，或者为20％-35％。
在一些实施方式中，所述奥司他韦制剂，奥司他韦1h释放量为25％-55％；奥司他韦4h释放量为25％-90％；奥司他韦10h释放量大于70％；奥司他韦的重量占制剂总重量的比例为3％-50％；还包含至少一种缓释材料，所述缓释材料的重量占制剂总重量的比为3％-50％；一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度的峰谷比小于2.5:1；所述奥司他韦制剂用于治疗成人甲型流感、成人乙型流感、儿童甲型流感或者儿童乙型流感，一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度大于100ng/mL；所述奥司他韦制剂一天一次给药后，奥司他韦活性代谢物2h的体内血药浓度在Cmax的20％以上，24h的体内血药浓度在Cmax的30％以上。
本发明第一方面至第七方面提供的奥司他韦制剂，可以制备成片剂，胶囊，混悬剂。在一些实施例中，所述奥司他韦制剂为片剂；在一些实施例中，所述奥司他韦制剂为胶囊；在一些实施例中，所述奥司他韦制剂为混悬剂。
本发明第一方面至第七方面提供的奥司他韦制剂，可以制备成双层片，所述双层片其中一层包含速释部分，另一层包含缓释部分。
本发明第一方面至第七方面提供的奥司他韦制剂，以缓释部分为片芯，速释部分包裹于片芯外。
本发明第一方面至第七方面提供的奥司他韦制剂，含有缓释部分和速释部分，所述缓释部分含有核芯 1，所述速释部分含有含有核芯2。
可以将奥司他韦与骨架缓释材料均匀混合制得所述核芯1，将奥司他韦与骨架材料均匀混合制得所述核芯2。
所述核芯1内可含奥司他韦且外部包裹有高分子聚合物及其他药用辅料形成的缓释包衣层，所述核芯2内可含奥司他韦且外部包裹有水溶性高分子成膜材料、增塑剂形成的速释包衣层。
可以将奥司他韦与骨架缓释材料混合后，采用挤出滚圆法制备得到所述核芯1，可以将奥司他韦与药用辅料混合后，采用挤出滚圆法制备得到所述核芯2。
可以将奥司他韦与缓释成膜材料喷涂于空白丸芯上制得所述核芯1，可以将奥司他韦与速释包衣材料混合后喷涂于空白丸芯上制得所述核芯2。
在一些实施方式中，所述核芯1和所述核芯2混合后压制成双层片或者多层片，或者所述核芯1和所述核芯2混合后直接填充于胶囊，或者所述核芯1和所述核芯2混合后装袋。
本发明第八方面，提供前面所述的奥司他韦制剂的制备方法。一种如第一方面至第七方面所述奥司他韦制剂的制备方法，包括以下步骤：
(1)将水溶性高分子成膜材料、增塑剂与奥司他韦形成的速释包衣层，包裹于空白核芯外，得到速释部分，
(2)将高分子聚合物及其他药用辅料形成的缓释包衣层，包裹于(1)所得到的速释部分，得到缓释部分，
(3)将(1)所得到的速释部分和(2)所得到的缓释部分填充于胶囊，或压制成片，或装袋，得到所述奥司他韦制剂。
一种如第一方面至第七方面所述奥司他韦制剂的制备方法，包括以下步骤：
(1)将高分子聚合物及其他药用辅料形成的缓释包衣层，包裹于含奥司他韦的核芯外，得到缓释部分，
(2)将水溶性高分子成膜材料、增塑剂与奥司他韦形成的速释包衣层，包裹于(1)所得到的缓释部分外，得到所述奥司他韦制剂。
一种如第一方面至第七方面所述奥司他韦制剂的制备方法，包括以下步骤：
(1)将奥司他韦、高分子聚合物及其他药用辅料形成的缓释包衣层，包裹于空白核芯外，得到缓释部分，
(2)将水溶性高分子成膜材料、增塑剂与奥司他韦形成的速释包衣层，包裹于(1)所得到的缓释部分外，得到所述奥司他韦制剂。
一种如第一方面至第七方面所述奥司他韦制剂的制备方法，包括以下步骤：
(1)缓释部分为含有奥司他韦及骨架缓释材料的核芯，
(2)将水溶性高分子成膜材料、增塑剂与奥司他韦形成的速释包衣层，包裹于(1)所述缓释部分外，得到所述奥司他韦制剂。
本发明所提供的制备方法中，所述核芯可包括颗粒、片芯或丸芯。
本发明所提供的制备方法中，所述核芯还可进一步包括，任选地，填充剂、粘合剂、促渗剂或润滑剂。
本发明所提供的制备方法中，制备所述核芯的方法包括湿法制粒、干法制粒或粉末直压。
本发明所提供的制备方法中，所述高分子聚合物可包括选自乙基纤维素、醋酸纤维素、甲基丙烯酸-丙烯酸乙酯共聚物RL、甲基丙烯酸-丙烯酸乙酯共聚物RS、甲基丙烯酸-丙烯酸乙酯共聚物NE 30D中，
Figure PCTCN2020117625-appb-000025
SR 30D，
Figure PCTCN2020117625-appb-000026
SR，甲基丙烯酸-丙烯酸乙酯共聚物L100-55，醋酸羟丙甲纤维素琥珀酸酯，醋酸纤维素钛酸酯中的至少一种。
本发明所提供的制备方法中，所述高分子聚合物包括非pH依赖性高分子材料或pH依赖性高分子材料。所述非pH依赖性高分子材料包括选自乙基纤维素，羟丙基甲基纤维素，醋酸纤维素，聚氧乙烯，聚乙烯醇，甲基丙烯酸-丙烯酸乙酯共聚物RL，甲基丙烯酸-丙烯酸乙酯共聚物RS，甲基丙烯酸-丙烯酸乙酯共聚物NE 30D，
Figure PCTCN2020117625-appb-000027
SR 30D，
Figure PCTCN2020117625-appb-000028
SR中的至少一种；所述pH依赖性高分子材料包括选自甲基丙烯酸-丙烯酸乙酯共聚物L100-55，醋酸羟丙甲纤维素琥珀酸酯，醋酸纤维素钛酸酯，壳聚糖，卡波姆，卡拉胶，海藻酸钠，羧甲基纤维素钠中的至少一种。
本发明所提供的制备方法中，所述其他药用辅料，可包括增塑剂、抗粘剂、乳化剂、或致孔剂。
本发明所提供的制备方法中，所述水溶性高分子成膜材料可包括选自羟丙甲纤维素，聚乙烯吡咯烷酮，聚乙烯醇，羟丙基纤维素，羟乙基纤维素，羟乙基甲基纤维素，共聚维酮中的至少一种。
本发明所提供的制备方法中，所述骨架缓释材料可包括选自羟丙甲纤维素、聚氧乙烯、聚乙烯醇、乙基纤维素、山嵛酸甘油酯、壳聚糖、卡波姆，巴西棕榈蜡，海藻酸钠，羧甲基纤维素钠，卡拉胶，十六醇，十八醇，十六十八醇，石蜡中的至少一种。
本发明所提供的制备方法中，所述骨架缓释材料包括非pH依赖性高分子材料，pH依赖性高分子材料或者蜡质骨架材料。所述非pH依赖性高分子材料包括选自乙基纤维素，羟丙基甲基纤维素，聚氧乙烯，聚乙烯醇中的至少一种；所述pH依赖性高分子材料包括选自壳聚糖，卡波姆，卡拉胶，海藻酸钠，羧甲基纤维素钠中的至少一种；所述蜡质骨架材料包括选自山嵛酸甘油酯，巴西棕榈蜡，十六醇，十八醇，十六十八醇，石蜡中的至少一种。
本发明所提供的制备方法中，所述速释包衣层外部包裹隔离层。
在一些实施方式中，所述隔离层含有水溶性高分子成膜材料、或增塑剂，任选地，含有抗粘剂或遮光剂。
附图说明
图1为成人空腹状态下口服本发明实施例12制备得到的奥司他韦制剂后，体内奥司他韦活性代谢物的药时曲线图。
图2为成人进食状态下口服本发明实施例12制备得到的奥司他韦制剂后，体内奥司他韦活性代谢物的药时曲线图。
图3为成人进食状态下口服本发明实施例18制备得到的奥司他韦制剂后，体内奥司他韦活性代谢物的药时曲线图。
具体实施方式
实施例1
处方表
Figure PCTCN2020117625-appb-000029
片芯制备：按处方称取磷酸奥司他韦和微晶纤维素，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加填充剂、促渗剂和润滑剂后压片即得100mg规格奥司他韦片芯。
控释膜：按处方配制控释膜包衣液，对上述片芯进行包衣，包衣增重占片芯的百分比为8％。
速释层：按处方配制速释层包衣液，对上述控释包衣片进行包衣，包衣膜中中含奥司他韦50mg。
隔离层：按处方配制隔离层包衣液，对上述速释包衣片进行包衣，包衣增重占速释包衣片的百分比为2％。
实施例2
处方表
Figure PCTCN2020117625-appb-000030
片芯制备：按处方称取磷酸奥司他韦和微晶纤维素101QD，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加填充剂、促渗剂和润滑剂后压片即得40mg规格奥司他韦片芯。
控释膜1：按处方配制控释膜包衣液，对上述片芯进行包衣，包衣增重占片芯的百分比为10％。
速释层：按处方配制速释层包衣液，对上述控释包衣片进行包衣，包衣膜中含奥司他韦20mg。
隔离层：按处方配制隔离层包衣液，对上述速释包衣片进行包衣，包衣增重占速释包衣片的百分比为2％。
实施例3
处方表
Figure PCTCN2020117625-appb-000031
片芯制备：按处方称磷酸奥司他韦和甘露醇，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加填充剂、促渗剂和润滑剂后压片即得130mg规格奥司他韦片芯。
控释膜：按处方配制控释膜包衣液，对上述片芯进行包衣，包衣增重占片芯的百分比为8％。
速释层：按处方配制速释层包衣液，对上述控释包衣片进行包衣，包衣膜中含奥司他韦50mg。
隔离层：按处方配制隔离层包衣液，对上述速释包衣片进行包衣，包衣增重占速释包衣片的百分比为2％。
实施例4
处方表
Figure PCTCN2020117625-appb-000032
Figure PCTCN2020117625-appb-000033
片芯制备：按处方称取磷酸奥司他韦和羟丙基甲基纤维K100LV，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加润滑剂后压片即得60mg规格奥司他韦缓释片芯。
速释层：按处方配制速释层包衣液，对上述缓释片芯进行包衣，包衣膜中含奥司他韦30mg。
隔离层：按处方配制隔离层包衣液，对上述速释包衣片进行包衣，包衣增重占速释包衣片的百分比为2％。
实施例5
处方表
Figure PCTCN2020117625-appb-000034
实施例6
处方表
Figure PCTCN2020117625-appb-000035
实施例5和实施例6制备方法：
缓释层总混颗粒制备：按处方称取磷酸奥司他韦、微晶纤维素和羟丙基甲基纤维，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加润滑剂后得缓释层总混颗粒。
速释层总混颗粒制备：按处方称取磷酸奥司他韦和微晶纤维素，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加润滑剂后得速释层总混颗粒。
双层片制备：用双层压片机，先填充100mg或150mg规格的缓释层总混颗粒，预压，得缓释层片芯；再填充50mg规格的速释层颗粒，压片，得速缓双层片芯。
隔离层：按处方配制隔离层包衣液，对上述速缓双层片芯进行包衣，包衣增重占片芯的百分比为2％。
实施例7
处方表
Figure PCTCN2020117625-appb-000036
Figure PCTCN2020117625-appb-000037
Figure PCTCN2020117625-appb-000038
Figure PCTCN2020117625-appb-000039
Figure PCTCN2020117625-appb-000040
速释颗粒制备：按处方称取磷酸奥司他韦和蔗糖，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，得速释颗粒。
缓释颗粒制备：按处方配制缓释包衣液，取速释颗粒，对其进行缓释包衣，包衣增重占颗粒的百分比为35％。
空白颗粒制备：按处方称取各组分(除聚乙烯吡咯烷酮外)，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干 燥、干整粒，得空白颗粒。
总混颗粒制备：按处方称取10mg规格速释颗粒、50mg规格缓释颗粒、空白颗粒，外加矫味剂、助流剂，混合，得最终总混颗粒，装袋得缓释干混悬。
实施例8
处方表
Figure PCTCN2020117625-appb-000041
Figure PCTCN2020117625-appb-000042
速释微丸制备：按处方配制速释层包衣液，以微晶丸芯当底物进行包衣，速释层包衣结束后；再在丸芯外包2％增重的隔离层，得速释微丸；
缓释微丸制备：按处方配制缓释包衣液，以速释微丸当底物进行缓释包衣，包衣增重占速释微丸的百分比为10％，缓释层包衣结束后，再在丸芯外包2％增重的隔离层，得缓释微丸；
胶囊填充：将50mg规格速释微丸和100mg规格缓释微丸填充进胶囊，得磷酸奥司他韦双相释放胶囊。
实施例9
处方表
Figure PCTCN2020117625-appb-000043
Figure PCTCN2020117625-appb-000044
速释微丸制备：按速释丸芯处方称取各组分(除聚乙烯吡咯烷酮外)，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、挤出滚圆、干燥、筛分；按处方配制隔离层包衣液，取筛分后微丸，对其进行包衣，包衣增重占微丸的百分比为2％，得速释微丸；
缓释微丸制备：按缓释包衣处方配制包衣液，以速释微丸当底物进行包衣，包衣增重占速释微丸的百分比为12％，得缓释微丸；按处方配制隔离层包衣液，取缓释微丸，对其进行包衣，包衣增重占缓释微丸的百分比为2％，得最终缓释微丸；
胶囊填充：将50mg规格速释微丸和100mg规格缓释微丸填充进胶囊，得磷酸奥司他韦双相释放胶囊。
实施例10
处方表
Figure PCTCN2020117625-appb-000045
Figure PCTCN2020117625-appb-000046
Figure PCTCN2020117625-appb-000047
75mg规格脉冲释放微丸：
速释微丸制备：按速释微丸处方称取各组分(除聚乙烯吡咯烷酮外)，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次挤出滚圆、干燥、筛分；
脉冲释放微丸制备：按处方配制缓释包衣液，取速释微丸，对其进行包衣，包衣增重占速释微丸的百分比为8％，得缓释微丸；按处方配制隔离层包衣液，取缓释微丸，对其进行包衣，包衣增重占缓释微丸的百分比为2％，得最终脉冲释放微丸。
225mg规格延迟缓释微丸：
缓释微丸制备：按含药微丸处方称取各组分(除聚乙烯吡咯烷酮外)，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次挤出滚圆、干燥、过筛，得含药微丸；
脉冲缓释微丸制备：按处方配制缓释包衣液，取含药微丸，对其进行包衣，包衣增重占缓释微丸的百分比为10％；按处方配制隔离层包衣液，取脉冲缓释微丸，对其进行包衣，包衣增重占脉冲缓释微丸的百分比为2％，得延迟缓释微丸。
胶囊填充：将75mg规格脉冲释放微丸和225mg规格延迟缓释微丸填充进胶囊，得磷酸奥司他韦延迟释放胶囊。
实施例11
处方表
Figure PCTCN2020117625-appb-000048
缓释层总混颗粒制备：按缓释层处方称取磷酸奥司他韦、微晶纤维素和羟丙基甲基纤维，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加乳糖、润滑剂后得缓释层总混颗粒。
速释层总混颗粒制备：按处方称取磷酸奥司他韦、微晶纤维素，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床 干燥、干整粒，外加崩解剂、润滑剂后得速释层总混颗粒。
双层片制备：用双层压片机，先填充100mg规格缓释层总混颗粒，预压，得缓释层片芯；再填充50mg规格速释层颗粒，压片，得速缓双层片芯。
隔离层：按处方配制隔离层包衣液，对上述速缓双层片芯进行包衣，包衣增重占片芯的百分比为2％。
实施例12
处方表
Figure PCTCN2020117625-appb-000049
片芯制备：按处方称取磷酸奥司他韦、微晶纤维素和羟丙基甲基纤维转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加润滑剂后压片即得120mg规格奥司他韦缓释片芯。
控释膜：按处方配制控释膜包衣液，对上述缓释片芯进行包衣，包衣增重占片芯的百分比为2％。
速释层：按处方配制速释层包衣液，对上述控释包衣片进行包衣，包衣膜中含奥司他韦30mg。
隔离层：按处方配制隔离层包衣液，对上述速释包衣片进行包衣，包衣增重占速释包衣片的百分比为3％。
实施例13
处方表
Figure PCTCN2020117625-appb-000050
片芯制备：按处方称取磷酸奥司他韦、微晶纤维素和羟丙基甲基纤维素，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加润滑剂后得缓释层总混颗粒，压片得300mg规格奥司他韦缓释片芯。
隔离层：按处方配制隔离层包衣液，对上述缓释片芯进行包衣，包衣增重占片芯的百分比为2％。
实施例14
处方表
Figure PCTCN2020117625-appb-000051
Figure PCTCN2020117625-appb-000052
Figure PCTCN2020117625-appb-000053
50mg规格速释微丸：
速释微丸制备：按速释丸芯处方称取各组分(除聚乙烯吡咯烷酮外)，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次挤出滚圆、干燥、筛分；按处方配制隔离层包衣液，取筛分后微丸，对其进行包衣，包衣增重占速释微丸的百分比为2％；得最终速释微丸。
50mg规格脉冲释放微丸：
脉冲释放微丸制备：按处方配制缓释包衣液，取速释微丸，对其进行包衣，包2种不同增重，包衣增重分别占微丸的百分比为8％或30％，得缓释微丸；按处方配制隔离层包衣液，取不同包衣增重的缓释微丸，分别对其进行包衣，包衣增重占缓释微丸的百分比为2％；得2-4h和7-9h脉冲释放微丸。
胶囊填充：将50mg规格速释微丸、50mg规格脉冲释放微丸(2-4h释放)和50mg规格脉冲释放微丸(7-9h释放)填充进胶囊，得磷酸奥司他韦缓释放胶囊。
实施例15
处方表
Figure PCTCN2020117625-appb-000054
Figure PCTCN2020117625-appb-000055
缓释微丸制备：先按处方配制促渗层包衣液，以微晶丸芯当底物进行包衣，包衣增重占丸芯重量的7％。接着按处方配置上药层，以促渗层丸芯为底物进行上药包衣，包衣增重占促渗层丸芯重量的150％。接着按处方配置按处方配制缓释包衣液，以上药丸芯为底物进行缓释包衣，包衣增重占上药丸芯重量的25％。接着，按处方配置隔离层包衣液，在缓释层外包一层隔离衣，包衣增重占缓释丸芯重量的2％。最后，将150mg规格奥司他韦缓释微丸填充于胶囊中，得磷酸奥司他韦缓释胶囊。
实施例16
处方表
Figure PCTCN2020117625-appb-000056
Figure PCTCN2020117625-appb-000057
Figure PCTCN2020117625-appb-000058
速释微丸制备：按速释微丸处方配制上药层包衣液，以微晶丸芯为底物进行包衣，上药层包衣增重占丸芯重量的150％；上药层包衣结束，再在上药丸芯外包2％增重的隔离层，得速释微丸；
缓释微丸制备：按缓释微丸处方配制促渗层包衣液，以微晶丸芯当底物进行包衣，包衣增重占丸芯重量的7％。接着按处方配置上药层，以促渗层丸芯为底物进行上药包衣，包衣增重占促渗层丸芯重量的150％。接着按处方配置按处方配制缓释包衣液，以上药丸芯为底物进行缓释包衣，包衣增重占上药丸芯重量的25％。接着，按处方配置隔离层包衣液，在缓释层外包一层隔离衣，包衣增重占缓释丸芯重量的2％，得缓释微丸。
胶囊填充：将30mg规格速释微丸和120mg规格缓释微丸填充进胶囊，得磷酸奥司他韦双相释放胶囊。
实施例17
处方表
Figure PCTCN2020117625-appb-000059
Figure PCTCN2020117625-appb-000060
Figure PCTCN2020117625-appb-000061
速释微丸制备：按速释微丸处方配制上药层包衣液，以微晶丸芯为底物进行包衣，上药层包衣增重占丸芯重量的150％；上药层包衣结束，再在上药丸芯外包2％增重的隔离层，得速释微丸；
缓释微丸制备：按缓释微丸处方配制促渗层包衣液，以微晶丸芯当底物进行包衣，包衣增重占丸芯重量的7％。接着按处方配置上药层，以促渗层丸芯为底物进行上药包衣，包衣增重占促渗层丸芯重量的150％。接着按处方配置按处方配制缓释包衣液，以上药丸芯为底物进行缓释包衣，包衣增重占上药丸芯重量的30％。接着，按处方配置隔离层包衣液，在缓释层外包一层隔离衣，包衣增重占缓释丸芯重量的2％，得缓释微丸。
胶囊填充：将75mg规格速释微丸和75mg规格缓释微丸填充进胶囊，得磷酸奥司他韦双相释放胶囊。
对比例1：奥司他韦重量比2％，含量均匀度差(与实施例7对比)
处方表
Figure PCTCN2020117625-appb-000062
Figure PCTCN2020117625-appb-000063
Figure PCTCN2020117625-appb-000064
Figure PCTCN2020117625-appb-000065
Figure PCTCN2020117625-appb-000066
速释颗粒制备：按处方称取磷酸奥司他韦和蔗糖，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，得速释颗粒。
缓释颗粒制备：按处方配制缓释包衣液，取速释颗粒，对其进行缓释包衣，包衣增重占颗粒的百分比为35％。
空白颗粒制备：按空白颗粒处方称取各组分(除聚乙烯吡咯烷酮外)，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，得空白颗粒。
总混颗粒制备：按处方称取10mg规格速释颗粒、50mg规格缓释颗、空白颗粒，外加矫味剂、助流剂，混合，得最终总混颗粒。
实验结果：对比例1(奥司他韦含量2％)总混颗粒的含量均匀度差，实施例7(奥司他韦含量3％)总混颗粒的含量均匀度合格。
表1 对比例1和实施例7的总混颗粒含量均匀度
Figure PCTCN2020117625-appb-000067
Figure PCTCN2020117625-appb-000068
处方表
Figure PCTCN2020117625-appb-000069
片芯制备：按处方称取磷酸奥司他韦、微晶纤维素和羟丙基甲基纤维素，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加润滑剂后得缓释层总混颗粒，压片。
实验结果：压片过程粘冲严重，片子表面凹凸不平整。
处方表
Figure PCTCN2020117625-appb-000070
Figure PCTCN2020117625-appb-000071
片芯制备：按处方称取磷酸奥司他韦和甘露醇，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加填充剂、促渗剂和润滑剂后压片即得130mg规格奥司他韦片芯。
控释膜：按处方配制控释包衣液，对片芯进行包衣，包衣增重占片芯的百分比为6％。
速释层：按处方配制速释层包衣液，对上述控释包衣片进行包衣，包衣膜中含奥司他韦50mg。
隔离层：按处方配制隔离层包衣液，对上述速释包衣片进行包衣，包衣增重占速释包衣片的百分比为2％。
表2 对比例3和实施例3的溶出数据
Figure PCTCN2020117625-appb-000072
处方表
Figure PCTCN2020117625-appb-000073
Figure PCTCN2020117625-appb-000074
片芯制备：按处方称取磷酸奥司他韦、微晶纤维素和羟丙基甲基纤维素，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加润滑剂后压片即得60mg规格奥司他韦缓释片芯。
速释层：按处方配制速释层包衣液，对上述缓释片芯进行包衣，包衣膜中含奥司他韦30mg。
隔离层：按处方配制隔离层包衣液，对上述速释包衣片进行包衣，包衣增重占速释包衣片的百分比为2％。
实验结果：对比例4溶出偏慢，10h溶出<70％。
表3 对比例4和实施例4的溶出数据
Figure PCTCN2020117625-appb-000075
对比例5 处方表
Figure PCTCN2020117625-appb-000076
Figure PCTCN2020117625-appb-000077
缓释层总混颗粒制备：按处方称磷酸奥司他韦、微晶纤维素和羟丙基甲基纤维素，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加乳糖、润滑剂后得缓释层总混颗粒。
速释层总混颗粒制备：按处方称取磷酸奥司他韦和微晶纤维素，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加、崩解剂、润滑剂后得速释层总混颗粒。
双层片制备：用双层压片机，先填充90mg规格缓释层总混颗粒，预压，得缓释层片芯；再填充60mg规格速释层颗粒，压片，得速缓双层片芯。
隔离层：按处方配制隔离层包衣液，对上述速缓双层片芯进行包衣，包衣增重占片芯的百分比为2％。
对比例6 处方表
Figure PCTCN2020117625-appb-000078
Figure PCTCN2020117625-appb-000079
片芯制备：按处方称取磷酸奥司他韦和微晶纤维素，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加填充剂、促渗剂和润滑剂后压片即得150mg规格奥司他韦片芯。
控释膜：按处方配制控释包衣液，对上述片芯进行包衣，包衣增重占片芯的百分比为12％。
溶出数据
在该实施例中，实施例1～14所制备的奥司他韦制剂在pH6.8介质中溶出，介质的体积900±9mL，介质的温度37.0±0.5℃，桨法，50rpm/分钟下进行体外溶出试验。pH6.8中溶出度取样时间点：0.25h、1h、2h、3h、4h、6h、8h、10h、12h。取样位置：在桨叶顶端至液面的中点，距溶出杯内壁10mm处。采用高效液相(HPLC)法进行体外溶出含量测定。试验结果如下表所示：
表4 各实施例产品在pH6.8介质中的溶出(％)(n＝3)
Figure PCTCN2020117625-appb-000080
Figure PCTCN2020117625-appb-000081
表5 各实施例和对比例产品的特性总结
Figure PCTCN2020117625-appb-000082
备注：实施例18至实施例26的“<4h内某1h释放量”和“4h释放量”为在0.1MHCl中耐酸1h再转入到pH6.8介质中溶出数据。表中其他实施例或对比例为Ph6.8介质中溶出数据。
动物试验：奥司他韦制剂在比格犬体内的药物代谢动力学研究
第一次奥司他韦制剂在比格犬体内的药物代谢动力学研究
给药方案：采用四制剂四周期四交叉试验(健康比格犬24只，雌雄各半，分成4组，每组6只，空腹给药)。其中三组给自研奥司他韦缓释制剂(150mg)，一天1次；另一组给参比制剂，参比制剂为75mg规格速释制剂(商品名：
Figure PCTCN2020117625-appb-000083
)，一天2次。
表6列出了实施例11产品、对比例5产品、对比例6产品和参比制剂在比格犬体内的药代动力学数据(检测奥司他韦活性代谢物浓度)。
对比例5释放速度快，吸收快，导致比格犬体内的Cmax远高于参比制剂，毒副作用风险增加；另由于短时间集中吸收，消除快，不能维持长时间平稳的有效血药浓度；对比例6释放速率慢，吸收慢，比格犬体内的Cmax远低于参比制剂，可能起不到快速起效的作用，且生物利用度只有参比制剂一日2次的47％；并且可能错过了最佳的吸收位置；实施例12释放速率适中，比格犬体内的Cmax为参比制剂一日2次的80％，生物利用度为参比制剂一日2次的81％，较为理想。因此选择实施例12产品进行第一次人体临床预试验。
表6 实施例12制剂、对比例5制剂、对比例6制剂和参比制剂在比格犬体内的药代动力学数据
Figure PCTCN2020117625-appb-000084
第二次奥司他韦制剂在比格犬体内的药物代谢动力学研究
给药方案：双制剂双交叉实验(健康比格犬12只，雌雄各半，分成2组，每组6只，空腹给药)，两组均给自研奥司他韦缓释制剂(150mg)，一天1次。
表7列出了实施例5产品和实施例12产品，在比格犬体内的药代动力学数据(检测奥司他韦活性代谢物浓度)。
实施例5产品和实施例12产品在比格犬体内的AUC 0-t差不多，但实施例5产品的Cmax远高于实施例12产品，考虑到血药浓度高，可能导致毒副作用风险增加。因此选择实施例12产品进行第二次人体临床预试验。
表7 实施例5制剂和实施例12制剂在比格犬体内的药代动力学数据
  Cmax AUC 0-t
  ((ng/mL)) (ng·h/mL)
实施例5 4810±750 53200±7100
实施例12 3980±670 48800±6800
第三次奥司他韦制剂在比格犬体内的药物代谢动力学研究
给药方案：双制剂双交叉实验(健康比格犬12只，雌雄各半，分成2组，每组6只，空腹给药)，两组均给自研奥司他韦缓释制剂(150mg)，一天1次。
表8列出了实施例18产品和实施例5产品，在比格犬体内的药代动力学数据(检测奥司他韦活性代谢物浓度)。
实施例18产品在比格犬体内的AUC 0-t是实施例5产品的1.17倍，且实施例18产品的Cmax略高于实施例5产品。因此选择实施例18产品进行第三次人体临床预试验。
表8 实施例18制剂和实施例5制剂在比格犬体内的药代动力学数据
Figure PCTCN2020117625-appb-000085
临床试验：奥司他韦制剂在人体内的药物代谢动力学研究
第一次人体临床预试验
给药方案：实施例12所制备得到的奥司他韦双相释放制剂(150mg)，空腹状态下给药，一天给药1次。
表9列出了实施例12所制备得到的奥司他韦双相释放制剂在人体内的药代动力学数据(检测奥司他韦活性代谢物浓度)。本发明产品具有良好的药代动力学性质，Tmax为6h，进食给药的Tmax为14h，Cmax大于300ng/mL。药时曲线图见图1。
从图1可看出，口服自研产品后，体内奥司他韦活性代谢物在3h至4h内达到150ng/mL，起到快速起效的作用；24h内血药浓度高于150ng/ml的维持时间为21h，24h内血药浓度峰谷浓度比为2.14，能长时间平稳的维持有效血药浓度。
表9 实施例12所制备得到的奥司他韦双相释放制剂在人体内的药代动力学数据
  实施例12
Tmax(h) 6
Cmax(ng/mL) 370
AUC 0-t(ng·h/mL) 8343
第二次人体临床预试验
给药方案：双制剂双交叉实验，其中一组给实施例12所制备得到的奥司他韦双相释放制剂(150mg)，进食状态下给药，一天给药1次；另一种给参比制剂，参比制剂为75mg规格速释制剂(商品名：
Figure PCTCN2020117625-appb-000086
)，一天给药2次。
表10列出了实施例12和参比制剂在人体内的药代动力学数据(检测奥司他韦活性代谢物浓度)。本发明产品具有良好的药代动力学性质，Tmax为14h，Cmax大于300ng/mL。药时曲线图见图2。
从图2可看出，口服自研产品后，体内奥司他韦活性代谢物在3h至4h内达到150ng/mL，起到快速起效的作用；24h内血药浓度高于150ng/ml的维持时间为21h，24h内血药浓度峰谷浓度比为1.21，能长时间平稳的维持有效血药浓度。
表10 实施例12所制备得到的奥司他韦双相释放制剂在人体内的药代动力学数据
  实施例12 参比制剂
Tmax(h) 14 17
Cmax(ng/mL) 318 526
AUC 0-t(ng·h/mL) 9537 12180
第三次人体临床预试验
给药方案：双制剂双交叉实验，其中一组给实施例18所制备得到的奥司他韦双相释放制剂(180mg)，进食状态下给药，一天给药1次；另一种给参比制剂，参比制剂为75mg规格速释制剂(商品名：
Figure PCTCN2020117625-appb-000087
)，一天给药2次。
表11列出了实施例18和参比制剂在人体内的药代动力学数据(检测奥司他韦活性代谢物浓度)。本发明产品具有良好的药代动力学性质，Tmax为8h，Cmax大于300ng/mL。药时曲线图见图3。
从图3可看出，口服自研产品后，体内奥司他韦活性代谢物在2h至3h内达到150ng/mL，与参比制剂相当，起到快速起效的作用；24h内血药浓度高于150ng/ml的维持时间为21.5h，24h内血药浓度峰谷浓度比为2.30，能长时间平稳的维持有效血药浓度。
表11 实施例18所制备得到的奥司他韦双相释放制剂在人体内的药代动力学数据
  实施例18 参比制剂
Tmax(h) 8 16
Cmax(ng/mL) 455 463
AUC 0-t(ng·h/mL) 9206 9737
实施例18
处方表
Figure PCTCN2020117625-appb-000088
实施例19
处方表
Figure PCTCN2020117625-appb-000089
实施例20
处方表
Figure PCTCN2020117625-appb-000090
实施例21
处方表
Figure PCTCN2020117625-appb-000091
实施例22
处方表
Figure PCTCN2020117625-appb-000092
Figure PCTCN2020117625-appb-000093
实施例23
处方表
Figure PCTCN2020117625-appb-000094
实施例24
处方表
Figure PCTCN2020117625-appb-000095
Figure PCTCN2020117625-appb-000096
实施例25
处方表
Figure PCTCN2020117625-appb-000097
实施例26
处方表
Figure PCTCN2020117625-appb-000098
Figure PCTCN2020117625-appb-000099
实施例18至实施例26制备方法：
缓释层总混颗粒制备：按处方称取磷酸奥司他韦、微晶纤维素和羟丙基甲基纤维，转移至制粒机中预混，用纯化水做制粒液进行湿法制粒，然后依次湿整粒、流化床干燥、干整粒，外加润滑剂后得缓释层总混颗粒。
速释层总混颗粒制备：按处方称取磷酸奥司他韦和微晶纤维素，转移至制粒机中预混，用聚乙烯吡咯烷酮-水做制粒液进行湿法制粒(最终干燥后的聚乙烯吡咯烷酮量如处方所示)，然后依次湿整粒、流化床干燥、干整粒，外加润滑剂后得速释层总混颗粒。
双层片制备：用双层压片机，先填充150mg规格的缓释层总混颗粒，预压，得缓释层片芯；再填充30mg规格的速释层颗粒，压片，得速缓双层片芯。
隔离层：按处方配制隔离层包衣液，对上述速缓双层片芯进行包衣，包衣增重占片芯的百分比为2％。
表12 实施例18-实施例26中缓释材料重量占制剂总重的比例
Figure PCTCN2020117625-appb-000100
溶出数据
在该实施例中，实施例18至实施例26所制备的奥司他韦制剂在pH6.8介质中溶出，介质的体积900±9mL，介质的温度37.0±0.5℃，桨法，100rpm/分钟下进行体外溶出试验。pH6.8中溶出度取样时间点：0.25h、1h、2h、3h、4h、6h、8h、10h、12h、14h和16h。取样位置：在桨叶顶端至液面的中点，距溶出杯内壁10mm处。采用高效液相(HPLC)法进行体外溶出含量测定。试验结果如下表所示：
表13 实施例18至实施例26产品在pH6.8介质中的溶出(％)(n＝3)
Figure PCTCN2020117625-appb-000101
溶出数据
在该实施例中，实施例18至实施例26所制备的奥司他韦制剂先在0.1MHCl中耐酸1h再转入到pH6.8介质中溶出，介质的体积900±9mL，介质的温度37.0±0.5℃，桨法，75rpm/分钟下进行体外溶出试验。0.1MHCl中溶出度取样时间点：0.25h、1h，pH6.8中溶出度取样时间点：1h、2h、3h、4h、6h、8h、10h、12h、14h、16h。取样位置：在桨叶顶端至液面的中点，距溶出杯内壁10mm处。采用高效液相(HPLC)法进行体外溶出含量测定。试验结果如下表所示：
表14 实施例18至实施例26产品在0.1MHCl中耐酸1h再转入到pH6.8介质中溶出(％)(n＝3)
Figure PCTCN2020117625-appb-000102
Figure PCTCN2020117625-appb-000103
本发明说明书的描述中，参考术语“一些实施例”、“一些实施方式”、“一个具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (43)

  1. 一种奥司他韦制剂，其特征在于，包括奥司他韦或其盐，所述制剂为一天一次给药的制剂。
  2. 权利要求1所述的奥司他韦制剂，其特征在于，奥司他韦或其盐在≤4h的某1h时间段内快速释放，释放量为25％-55％。
  3. 权利要求1或2所述的奥司他韦制剂，其特征在于，奥司他韦或其盐在第1h快速释放，释放量为25％-55％。
  4. 权利要求1-3任一项所述的奥司他韦制剂，其特征在于，奥司他韦4h释放量为25％-90％。
  5. 权利要求1-4任一项所述的奥司他韦制剂，其特征在于，奥司他韦10h释放量大于70％。
  6. 权利要求1-5任一项所述的奥司他韦制剂，其特征在于，奥司他韦10h释放量为70％-99％。
  7. 权利要求1-6任一项所述的奥司他韦制剂，其特征在于，奥司他韦的重量占制剂总重量的比例为3％-50％。
  8. 权利要求1-7任一项所述的奥司他韦制剂，其特征在于，一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度的峰谷比小于2.5:1。
  9. 权利要求1-8任一项所述的奥司他韦制剂，其特征在于，按照奥司他韦重量计，单剂量规格为60mg-300mg。
  10. 权利要求1-9任一项所述的奥司他韦制剂，其特征在于，还包含至少一种缓释材料，所述缓释材料的重量占制剂总重量的比为3％-50％。
  11. 权利要求1-10任一项所述的奥司他韦制剂，其特征在于，还包含至少一种缓释材料，所述缓释材料包括选自乙基纤维素，羟丙基甲基纤维素，醋酸纤维素，聚氧乙烯，聚乙烯醇，甲基丙烯酸-丙烯酸乙酯共聚物RL，甲基丙烯酸-丙烯酸乙酯共聚物RS，甲基丙烯酸-丙烯酸乙酯共聚物NE30D，甲基丙烯酸-丙烯酸乙酯共聚物L100-55，醋酸羟丙甲纤维素琥珀酸酯，山嵛酸甘油酯，壳聚糖，卡波姆，巴西棕榈蜡，
    Figure PCTCN2020117625-appb-100001
    SR 30D，
    Figure PCTCN2020117625-appb-100002
    SR，醋酸纤维素钛酸酯，海藻酸钠，羧甲基纤维素钠，卡拉胶，十六醇，十八醇，十六十八醇，石蜡中的至少一种。
  12. 权利要求1-11任一项所述的奥司他韦制剂，其特征在于，包含至少一种缓释材料；奥司他韦的重量占制剂总重量的比例为3％-50％；奥司他韦或其盐4h释放量为25％-90％，奥司他韦或其盐10h释放量大于70％。
  13. 权利要求1-12任一项所述的奥司他韦制剂，其特征在于，包括含有奥司他韦或其盐的缓释部分和含有奥司他韦或其盐的速释部分。
  14. 权利要求13所述的奥司他韦制剂，其特征在于，所述速释部分中的奥司他韦规格为10mg-75mg；所述缓释部分中的奥司他韦规格为30mg-225mg。
  15. 权利要求1-14任一项所述的奥司他韦制剂，其特征在于，用于治疗成人甲型流感或成人乙型流感， 一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度大于100ng/mL，或者大于150ng/mL。
  16. 权利要求15所述的奥司他韦制剂，其特征在于，按照奥司他韦重量计，单剂量规格为150mg-300mg。
  17. 权利要求1-14任一项所述的奥司他韦制剂，其特征在于，用于治疗儿童甲型流感或儿童乙型流感，一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度大于100ng/mL，或者大于150ng/mL。
  18. 权利要求17所述的奥司他韦制剂，其特征在于，按照奥司他韦重量计，单剂量规格为60mg-180mg。
  19. 权利要求1-18任一项所述的奥司他韦制剂，其特征在于，用于治疗成人或儿童甲型流感或乙型流感，所述制剂按照奥司他韦重量计，单剂量规格为60mg-300mg。
  20. 权利要求1-19任一项所述的奥司他韦制剂，其特征在于，一天一次给药后，奥司他韦活性代谢物2h的体内血药浓度在Cmax的20％以上；24h的体内血药浓度在Cmax的30％以上。
  21. 权利要求1-20任一项所述的奥司他韦制剂，其特征在于，在至少24h期间持续释放奥司他韦。
  22. 权利要求1-21任一项所述的奥司他韦制剂，其特征在于，奥司他韦活性代谢物体内血药浓度大于100ng/mL，或者大于150ng/ml，维持时间大于16h。
  23. 权利要求1-22任一项所述的奥司他韦制剂，其特征在于，所述奥司他韦制剂为双相释放制剂，包括含有奥司他韦或其盐的缓释部分和含有奥司他韦或其盐的速释部分。
  24. 权利要求1-23任一项所述的奥司他韦制剂，其特征在于，包括含有奥司他韦或其盐的缓释部分和含有奥司他韦或其盐的速释部分，基于所述制剂中奥司他韦的总重，所述速释部分中的奥司他韦的重量比例为20％-50％。
  25. 权利要求1-24任一项所述的奥司他韦制剂，其特征在于，包括含有奥司他韦或其盐的缓释部分和含有奥司他韦或其盐的速释部分，所述速释部分中的奥司他韦和所述缓释部分中的奥司他韦的重量比为1:4-1:1。
  26. 权利要求1-25任一项所述的奥司他韦制剂，其特征在于，包含缓释材料，所述缓释材料包括羟丙基甲基纤维素和/或甲基丙烯酸-丙烯酸乙酯共聚物。
  27. 权利要求26所述的奥司他韦制剂，其特征在于，所述缓释材料的重量占制剂总重量的比例为3％-50％。
  28. 权利要求26或27所述的奥司他韦制剂，其特征在于，所述的羟丙基甲基纤维素重量占制剂总重量的比例为4％-30％，所述甲基丙烯酸-丙烯酸乙酯共聚物重量占制剂总重量的比例为0-35％。
  29. 权利要求1所述的奥司他韦制剂，其特征在于，奥司他韦1h释放量为25％-55％；奥司他韦4h 释放量为25％-90％；奥司他韦10h释放量大于70％；奥司他韦的重量占制剂总重量的比例为3％-50％；还包含至少一种缓释材料，所述缓释材料的重量占制剂总重量的比为3％-50％；一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度的峰谷比小于2.5:1；所述奥司他韦制剂用于治疗成人甲型流感、成人乙型流感、儿童甲型流感或者儿童乙型流感，一天一次给药后，24h内奥司他韦活性代谢物体内血药浓度大于100ng/mL；所述奥司他韦制剂一天一次给药后，奥司他韦活性代谢物2h的体内血药浓度在Cmax的20％以上，24h的体内血药浓度在Cmax的30％以上。
  30. 权利要求1-29任一项所述的奥司他韦制剂，其特征在于，可以制备成片剂，胶囊，或者混悬剂。
  31. 权利要求1-29任一项所述的奥司他韦制剂，其特征在于，可以制备成双层片，所述双层片其中一层包含速释部分，另一层包含缓释部分。
  32. 权利要求13-28任一项所述的奥司他韦制剂，其特征在于，以缓释部分为片芯，速释部分包裹于片芯外。
  33. 权利要求1-32所述的奥司他韦制剂，其特征在于，含有缓释部分和速释部分，所述缓释部分含有核芯1，所述速释部分含有核芯2；其中，所述核芯1为将奥司他韦与骨架缓释材料均匀混合制得，所述核芯2为将奥司他韦与骨架材料均匀混合制得；或者所述核芯1内含奥司他韦且外部包裹有高分子聚合物及其他药用辅料形成的缓释包衣层，所述核芯2内含奥司他韦且外部包裹有水溶性高分子成膜材料、增塑剂形成的速释包衣层；或者所述核芯1为将奥司他韦与骨架缓释材料混合后，采用挤出滚圆法制备得到，所述核芯2为将奥司他韦与药用辅料混合后，采用挤出滚圆法制备得到；或者所述核芯1为将奥司他韦与缓释成膜材料喷涂于空白丸芯上制得，所述核芯2为将奥司他韦与速释包衣材料混合后喷涂于空白丸芯上制得。
  34. 权利要求33所述的奥司他韦制剂，其特征在于，所述核芯1和所述核芯2混合后压制成双层片或者多层片，或者所述核芯1和所述核芯2混合后直接填充于胶囊，或者所述核芯1和所述核芯2混合后装袋。
  35. 一种如权利要求1-34任一项所述的奥司他韦制剂的制备方法，其特征在于，包括以下步骤：
    (1)将水溶性高分子成膜材料、增塑剂与奥司他韦形成的速释包衣层，包裹于空白核芯外，得到速释部分，(2)将高分子聚合物及其他药用辅料形成的缓释包衣层，包裹于(1)所得到的速释部分，得到缓释部分，(3)将(1)所得到的速释部分和(2)所得到的缓释部分填充于胶囊，或压制成片，或装袋，得到所述奥司他韦制剂；
    或者包括以下步骤：
    (1)将高分子聚合物及其他药用辅料形成的缓释包衣层，包裹于含奥司他韦的核芯外，得到缓释部分，
    (2)将水溶性高分子成膜材料、增塑剂与奥司他韦形成的速释包衣层，包裹于(1)所得到的缓释部分外，得到所述奥司他韦制剂；
    或者包括以下步骤：
    (1)将奥司他韦、高分子聚合物及其他药用辅料形成的缓释包衣层，包裹于空白核芯外，得到缓释部分，(2)将水溶性高分子成膜材料、增塑剂与奥司他韦形成的速释包衣层，包裹于(1)所得到的缓释部分外，得到所述奥司他韦制剂；
    或者包括以下步骤：
    (1)使缓释部分包含含有奥司他韦及骨架缓释材料的核芯，
    (2)将水溶性高分子成膜材料、增塑剂与奥司他韦形成的速释包衣层，包裹于(1)所述缓释部分外，得到所述奥司他韦制剂。
  36. 权利要求35所述的制备方法，其特征在于，所述核芯包括颗粒、片芯或丸芯；或者所述核芯还进一步包括，任选地，填充剂、粘合剂、促渗剂或润滑剂。
  37. 权利要求35所述的制备方法，其特征在于，制备所述核芯的方法包括湿法制粒、干法制粒或粉末直压。
  38. 权利要求35-37任一项所述的制备方法，其特征在于，所述高分子聚合物包括选自乙基纤维素，醋酸纤维素，甲基丙烯酸-丙烯酸乙酯共聚物RL，甲基丙烯酸-丙烯酸乙酯共聚物RS，甲基丙烯酸-丙烯酸乙酯共聚物NE 30D中，甲基丙烯酸-丙烯酸乙酯共聚物L100-55，醋酸羟丙甲纤维素琥珀酸酯，巴西棕榈蜡，
    Figure PCTCN2020117625-appb-100003
    SR 30D，
    Figure PCTCN2020117625-appb-100004
    SR中的至少一种。
  39. 权利要求35-37任一项所述的制备方法，其特征在于，所述其他药用辅料，包括增塑剂，抗粘剂，乳化剂，或致孔剂。
  40. 权利要求35-37任一项所述的制备方法，其特征在于，所述水溶性高分子成膜材料包括选自羟丙基甲基纤维素，聚维酮，聚乙烯醇，羟丙基纤维素中的至少一种。
  41. 权利要求35-37任一项所述的制备方法，其特征在于，所述骨架缓释材料包括选自羟丙基甲基纤维素，聚氧乙烯，聚乙烯醇，乙基纤维素，山嵛酸甘油酯，壳聚糖，卡波姆，海藻酸钠，羧甲基纤维素钠，卡拉胶，十六醇，十八醇，十六十八醇，石蜡中的至少一种。
  42. 权利要求35-37任一项所述的制备方法，其特征在于，所述速释包衣层外部包裹隔离层。
  43. 权利要求42所述的制备方法，其特征在于，所述隔离层含有水溶性高分子成膜材料、增塑剂，任选地，含有抗粘剂或遮光剂。
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