WO2020258081A1 - 低剂量塞来昔布制剂 - Google Patents

低剂量塞来昔布制剂 Download PDF

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WO2020258081A1
WO2020258081A1 PCT/CN2019/093044 CN2019093044W WO2020258081A1 WO 2020258081 A1 WO2020258081 A1 WO 2020258081A1 CN 2019093044 W CN2019093044 W CN 2019093044W WO 2020258081 A1 WO2020258081 A1 WO 2020258081A1
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celecoxib
preparation
formulation
suspension
capsule
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PCT/CN2019/093044
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English (en)
French (fr)
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孙弘
王涛
胡岩
罗奋熔
展金祥
谢云根
祁嘉维
赵履伟
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杭州艾瑞莎生物医药科技有限公司
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Priority to US17/622,669 priority Critical patent/US20220395514A1/en
Priority to PCT/CN2019/093044 priority patent/WO2020258081A1/zh
Priority to CN201980097871.0A priority patent/CN114340638A/zh
Publication of WO2020258081A1 publication Critical patent/WO2020258081A1/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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • A—HUMAN NECESSITIES
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    • 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
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    • 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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to the field of preparations; in particular, it relates to the preparation and application of a low-specification (low-dose) celecoxib oral preparation that can be used to treat pain and inflammation, including celecoxib nano-preparation, formulation stabilization and process technology.
  • a low-specification (low-dose) celecoxib oral preparation that can be used to treat pain and inflammation, including celecoxib nano-preparation, formulation stabilization and process technology.
  • Celecoxib is a non-steroidal anti-inflammatory drugs ("NSAIDs"), which is mainly used to treat osteoarthritis, rheumatoid arthritis and some acute pain.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Original product of Celecoxib The Chinese name “Celebrex” is developed by Pfizer Pharmaceuticals in the United States and marketed in many countries around the world; its oral preparations are capsules; specifications: 50mg, 100mg, 200mg, 400mg.
  • Celecoxib Although Celecoxib has excellent efficacy, it has side effects such as the risk of heart disease and gastrointestinal irritation.
  • Commercially available preparations carry the U.S. Food and Drug Administration (“FDA”) safety black-box warning (“black-box warning”), which means that the treatment goals are met and “where possible, Reduce the dosage and time limit of use.”
  • FDA Food and Drug Administration
  • celecoxib has a large space for optimization of formulations in terms of safety.
  • the present invention aims to provide a new celecoxib preparation product which can reduce the dosage of the drug and can achieve bioequivalent with the commercial preparation.
  • an oral preparation of celecoxib is provided, the specification of the preparation is 60-90% of the commercial preparation specification of celecoxib; and the preparation and the corresponding specification of celecoxib
  • the commercially available preparations are bioequivalent.
  • the dosage form of the preparation includes: tablets, capsules, granules, and suspensions.
  • the particle size D50 of celecoxib in the formulation is not greater than 160 nm, and D90 is not greater than 300 nm.
  • the particle size of celecoxib in the formulation is maintained at D50 not greater than 160 nm and D90 not greater than 300 nm for at least 5 days, more preferably at least 7 days, and even more preferably 7-15 days.
  • the formulation when it is a tablet, capsule or granule, based on the total weight of the formulation, it contains sodium lauryl sulfate 0.5-12% w/w, more preferably 2-10% w /w, more preferably 4-8%w/w.
  • the preparation when it is a tablet, capsule or granule, based on the total weight of the preparation, it contains 0.5-7% w/w of polyvinylpyrrolidone, more preferably 0.5-5% w/w, More preferably, it is 0.5-3% w/w.
  • the formulation when it is a tablet, capsule or granule, based on the total weight of the formulation, it contains sucrose in 10-70% w/w, more preferably 10-50% w/w, and more preferably It is 10-30% w/w.
  • the formulation specifications include: 40mg, 80mg, 160mg, 320mg; which respectively correspond to the specifications of the commercially available celecoxib formulation: 50mg , 100mg, 200mg, 400mg.
  • the pharmaceutical excipients in the formulation also include one or more of the following: fillers, disintegrants, and binders , Glidants, lubricants.
  • the US Pharmacopoeia dissolution method I is used, which is at a speed of 50 rpm when the dissolution medium is pH 1.0 or pH 6.1
  • the measured dissolution of celecoxib is not less than 30% in 30 minutes and not less than 45% in 60 minutes.
  • the total weight of the preparation when the preparation is a suspension, contains 0.5-5% (w/v) of celecoxib, more preferably 0.5-3% (w/v) , More preferably 1-2% (w/v).
  • the formulation when it is a suspension, based on the total weight of the formulation, it contains sodium lauryl sulfate 0.1-2% (w/v), more preferably 0.1-1.5% (w/ v), more preferably 0.1-1% (w/v).
  • the preparation when it is a suspension, based on the total weight of the preparation, it contains 0.05-2% (w/v) of polyvinylpyrrolidone, more preferably 0.05-1% (w/v), More preferably, it is 0.05-0.5% (w/v).
  • the formulation when it is a suspension, based on the total weight of the formulation, it contains 0.5-30% (w/v) of sucrose, more preferably 0.5-20% (w/v), and more preferably It is 0.5-10% (w/v).
  • the preparation is a tablet, capsule or granule
  • the method includes the steps:
  • Step A The celecoxib is ground into a nanoparticle suspension by a full-water phase wet method; sodium lauryl sulfate is used as a surfactant, and polyvinylpyrrolidone is used as a hydrophilic polymer;
  • Step B Add sugars to the nanoparticle suspension obtained in Step A, and continue to add sodium lauryl sulfate and polyvinylpyrrolidone to mix to obtain a nanosuspension;
  • the sugars are monosaccharides, disaccharides, And one or two or more of polyols; preferably one or two or more of lactose, sucrose, fructose, mannitol, and sorbitol; preferably mixing by stirring;
  • Step C spray drying the nano suspension obtained in step B on a fluidized bed to obtain drug-loaded particles or drug-loaded pellets;
  • Step D Prepare the drug-loaded granules or drug-loaded pellets into oral solid preparations including tablets, capsules, and granules.
  • the total weight of the nanoparticle suspension obtained in the wet grinding in step A contains more than 10% w/w of celecoxib, more preferably 10-35 %W/w, more preferably 15-25%w/w.
  • the amount of sodium lauryl sulfate is 0.5-12% w/w, more preferably 2-10% w/w, and It is preferably 4-8% w/w;
  • the amount of polyvinylpyrrolidone is 0.5-7% w/w, more preferably 0.5-5% w/w, and even more preferably 0.5-3% w/w;
  • the amount of sugar It is 10-70% w/w, more preferably 10-50% w/w, still more preferably 10-30% w/w.
  • the carrier used in step C includes a filler; the filler includes a sugar and a pellet core of 100-1000 ⁇ m; the sugar is one of monosaccharides, disaccharides, and polyols. Or two or more; the pellet core is selected from sucrose pellet core, microcrystalline cellulose pellet core, starch pellet core, tartaric acid pellet core, lactose pellet core, silicon dioxide pellet core, hypromellose pellet core, Citric acid pellets, or tartaric acid pellets.
  • the carrier further includes one or more of a disintegrant, a binder, a glidant, a lubricant, and an antioxidant.
  • the method includes step A, step B and step E:
  • Step A The celecoxib is ground into a nanoparticle suspension by a full-water phase wet method; sodium lauryl sulfate is used as a surfactant, and polyvinylpyrrolidone is used as a hydrophilic polymer;
  • Step B Add sugars to the nanoparticle suspension obtained in Step A, and continue to add sodium lauryl sulfate and polyvinylpyrrolidone to mix to obtain a nanosuspension;
  • the sugars are monosaccharides, disaccharides, And one or two or more of polyols; preferably one or two or more of lactose, sucrose, fructose, mannitol, and sorbitol; preferably mixing by stirring; and
  • Step E Add one or more of the following auxiliary materials to the nanosuspension obtained in Step B: suspending agent, antioxidant, taste masking agent, sweetener, preservative, defoamer, thickener , Essence, pH buffer salt; preferably mixed by stirring.
  • the celecoxib oral preparation provided by the present invention as described above for the treatment of mild to moderate acute pain, mild to moderate chronic pain or It is used to prepare medicines for treating mild to moderate acute pain and mild to moderate chronic pain.
  • Figure 1 shows the chemical structure of Celecoxib.
  • Figure 2A shows the particle size distribution curve of celecoxib of the present invention (before wet grinding);
  • Figure 2B shows the particle size distribution curve of celecoxib in the celecoxib suspension of the present invention after wet grinding .
  • FIG 3 shows the process of celecoxib preparation, including oral solid preparations such as tablets, capsules and granules, and oral liquid preparations such as suspensions.
  • Figure 4 shows the average blood concentration curve from time zero to 12 hours after a single administration of male and female beagle dogs in an embodiment of the present invention, including celecoxib preparation (50mg/capsule), celecoxib Preparation (25 mg/capsule), and celecoxib, a commercial preparation, celecoxib (100 mg/capsule).
  • Fig. 5A and Fig. 5B show the average drug-time curve of healthy people in the same embodiment of the present invention after administration.
  • 12 healthy volunteers were administered separately in 4 time sequence (A, B, C, D) tests under fasting conditions; among them: Group A: Celecoxib preparation AP2500, 50 mg/capsule; Group B: Celiac Celecoxib 100mg/capsule; Group C: Celecoxib preparation AP2500, 75mg/capsule; Group D: Celecoxib preparation AP2500, 100mg/capsule.
  • Figure 5A shows the average blood concentration-time curve of celecoxib for 0-48 hours;
  • Figure 5B shows the average blood concentration-time curve of celecoxib for 0-12 hours.
  • AUC area under the curve
  • area under the curve refers to the integration of the area under the curve of blood drug concentration versus time or the drug-time curve after administration, reflecting the absorption of the drug in the human body degree.
  • C max peak concentration used in the present invention refers to the peak concentration of drug components in plasma after administration.
  • T max time to peak concentration
  • bioavailability refers to the part of a pharmaceutical ingredient that is used in a biological system.
  • celecoxib refers to the chemical: 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1hydro-pyrazol-1-yl]benzenesulfon Amide, the chemical structure is shown in Figure 1.
  • Celecoxib has a molecular weight of 381.4 and is a white crystalline powder with a melting point of 157-158°C.
  • Celecoxib is a selective cyclooxygenase-2 ("COX-2") inhibitor used to treat osteoarthritis (OA), rheumatoid arthritis (RA), some acute pain, menstrual pain, etc.
  • COX-2 selective cyclooxygenase-2
  • reference preparation used in the present invention refers to Celebrex (English name: ) Capsules; its specifications are: 50mg, 100mg, 200mg or 400mg.
  • celecoxib formulation or “celecoxib formulation” or “celecoxib oral formulation” or “low-strength celecoxib formulation” or “decreased dose celecoxib formulation” or “AP2500” refers to the formulation developed by the present invention.
  • Celecoxib preparations include oral liquid preparations (such as suspensions) and oral solid preparations (such as capsules, tablets, granules, etc.).
  • AP2500 specifically refers to an oral capsule of celecoxib.
  • the "commercial preparation” or “celecoxib commercial preparation” used in the present invention refers to celecoxib Or a generic drug product with the same specifications and bioequivalent as Celebrex, the specifications are: 50mg, 100mg, 200mg or 400mg; the dosage form is capsule or tablet.
  • bioequivalent refers to the Cmax of the reduced-dose celecoxib formulation developed by the present invention at the same level (ie within a 90% confidence interval , The geometric mean ratio of C max is in the range of 80%-125%), or the AUC is at the same level (that is, in the 90% confidence interval, the geometric mean ratio of AUC is in the range of 80%-125%), or celecoxib
  • the C max and AUC of the cloth preparation in vivo are at the same level (that is, in the 90% confidence interval, the geometric mean ratio of C max and AUC is in the range of 80%-125%).
  • the “confidence interval” used in the present invention refers to the estimated interval of the overall parameter constructed by the sample statistics.
  • the confidence interval ("CV") of a probability sample is an interval estimate of a certain population parameter of the sample.
  • the confidence interval shows the degree to which the true value of this parameter has a certain probability to fall around the measurement result.
  • the confidence interval gives the credibility of the measured value of the measured parameter, that is, the "a probability" required above.
  • dissolution refers to the process of drug release from dosage forms such as capsules or tablets.
  • dissolution rate or “dissolution rate” refers to the rate and extent of dissolution of a solid preparation such as a drug tablet in a predetermined solvent.
  • Dose refers to the amount that produces a therapeutic effect after one administration.
  • effective dose used in the present invention refers to the dose of a drug that produces a therapeutic effect in the body through a specific route of administration.
  • the term "strength" used in the present invention refers to a certain dosage form, such as the total amount of medicine contained in a capsule, a tablet or a unit volume suspension.
  • non-steroidal anti-inflammatory and analgesic drugs or “NSAIDs” (non-steroidal anti-inflammatory drugs) used in the present invention refers to a class of anti-inflammatory, antipyretic and analgesic drugs that do not contain glucocorticoids The role of drugs. The chemical structure of these drugs lacks the steroidal ring of glucocorticoids, and they have antipyretic, analgesic, and anti-inflammatory effects, so they are called non-steroidal anti-inflammatory drugs. Non-steroidal anti-inflammatory drugs are also the first-line drugs for the treatment of osteoarthritis. They are also widely used in other bone and joint diseases, rheumatic immune diseases and painful diseases to reduce the pain and stiffness of the above diseases and improve the bones and joints. Features. Celecoxib is a kind of NSAIDs, which can be administered orally by patients and can also be used for acute analgesia.
  • acute pain refers to pain that has a rapid onset, which can be severe but lasts for a relatively short period of time.
  • mild to moderate acute pain refers to the pain when his/her pain is less than the value "7" when the value of "0" to "10” is used to indicate different degrees of pain. Mild to moderate acute pain can include back and neck pain, migraine, pain after surgery, etc.
  • chronic pain is a term used relative to "acute pain", and its duration exceeds 6 months.
  • Chronic pain can be mild or unbearable pain, intermittent or continuous pain, and can be slightly inconvenient or completely incapacitating pain.
  • rheumatoid arthritis pain The most common sources of pain are: rheumatoid arthritis pain, osteoarthritis pain, pain caused by injury, headache, back pain, etc.
  • Other types of chronic pain include tendinitis, sinus pain, carpal tunnel syndrome, and induced pain in specific parts of the body, such as shoulder pain, pelvic pain, and neck pain.
  • General muscle or nerve pain can also develop into chronic pain diseases.
  • subject or “individual” or “patient” used in the present invention are used interchangeably and refer to mammals (including humans).
  • Non-compartmental model is a commonly used calculation method in pharmacokinetic research and analysis.
  • particle size used in the present invention is used to describe the important biophysical properties of pharmaceutical nanoparticles, that is, the particle size.
  • the size and stability of the particle size directly affect the absorption, distribution, efficacy and safety of nanoparticle-based pharmaceutical products in the human body.
  • the particle size distribution such as D50 and D90, also called d(0.5) and d(0.9), can be measured by a laser particle size analyzer.
  • D50 refers to the particle size value when the cumulative particle size distribution percentage of particles reaches 50%, and the average particle size is usually replaced by D50 data.
  • D90 refers to the particle size value when the cumulative particle size distribution percentage reaches 90%.
  • “stability” refers to the physical and chemical stability of the preparation under defined storage conditions.
  • the storage conditions of 40°C/75% RH referred to in the present invention are commonly used experimental conditions for stability research, aiming to evaluate the physical and chemical stability of celecoxib preparations under accelerated storage conditions.
  • Storage conditions are usually accompanied by a "period of time” (for example, 2 weeks, 1 month, 3 months), which refers to the actual time elapsed by the preparation sample under specific storage conditions.
  • pharmaceutical excipients refer to excipients and adjuvants used in preparations; except for the active ingredients, they have been reasonably evaluated in terms of safety and are included in pharmaceutical preparations Of the substance.
  • pharmaceutical excipients which have different functions according to different preparations.
  • they are used for oral solid preparations. They include: excipient, filling, adhesion, disintegration, solubilization, flow aid, anti-oxidation, etc.; such as oral mixture
  • Suspension agents include: suspension, anti-oxidation, taste masking, sweetening, anti-corrosion, defoaming, thickening, pH buffer salt of solution, etc.
  • Pharmaceutical excipients are an important part of pharmaceutical preparations; their selection and use directly affect the safety, effectiveness and product stability of drugs.
  • wet grinding used in the present invention refers to a process for preparing drug nanosuspensions: in the grinding chamber of the grinding device, a grinding medium ("grinding beads"), containing drugs, surfactants, Suspension of hydrophilic polymer and other pharmaceutical excipients; then start the high-speed rotation of the stirring rod in the grinding chamber, and drive the grinding medium to impact, shear, and grind the drug particles in the water phase to make the drug particles
  • the particle size is reduced from the common micron range to the nanometer range (usually in the 20-1000 nanometer range).
  • carrier used in the present invention specifically refers to pharmaceutical excipients placed at the bottom in fluidized bed drying.
  • the present invention provides a low-specification (ie, low-dose) celecoxib oral preparation that can be used to treat pain and inflammation, so as to achieve the purpose of safer use.
  • a low-specification (ie, low-dose) celecoxib oral preparation that can be used to treat pain and inflammation, so as to achieve the purpose of safer use.
  • the present invention is a celecoxib preparation such as a capsule, tablet, granule or suspension; in the fasting pharmacokinetic study of healthy people, it is the same as the commercial preparation of celecoxib Celebrex
  • the peak blood concentration C max in the human body can reach bioequivalence, that is, in the 90% confidence interval, the geometric mean ratio of C max is 80%-125%; or the absorption AUC energy in the human body Achieve bioequivalence, that is, in the 90% confidence interval, the geometric mean ratio of AUC is 80%-125%; or the peak blood concentration C max and AUC in humans are both bioequivalent, that is, at 90% Confidence interval, the geometric mean ratios of C max and AUC are both 80%-125%; but the dosage of the celecoxib preparation of the present invention is reduced by 10-40% w/w compared with the commercial preparation celecoxib of the same specification.
  • Celecoxib celecoxib The specifications of its generic drugs are: 50mg, 100mg, 200mg, 400mg.
  • the specifications of the celecoxib oral solid preparations such as tablets, capsules or granules of the present invention are reduced by 10-40%, that is, the content of celecoxib in the preparation is reduced by 10-40%;
  • it can be 30mg, 30.5mg, 31mg, 31.5mg, 32mg, 32.5mg, 33mg, 33.5mg, 34mg, 34.5mg, 35mg, 35.5mg, 36mg, 36.5mg, 37mg, 37.5 for the 50mg of the commercial preparation mg, 38mg, 38.5mg, 39mg, 39.5mg, 40mg, 40.5mg, 41mg, 41.5mg, 42mg, 42.5mg, 43mg, 43.5mg, 44mg, 44.5mg, 45mg; if it is equal to
  • the oral solid preparation of celecoxib according to the present invention when the specifications of celecoxib contained in it are reduced by 20%, they are: 40mg, 80mg, 160mg, 320mg; Preparation specifications: 50mg, 100mg, 200mg, 400mg.
  • the oral solid preparation of celecoxib may be any one of the following: tablets, capsules, granules, orally disintegrating tablets, and sublingual tablets.
  • the celecoxib formulation is an oral suspension.
  • the specifications of the celecoxib formulation are capsules of 40 mg and 80 mg, respectively.
  • USP Apparatus I USP Apparatus I, basket method, rotating speed 50 rpm
  • the dissolution medium is pH 1.0
  • Celecoxib dissolution is not less than 30% in 30 minutes and not less than 45% in 60 minutes.
  • the specifications of the celecoxib formulation are 40 mg and 80 mg capsules respectively.
  • USP Apparatus I USP Apparatus I, basket method, rotating speed 50 rpm
  • the dissolution medium is pH 6.1
  • the dissolution of celecoxib is not less than 30% in 30 minutes and not less than 45% in 60 minutes.
  • the preparation of the celecoxib oral solid preparation of the present invention mainly involves the following four steps (see Figure 3):
  • Step A Preparation of nano suspension by wet grinding
  • Step B Add sugars and other auxiliary materials to prepare a stable nano suspension
  • Step C Fluidized bed drying and removing water to prepare drug-loaded particles
  • Step D Make Celecoxib solid preparation
  • the celecoxib nano preparation of the present invention adopts a two-step preparation process, namely "step A + step B", or it is called “grind first, then stabilize”.
  • Step A Prepare nano suspension by wet grinding process, that is, add celecoxib, surfactant, and hydrophilic polymer to the water phase to make a suspension, and then start the stirring in the grinding chamber
  • the rod rotates at a high speed (2600-4500rpm), and drives the grinding medium ("grinding beads") in the grinding chamber to impact, shear and grind the drug particles in the water phase, so that the particle size of the drug particles is from the common micron
  • the range (such as: 20-200 ⁇ m) is reduced to the nanometer range (such as: 20-400nm).
  • the wet grinding process has higher requirements for the selection, combination and content of surfactants and hydrophilic polymers, which is the key to ensuring that the particle size of celecoxib drug particles can be ground to the nanometer range.
  • the particle size of the drug particles gradually decreases, but the surface area of the drug particles increases rapidly.
  • the size of the grinding chamber depends on the scale of production required.
  • the chamber volume of the grinding chamber is usually 0.2 liters, 0.5 liters, 1 liter, 2 liters, 5 liters, 10 liters; the grinding chamber can be externally connected to a container that is 2-20 times the suspension in the grinding chamber for use in the laboratory, The need for pilot scale production.
  • the grinding beads are held in the grinding chamber by a dynamic gap separator.
  • Grinding beads are usually composed of yttria-stabilized zirconia (YTZ) beads with a diameter of 0.1-0.5mm, or polystyrene spherical resin beads with a high degree of crosslinking.
  • the grinding temperature is usually thermostatically controlled within the range of 20-45°C.
  • the suspension used for grinding is an all-aqueous phase without organic solvents.
  • the invention also does not use any high-pressure homogenization technology.
  • Celecoxib is no exception.
  • the grinding process of celecoxib needs to evaluate many factors in order to optimize the formulation of the grinding liquid and the grinding process parameters to obtain a celecoxib nano-suspension with stable particle size and other good physical and chemical properties.
  • the key parameters of the grinding process include: drug concentration, the type and concentration of auxiliary materials, the amount of grinding beads, the diameter of the grinding beads, the grinding speed, the grinding time, the material temperature and the flow rate of the peristaltic pump.
  • Step B In the collected nanosuspension prepared by wet grinding (complete step A), add auxiliary materials to prepare a stable nanosuspension, and assist with appropriate mechanical stirring.
  • the added auxiliary materials include: a certain amount of monosaccharides, disaccharides, or polyols and other highly hydrophilic auxiliary materials; while continuing to add a certain amount of surfactants and hydrophilic polymers.
  • wet grinding which is described in step A, is in the water phase where surfactants and hydrophilic polymers exist, the grinding rod is rotated in the grinding chamber to drive the grinding beads, and through high-speed impact, shearing, grinding and other processes , The drug particles are reduced from the micron range to the nanometer range; and after that, the nanometer solid preparation of the drug is prepared through the steps of fluidized bed drying or other drying and water removal processes, and mixing with other pharmaceutical excipients.
  • the preparation of nano-medicine by wet grinding should meet the following requirements:
  • the particle size of the drug is reduced to the nanometer range, such as: D50 is less than 200nm; D90 is less than 400nm; or better: D50 is less than 150nm, D90 is less than 300nm;
  • the drug has a higher drug loading in the suspension, so there is a higher grinding efficiency; usually the drug loading should be higher than 5%, higher than 10%; for drugs with higher specifications (such as : Above 50mg), the drug loading in the grinding fluid should be 15-25%w/w;
  • the nano suspension should be stable enough to ensure the operability of the production process.
  • the minimum requirement is to be stable for 48-72 hours, and preferably for 7 days, that is, the chemical and physical properties of the drug are stable, especially the nanoparticles of the drug No significant change in diameter (change in particle size is less than 10%, or optimally less than 5%);
  • the particle size of the drug should remain stable during the process of removing water and solidifying into particles or powder of the nanosuspension, that is, within the required nanometer range (20-400nm). This is the most important thing; that is to say, in the production process of preparing nano-solid preparations such as tablets, capsules or granules, when the water in the nano-suspension is removed, the drug particles can be solidified in the excipients (in fluidization). During bed drying, it is also called “carrier”) and maintains a stable nanoparticle size state. Because only in this way, a stable nano-preparation can be made: when the drug is released in the body, the nano-drug can play the role it should play: fast dissolution and high absorption.
  • the preparation of celecoxib nano suspension adopts "grind first, then stabilize", that is, “step A + step B", which effectively solves several important problems of celecoxib nanogrinding:
  • the viscosity and foam of the grinding suspension can be controlled within the controllable range of the production operation; at the same time, the temperature of the grinding chamber is maintained in a reasonable range ( 25°C-40°C).
  • the celecoxib loading in the suspension can be increased to 20%-30% w/w. This greatly improves the grinding efficiency of Celecoxib; and the drug can reach the expected set nanometer range (ie D50 is less than 160nm, D90 is less than 300nm) in a relatively short time (such as 2-4 hours);
  • auxiliary materials such as sugars or polyols (such as lactose, mannitol or sucrose)
  • water that is, the drug-carrying curing process of mixing with other auxiliary materials under the action of hot air flow
  • Step C Dry and remove water and mix with other pharmaceutical excipients to prepare drug-loaded powder or drug-loaded pellets. Fluidized bed drying to remove water is the most commonly used water removal granulation process. The two ways are:
  • Preparation of drug-loaded granular powder it can be through the top spray process or the bottom spray process.
  • the principle is: spray the celecoxib nano-suspension onto the pharmaceutical excipients placed in the bottom of the fluidized bed pan (these pharmaceutical excipients placed at the bottom of the pan are also called “carriers").
  • the nano suspension and the carrier are continuously and vigorously mixed, flowed, dewatered and dried in the cavity of the fluidized bed by hot air flow. Finally, the nano particles adhere to the surface of these auxiliary materials to form dry drug-carrying particle powder.
  • Preparation of drug-loaded coated pellets usually a bottom spray process.
  • the principle is: spray the celecoxib nano suspension onto the medicinal pellet core placed in the bottom of the fluidized bed pot in advance.
  • the nano-suspension and the carrier are continuously mixed, flowed, dewatered, and dried in the cavity of the fluidized bed by hot air flow.
  • the nanoparticles adhere to the surface of the pellets to form drug-loaded coated pellets (referred to as "Drug-loaded pellets").
  • the stability of celecoxib nano-formulations and the fluidity of the particles are directly related to the following factors: the type and amount of pharmaceutical excipients, the ratio between the drug and these excipients, and the specific fluidized bed equipment (pot volume, nozzle diameter ), the operating technical parameters include: inlet air temperature, inlet air volume, material temperature, atomization pressure, spray speed, drying time, etc.
  • the pharmaceutical excipients (carriers) used include sugars, including but not limited to monosaccharides (such as glucose, fructose, galactose, ribose, deoxyribose), disaccharides (such as sucrose, maltose, lactose), or multiple Alcohols (such as mannitol, xylitol, sorbitol), etc.; based on the total weight of the drug-loaded particles prepared by the fluidized bed drying process, the content of the sugars is 30-70% w/w.
  • monosaccharides such as glucose, fructose, galactose, ribose, deoxyribose
  • disaccharides such as sucrose, maltose, lactose
  • Alcohols such as mannitol, xylitol, sorbitol
  • the pharmaceutical excipients (carriers) used can also be pellet cores, including but not limited to: sucrose pellets, microcrystalline cellulose pellets, starch pellets, tartaric acid pellets, lactose pellets, etc.; to be dried in a fluidized bed Based on the total weight of the drug-loaded particles prepared by the process, the content of the pellet core is 30-70% w/w.
  • step C can also use other production processes to dry and remove water and granulate, including: high-efficiency coating machine drying, vacuum drying, box drying, and spray coating drying.
  • Step D Preparation of celecoxib preparation: after fluidized bed drying and granulation, the drug-loaded powder or drug-loaded pellets of celecoxib usually have good fluidity and can be directly used to prepare capsules and tablets Or granules; it can also be combined with step C or after step C is completed, with appropriate pharmaceutical excipients, including: disintegrants, and/or binders, and/or glidants, and/or lubricants, etc. Mix well, and fill capsules, press tablets, or make granules according to different preparation requirements.
  • the surfactants used in the wet grinding of celecoxib (step A) and the subsequent preparation of stable nanosuspensions (step B) include nonionic surfactants and cationic surface Active agents, anionic surfactants, zwitterionic surfactants, including but not limited to: sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium stearyl sulfate, dioctyl succinate Sodium ester sulfonate (DOSS), sodium deoxycholate, monooleate, monolaurate, monopalmitate, monostearate or polyoxyethylene sorbitan, phospholipid, poloxamer 188, poise Loxamer 338, Poloxamer 407, cholic acid, sodium cholate, deoxycholic acid, sodium taurocholate, taurocholic acid, taurodeoxycholate, taurodeoxycholic acid, soy lecithin, Casein, phospholipid,
  • the surfactants required in the wet grinding of celecoxib (step A) and subsequent preparation of stable nanosuspensions (step B) include: sodium lauryl sulfate; Its total content in the suspension (ie step A + step B) is 4-8% w/w.
  • the hydrophilic polymers required for wet grinding (step A) and subsequent preparation of stable nanosuspensions (step B) include: polyvinylpyrrolidone (PVP), polyethylene Pyrrolidone/vinyl acetate (PVP/VA) copolymer (such as: PVP/VA 64, PVP/VA37), hydroxymethyl cellulose (HMC), hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), ethyl cellulose (EC), hydroxymethyl ethyl cellulose (HEMC), hydroxyethyl cellulose ethyl ether (EHEC) ) And carboxymethyl cellulose, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 20000; after completing steps A and B, hydrophilic polymerization The total content of celecoxib suspension is 0.
  • PVP
  • the hydrophilic polymers required for wet grinding of celecoxib (step A) and subsequent preparation of stable nanosuspensions (step B) include: polyvinylpyrrolidone;
  • the total content in the celecoxib suspension (ie step A + step B) is 0.5-3% w/w.
  • the carbohydrate excipients needed to prepare the celecoxib stable nanosuspension include: monosaccharides (such as glucose, fructose, galactose, ribose, deoxyribose), Or disaccharides (such as: sucrose, maltose, lactose), or polyols (such as: mannitol, xylitol, sorbitol) and other highly hydrophilic excipients; its dosage in the celecoxib suspension is 10- 60% w/w, preferably 10-40% w/w, more preferably 10-30% w/w.
  • monosaccharides such as glucose, fructose, galactose, ribose, deoxyribose
  • disaccharides such as: sucrose, maltose, lactose
  • polyols such as: mannitol, xylitol, sorbitol
  • its dosage in the celecoxib suspension is 10- 60%
  • the total content of sucrose required in step B of the preparation of celecoxib formulation (ie stable nanosuspension) in the celecoxib suspension is 10-30% w/w.
  • the pharmaceutical excipients used in fluidized bed drying and preparation of celecoxib drug-loaded granules (used as the bottom material of the fluidized bed, also called “carrier”) (step C), including One or several of the following and any combination of these auxiliary materials: fillers, binders, disintegrants, lubricants, glidants, antioxidants.
  • carrier used as the bottom material of the fluidized bed, also called “carrier”.
  • the total content of these excipients in the celecoxib preparation is 5%-80% w/w.
  • the fillers used for celecoxib in fluidized bed drying and granulation and subsequent mixing include, but are not limited to: monosaccharides (such as glucose, fructose, galactose, ribose, deoxyribose), disaccharides (Such as: sucrose, maltose, lactose), polyols (such as: mannitol, xylitol, sorbitol); starch, cellulose (microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl Methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose), silicified microcrystalline cellulose ("SMCC”), anhydrous calcium phosphate or calcium dihydrogen phosphate, calcium carbonate, calcium sulfate; pellet cores, such as : Sucrose pellets, microcrystalline cellulose pellets, starch pellets, tartaric acid pellets, lactose pellets, silicon dioxide pellets, hyprome
  • pellet cores include various specifications: 0.212-0.355mm; 0.3-0.5mm; 0.3-0.425mm; 0.425-0.5mm; 0.425-0.6mm; 0.5-0.6mm; 0.5-0.71mm; 0.6-0.71mm; 0.71 -0.85mm; 0.71-0.9mm; 0.8-0.9mm; 0.85-1.0mm; 0.9-1.12mm; 1.0-1.18mm.
  • the total content of fillers in celecoxib preparations is 20-80% w/w.
  • the binders used for celecoxib in fluidized bed drying and granulation and subsequent mixing include but are not limited to: gum arabic, gelatin, polymethacrylate, polyvinylpyrrolidone, starch, pre-gel Starch, tragacanth, xanthan gum, alginate, magnesium-aluminum silicate, bentonite, etc.
  • the disintegrants used for celecoxib in fluidized bed drying and granulation and subsequent mixing include, but are not limited to: starch, pregelatinized starch, hydroxypropyl starch, sodium starch glycolate, carboxymethyl starch Base cellulose sodium, croscarmellose sodium, cross-linked polyvinylpyrrolidone.
  • the lubricants and/or glidants used for celecoxib in the fluidized bed drying and granulation and subsequent mixing include, but are not limited to: magnesium stearate, calcium stearate, talc, poly Ethylene glycol, ethylene oxide polymer, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearate fumarate, stearic acid, silica, micronized silica gel, silica gel.
  • the antioxidants used for celecoxib in fluidized bed drying and granulation and subsequent mixing may include, but are not limited to: free radical absorbers (such as vitamin E, carotenoids), oxygen scavengers (Such as: carotenoids and their derivatives, ascorbic acid, ascorbyl palmitate, erythorbic acid, sodium erythorbate), metal ion chelating agents (such as: citric acid, EDTA and phosphoric acid derivatives), butylated hydroxyanisole ( BHA), dibutyl hydroxytoluene (BHT).
  • free radical absorbers such as vitamin E, carotenoids
  • oxygen scavengers such as: carotenoids and their derivatives, ascorbic acid, ascorbyl palmitate, erythorbic acid, sodium erythorbate
  • metal ion chelating agents such as: citric acid, EDTA and phosphoric acid derivatives
  • BHA butylated hydroxyanisole
  • BHT dibut
  • the celecoxib preparation contains sucrose; the total weight of its content in the oral preparation is 10%-80% w/w, preferably 20-70% w/w, more preferably 30-70% w/ w.
  • the celecoxib preparation contains a sucrose pellet core; its content in the preparation is 10%-80% w/w, preferably 20-70% w/w, more preferably 30-70% w/w .
  • the celecoxib preparation contains microcrystalline cellulose pellet core; its content in the preparation is 10%-80% w/w, preferably 20-70% w/w, more preferably 30-70% w/w.
  • the celecoxib formulation includes a moisture-proof film coating;
  • the film coating material is usually composed of various celluloses such as hydroxypropyl methyl cellulose, ethyl cellulose, and titanium dioxide, talc, etc. .
  • Commonly used moisture-proof film coatings include: Opadry II(" II"). Its content in oral solid preparations is 1-5% w/w.
  • the oral solid preparation of celecoxib may be one of the following preparations: capsules, tablets, and granules.
  • the celecoxib preparation is prepared, and its specification is 25 mg capsules; in one embodiment, the celecoxib preparation is prepared, and its specification is 40 mg capsules; in one embodiment, the celecoxib preparation is prepared , The specification is 50 mg capsules; in one embodiment, the celecoxib preparation is prepared, and the specification is 75 mg capsules; in one embodiment, the celecoxib preparation is prepared, and the specification is 80 mg capsules; in one embodiment , The celecoxib preparation was prepared, and its specification was 160 mg capsules; in one embodiment, the celecoxib preparation was prepared, and its specification was 320 mg capsules
  • a celecoxib preparation is prepared, and its specification is 25 mg tablets; in one embodiment, a celecoxib preparation is prepared, and its specification is 40 mg tablets; in one embodiment, celecoxib is prepared
  • the specification of the cloth preparation is 50 mg tablets; in one embodiment, the specification of celecoxib preparation is 80 mg tablets; in one embodiment, the specification of celecoxib preparation is 80 mg tablets; In one embodiment, the celecoxib formulation is prepared, and its specification is 160 mg tablets; in one embodiment, the celecoxib formulation is prepared, and its specification is 320 mg tablets.
  • the production and preparation of celecoxib suspension goes through the following steps (see Figure 3): Step A: prepare nano-suspension by wet grinding; this step is the same as step A in the above oral solid preparation Wet grinding, that is, adding the drug celecoxib, surfactant, and hydrophilic polymer to the whole water phase to make a suspension, and then start the high-speed rotation of the stirring rod in the grinding chamber to drive the grinding
  • the grinding medium in the cavity impacts, shears, and grinds the drug particles in the water phase, so that the particle size of the drug particles is reduced from the common micron range to the nanometer range (such as 100-300nm);
  • Step B Add sugars, etc. Excipients prepare stable nano-suspensions.
  • Step E On the basis of Step B, continue to add a certain amount of one or more of the following auxiliary materials, including: Suspending agents, antioxidants, taste masking agents, sweeteners, preservatives, defoamers, thickeners, pH buffer salts of the solution; preferably mixed by mechanical stirring.
  • the preparation Based on the total weight of the preparation, it contains 0.5-5% (w/v) of celecoxib, preferably 0.5-3% (w/v), more preferably 1-2% (w/v); contains dodecyl Sodium sulfate 0.1-2% (w/v), preferably 0.1-1.5% (w/v), more preferably 0.1-1% (w/v); containing polyvinylpyrrolidone 0.05-2% (w/v), preferably 0.05-1% (w/v), more preferably 0.05-0.5% (w/v); containing sucrose 0.5-30% (w/v), preferably 0.5-20% (w/v), more preferably 0.5-10 %(W/v).
  • the celecoxib oral preparation provided by the present invention can be used for the treatment of mild to moderate acute pain, mild to moderate chronic pain or for the preparation and treatment of mild to moderate acute pain, mild to moderate Medications for chronic pain.
  • the subject is a mammal (beagle).
  • the subject is a healthy person.
  • Table 1-1 lists part of the prescription screening for celecoxib wet grinding.
  • the high-speed wet grinding machine used in this invention includes: Mill ResearchLab, Multi-Lab; Grinding technical parameters and scope: Grinding chamber volume: 75-600ml; Rotating speed: 2600-4200rpm (revolution/min); Grinding time: 1-3 hours; Grinding beads: 0.3-0.5mm YTZ grinding Beads (ie, zirconia beads stabilized by yttria); suspension injection speed: 10 ⁇ 5ml/min.
  • Particle size detection Malvern2000 laser particle size detector is used to detect drug particle size distribution (D50, D90); Leica optical microscope is used to observe particle size dispersion.
  • the study in Table 1-1 shows that: suspension 6 and suspension 7 have a good particle size distribution. Note: The suspension here refers to the wet grinding prescription, not the suspension of the preparation.
  • Figures 2A-2B are the drug particle size distribution curves of a representative batch of celecoxib suspension before and after grinding.
  • Figure 2A shows the particle size distribution diagram of a representative batch of celecoxib bulk medicine used in the present invention: D50: 7.7 ⁇ m, D90: 104.7 ⁇ m.
  • Figure 2B shows the particle size distribution of the milling prescription "Suspension 10" after wet milling of Celecoxib: D50: 122 nm; D90: 250 nm. Note: D50 is d(0.5); D90 is d(0.9).
  • SLS sodium lauryl sulfate
  • HPMC hydroxypropyl methylcellulose
  • PVP polyvinylpyrrolidone
  • DOSS dioctyl sodium sulfosuccinate (also known as: docusate sodium)
  • Poloxamer Polox Sham, namely: (ethylene oxide)-poly(propylene oxide) block copolymer
  • the drug loading in the suspension is an important indicator of the efficiency of celecoxib nano preparation.
  • Nanosuspension 9 and suspension 10 in Table 1-2 are further studies of suspensions 6-7, that is, studies to increase the drug loading in the suspension, that is, to improve the efficiency of drug grinding.
  • Table 1-2 lists some of the results of the study, that is, increasing the celecoxib drug loading in the suspension from 10% w/w to 20% w/w: the particle size of the drug in the suspension 9 is greatly increased .
  • surfactant SLS sodium lauryl sulfate
  • HPMC hydrophilic polymer
  • Suspension 10 (see Table 1-2): The particle size of celecoxib remained stable after increasing the drug loading, indicating that SLS and PVP ("polyvinylpyrrolidone") are a good combination and can be optimized for further optimization. Suitable for mass production.
  • SLS and PVP K30 polyvinylpyrrolidone
  • the particle size is not stable enough: on the third day at room temperature, the particle size increases significantly. In mass production, this is an uncertain factor.
  • Suspension 11 uses a two-step preparation process, that is, a "grind first, then stabilize” process: after the wet grinding (step A), in the collected nanosuspension Continue to add surfactant (SLS, to 5.4% w/w) and hydrophilic polymer (polyvinylpyrrolidone, to 1.4% w/w) (ie: step B). This step can be carried out by mechanical stirring (non-wet grinding). From the subsequent stability studies of the suspension, the particle size of celecoxib can remain highly stable.
  • Suspension 12 in Table 1-2 is similar to Suspension 11, using a two-step preparation process, that is, in the collected nanosuspension 10, continue to add SLS 5% through mechanical stirring (non-wet grinding) w/w and PVP K30 1% w/w, and add sucrose 20% w/w at the same time (ie "Step B").
  • This makes the final concentration of SLS, PVP K30 and sucrose in the nanosuspension are: 5.4% and 1.4% and 20% w/w, respectively.
  • the research results show that the particle size stability of suspension 12 after adding sucrose is similar to that of suspension 11.
  • sucrose helps the nano-drug particles to quickly solidify on the excipients and maintain a stable nano-particle size (see Celecix Study on the dissolution stability of cloth preparations: Table 2-1, Table 3-1, Table 3-2).
  • Table 2-1 shows the prescription and technology of some celecoxib preparations (capsules). These are capsules used to prepare a 40 mg celecoxib preparation (loading amount 160 mg; No. 3 capsule). Recipe 1 and Recipe 2 are prepared by fluidized bed top spray to prepare drug-loaded particles; the equipment and process parameters of fluidized bed drying used: Germany Diosna Minilab-XP fluidized bed drying granulator; inlet air temperature: 65 ⁇ 5°C; material temperature: 45 ⁇ 5°C; air inlet: 25 ⁇ 5m 3 /h; sampling speed: 10 ⁇ 5ml/min.
  • Recipe 3 and Recipe 4 are prepared by spraying at the bottom of a fluidized bed to prepare drug-loaded pellets; the fluidized bed drying and granulation process is prepared by FLZB-0.5 fluidized bed produced by Changzhou Chuangzhi Electromechanical Technology Company; main technical parameters As follows: inlet air temperature: 60 ⁇ 5°C; material temperature: 40 ⁇ 5°C; inlet air volume: 15 ⁇ 5m 3 /h; sampling speed: 7 ⁇ 2ml/min.
  • SLS sodium lauryl sulfate
  • HPMC hydroxypropyl methylcellulose
  • PVP polyvinylpyrrolidone
  • CCS (croscamelose sodium): croscarmellose sodium
  • Step A Prepare a nano-suspension by wet grinding
  • Step B Add auxiliary materials such as sugars to prepare a stable nano-suspension, as well as a certain amount of surfactants and hydrophilic polymers; preferably, mix by mechanical stirring.
  • Step E Continue to add a certain amount of one or more of the following auxiliary materials, including: suspending agent, antioxidant, taste masking agent, sweetener, preservative, defoamer, thickener, solution pH Buffer salt; preferably mixing by mechanical stirring.
  • the production process of celecoxib preparation is shown in Figure 3.
  • Table 2-2 lists a representative prescription of celecoxib preparation (suspension); its specification: 16mg/ml, 60ml/bottle.
  • Table 3-1 and Table 3-2 list the accelerated stability study (40°C/75%RH) of some celecoxib preparations (capsules; see Table 2-1 for specific formulation composition and process). , 1, 2, and 3 months of change.
  • the dissolution conditions here are non-sink conditions, that is, the drug is not completely dissolved; it is mainly used to compare the effects of different nano formulations and preparation processes on the stability of the formulation (mainly dissolution stability).
  • both prescription 1 and prescription 3 use sucrose as an important excipient for preparing stable nanosuspension in "Step B", but prescription 2 and prescription 4 do not.
  • the stability of drug dissolution is directly related to whether the particle size of celecoxib is stable, that is, whether it produces aggregation and increases the particle size, resulting in a decrease in dissolution.
  • the stability of the dissolution of the drug is very important for the in vivo absorption of the nanoformulation.
  • Tables 3-1 and 3-2 show that the dissolution and stability of prescription 1 are significantly better than prescription 2; prescription 3 is better than prescription 4.
  • Sample collection and processing After the three preparations were administered separately, blood samples were collected at a series of sampling time points in the peripheral blood vessels of the beagle. The sampling time points are 10, 20, 30, 45 minutes, 1, 1.25, 1.5, 2, 3, 4, 6, 12, and 48 hours.
  • the blood sample at each sampling point contains approximately 0.5 ml of K 2 EDTA Anticoagulant.
  • After the blood sample is collected in the sampling test tube gently invert the test tube several times, centrifuge at 3000g for 10 minutes at 2-8°C, and place it on wet ice immediately after taking it out. Transfer 0.2ml of plasma to a pre-labeled vial and store it at -60°C or lower. When sending samples for analysis, transfer them with dry ice.
  • mice Observe the general health and appearance of the animals outside the cage twice a day (about 9:30 a.m. and 4:00 p.m.). The animals have undergone a health check before the start of the experimental study. On the day of administration, the experimental animals will be observed before and after each sampling point. The general condition, behavior, activity, excretion, breathing or other unusual places of the animal will be recorded in writing.
  • the concentration data of celecoxib in plasma will be analyzed using WinNonlin Version 6.2.1 (Pharsight, Mountain View, CA) software.
  • the plasma concentration peak (C max ) and the corresponding peak time (T max ) can be directly read on the plasma concentration versus time curve.
  • Pharmacokinetic parameters half-life (t 1/2 ), mean residence time 0 to infinity (MRT 0-inf ), mean residence time (MRT 0-last ), area under the blood concentration-time curve (AUC 0-inf ) And the area under the blood concentration time curve (AUC 0-last ) will be calculated by software. All pharmacokinetic parameters, such as C max , T max , AUC, t 1/2 and MRT values will retain 3 significant digits. The sampling points of the sample blood collected within the first hour after administration will be completed within ⁇ 1 minute, and the remaining sampling points will be collected within 5% of the scheduled time. Therefore, the theoretical sampling time is usually used for calculation, and the results of pharmacokinetic parameters will have certain deviations.
  • Table 4 shows the celecoxib preparation and the reference preparation celecoxib by a single oral administration
  • the average values of the main pharmacokinetic parameters obtained by Beagles such as C max , T max , AUC 0-last , AUC 0-inf , AUC Extrap (%), t 1/2 , MRT 0-last and MRT 0- inf .
  • the first group Celecoxib preparation (50mg/capsule/beagle)
  • the third group Celecoxib preparation (25mg/capsule/beagle)
  • Figure 5 shows the average blood drug concentration curve of the case of the present invention (enlarged curve: 0-12 hours), which consists of a single oral administration of celecoxib preparation (50mg/capsule/beagle), celecoxib Cloth preparation (25mg/capsule/beagle) and commercial preparation (100mg/capsule/beagle) obtained from male and female beagles.
  • C max the unit dose of drug absorption
  • C max the unit dose of drug absorption
  • celecoxib preparation 50mg/capsule
  • celecoxib preparation 25mg/capsule
  • AUC 0-inf and C max also increased 1.50 times and 1.24 times correspondingly, which is still increasing, although Not fully proportional.
  • the subjects were given a light diet the day before the test, and after an overnight fast (without water) for at least 10 hours According to the random schedule and the method of administration, the subjects were given the following study drugs on an empty stomach with 240 mL of warm water:
  • Test preparation 1 (T 1 ): Celecoxib preparation AP2500 capsule 50mg
  • Test preparation 2 (T 2 ): Celecoxib preparation AP2500 capsule 75mg
  • Test preparation 3 (T 3 ): Celecoxib preparation AP2500 capsule 100mg
  • the cleaning period is 1 week.
  • the subjects had a light diet on the day before the test, and fasted for 10 hours with water overnight. On the day of the test, they followed the random schedule. On an empty stomach, the subjects were given the following study drugs with 240 mL of warm water:
  • Test preparation 1 (T 1 ): Celecoxib preparation AP2500; 50 mg capsule
  • Test preparation 2 (T 2 ): Celecoxib preparation AP2500; 75 mg capsule
  • Test preparation 3 (T 3 ): Celecoxib preparation AP2500; 100 mg capsule
  • the medication cycle is shown in Table 6. Drinking water is forbidden from 1 hour before taking the medicine to 1 hour after taking the medicine, and you can drink freely at other times; fasting within 4 hours after taking the medicine, the subjects should be at the same specific time point in each test cycle (4 hours and 10 hours after administration) ) Use standard meals.
  • Subjects should avoid strenuous activities after taking the drug, and should not stay in bed for a long time. During the study period, the subjects' diet and work and rest time were arranged uniformly. It is forbidden to consume any food and beverages containing alcohol and xanthines: chocolate, tea, coffee and cola, etc., and smoking is prohibited, and it is prohibited to drink grapefruit (grapefruit) juice or products containing grapefruit. Subjects should abide by the test protocol and not use any drugs (including the wash period). Unless it is necessary to use medicine when treating sudden diseases, and should be informed in time.
  • Blood sample collection and processing groups A, B, C, and D were taken before (0 hours) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, respectively , 36, 48 hours to collect 4mL of venous blood (placed in EDTA anticoagulation tube), a total of 16 points; after blood sample collection, 3000 rpm / 10 minutes of separation of the heart, take the plasma and store below -70 °C for use.
  • Sample analysis test HPLC-MS/MS method to determine the drug concentration of celecoxib in plasma.
  • WINNONLIN program is used to calculate the main pharmacokinetic parameters and perform equivalent analysis.
  • the pharmacokinetic parameters are calculated based on the actual blood collection time.
  • the data in Table 6 shows that the PK parameters of AP2500 at a dose of 50mg-100mg are basically proportional to the dose, and there is a linear kinetic trend.
  • the area under the plasma concentration-time curve (AUC 0-t and AUC 0- ⁇ ) was 53.52% and 53.59%, and the peak plasma concentration was ( 77.07%).
  • Celecoxib preparation T 2 group AP2500 (75mg), the area under the blood concentration-time curve (AUC 0-t and AUC 0- ⁇ ) were 83.71% and 83.93%, and the peak blood concentration was 94.58%.
  • the present invention discloses a new celecoxib preparation prescription and preparation method for treating mild to moderate acute pain and chronic pain. Some specific embodiments are listed, which are intended to illustrate rather than limit the claims. After reading, those skilled in the art can easily implement and make some changes. The full scope covered by the present invention is defined by the claims.

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Abstract

一种低剂量塞来昔布口服制剂及其制备方法，其特征在于，所述制剂的规格为塞来昔布市售制剂规格的60-90％；且所述制剂与对应规格的塞来昔布市售制剂生物等效。该制剂可用于制备治疗轻度至中度的急性疼痛、轻度至中度的慢性疼痛的药物。

Description

低剂量塞来昔布制剂 技术领域
本发明涉及制剂领域；具体涉及一种低规格(低剂量)的、可用于治疗疼痛和炎症的塞来昔布口服制剂的制备及应用，包括塞来昔布纳米制备、处方稳定及工艺技术。
背景技术
塞来昔布(celecoxib)属非甾体类抗炎镇痛药(non-steroidal anti-inflammatory drugs,“NSAIDs”)，主要用于治疗骨关节炎、风湿性关节炎以及部分急性疼痛。塞来昔布的原研产品
Figure PCTCN2019093044-appb-000001
中文名“西乐葆”，系美国辉瑞(Pfizer)制药公司研制并在全球多个国家上市；其口服制剂系胶囊；规格：50mg、100mg、200mg、400mg。
塞来昔布虽然药效优良，但其有心脏疾病风险及胃肠道刺激等副作用。市售制剂产品携有美国药品和食品监督管理署(Food and Drug Administration，“FDA”)的安全性黑框警示(“black-box warning”)，即在满足治疗目标并“在可能情况下，降低使用剂量和降低使用时限”。
因此，塞来昔布在安全性方面存有较大的制剂优化空间。本领域迫切需要提供一种在降低药物使用剂量的同时，达到与市售制剂生物等效的新的塞来昔布制剂产品。
发明内容
本发明旨在提供一种降低药物使用剂量同时，可达到与市售制剂生物等效的新的塞来昔布制剂产品。
在本发明的第一方面，提供一种塞来昔布口服制剂，所述制剂的规格为塞来昔布市售制剂规格的60-90％；且所述制剂与对应规格的塞来昔布市售制剂生物等效。
在另一优选例中，所述制剂的剂型包括：片剂、胶囊剂、颗粒剂、和混悬剂。
在另一优选例中，所述制剂中塞来昔布的粒径D50不大于160nm，D90 不大于300nm。
在另一优选例中，所述制剂中塞来昔布的粒径保持在D50不大于160nm和D90不大于300nm为至少5天，更优选为至少7天，再优选为7-15天。
在另一优选例中，所述制剂为片剂、胶囊或颗粒剂时，以制剂的总重量计，含有十二烷基硫酸钠0.5-12％w/w，更优选为2-10％w/w，再优选为4-8％w/w。
在另一优选例中，所述制剂为片剂、胶囊或颗粒剂时，以制剂的总重量计，含有聚乙烯吡咯烷酮0.5-7％w/w，更优选为0.5-5％w/w，再优选为0.5-3％w/w。
在另一优选例中，所述制剂为片剂、胶囊或颗粒剂时，以制剂的总重量计，含有蔗糖10-70％w/w，更优选为10-50％w/w，再优选为10-30％w/w。
在另一优选例中，所述制剂为片剂、胶囊或颗粒剂时，所述制剂规格包括：40mg、80mg、160mg、320mg；其分别对应于塞来昔布市售制剂的规格为：50mg、100mg、200mg、400mg。
在另一优选例中，所述制剂为片剂、胶囊或颗粒剂时，所述制剂中的药用辅料还包括下述的一种或两种以上：填充剂、崩解剂、粘合剂、助流剂、润滑剂。
在另一优选例中，所述制剂为片剂、胶囊或颗粒剂、且规格是40-80mg时，使用美国药典溶出方法I，其在溶出介质为pH 1.0或pH 6.1时并在转速50rpm下测定的塞来昔布的溶出量在30分钟不低于30％和在60分钟不低于45％。
在另一优选例中，所述制剂为混悬剂时，以制剂的总重量计，含有塞来昔布0.5-5％(w/v)，更优选为0.5-3％(w/v)，再优选为1-2％(w/v)。
在另一优选例中，所述制剂为混悬剂时，以制剂的总重量计，含有十二烷基硫酸钠0.1-2％(w/v)，更优选为0.1-1.5％(w/v)，再优选为0.1-1％(w/v)。
在另一优选例中，所述制剂为混悬剂时，以制剂的总重量计，含有聚乙烯吡咯烷酮0.05-2％(w/v)，更优选为0.05-1％(w/v)，再优选为0.05-0.5％(w/v)。
在另一优选例中，所述制剂为混悬剂时，以制剂的总重量计，含有蔗糖0.5-30％(w/v)，更优选为0.5-20％(w/v)，再优选为0.5-10％(w/v)。
在本发明的第二方面，提供一种如上所述的本发明提供的塞来昔布口服制剂的制备方法，当所述制剂为片剂、胶囊剂或颗粒剂时，所述方法包括步骤：
步骤A：将塞来昔布经全水相湿法研磨制成纳米颗粒混悬液；其中使用十二烷基硫酸钠为表面活性剂，使用聚乙烯吡咯烷酮为亲水性聚合物；
步骤B：在步骤A得到的纳米颗粒混悬液中加入糖类，并继续加入十二烷基硫酸钠和聚乙烯吡咯烷酮进行混合得到纳米混悬液；所述糖类为单糖、双糖、和多元醇中的一种或两种以上；优选为乳糖、蔗糖、果糖、甘露醇、和山梨醇中的一种或两种以上；优选通过搅拌进行混合；
步骤C：将步骤B得到的纳米混悬液经流化床喷雾干燥得到载药颗粒或载药微丸；和
步骤D：将载药颗粒或载药微丸制成口服固体制剂包括片剂、胶囊剂、颗粒剂。
在另一优选例中，步骤A所述的湿法研磨中，以获得的纳米颗粒混悬液的总重量计，其中含有超过10％w/w的塞来昔布，更优选为10-35％w/w，再优选为15-25％w/w。
在另一优选例中，以步骤B所获得的纳米混悬液的总重量计：十二烷基硫酸钠的用量0.5-12％w/w，更优选为2-10％w/w，再优选为4-8％w/w；聚乙烯吡咯烷酮的用量为0.5-7％w/w，更优选为0.5-5％w/w，再优选为0.5-3％w/w；糖类的用量为10-70％w/w，更优选为10-50％w/w，再优选为10-30％w/w。
在另一优选例中，用于步骤C的载体包括填充剂；所述填充剂包括糖类和100-1000μm的微丸丸芯；所述糖类为单糖、双糖、和多元醇中的一种或两种以上；所述微丸丸芯选自蔗糖丸芯、微晶纤维素丸芯、淀粉丸芯、酒石酸丸芯、乳糖丸芯、二氧化硅丸芯、羟丙甲纤维素丸芯、柠檬酸丸芯、或酒石酸丸芯。
在另一优选例中，所述载体还包括崩解剂、粘合剂、助流剂、润滑剂、和抗氧剂中的一种或两种以上。
当所述制剂为混悬剂时，所述方法包括步骤A、步骤B和步骤E：
步骤A：将塞来昔布经全水相湿法研磨制成纳米颗粒混悬液；其中使用十二烷基硫酸钠为表面活性剂，使用聚乙烯吡咯烷酮为亲水性聚合物；
步骤B：在步骤A得到的纳米颗粒混悬液中加入糖类，并继续加入十二烷基硫酸钠和聚乙烯吡咯烷酮进行混合得到纳米混悬液；所述糖类为单糖、双糖、和多元醇中的一种或两种以上；优选为乳糖、蔗糖、果糖、甘露醇、和山梨醇中的一种或两种以上；优选通过搅拌进行混合；和
步骤E:在步骤B得到的纳米混悬液中加入一种或两种以上下述辅料：助悬剂、抗氧剂、掩味剂、增甜剂、防腐剂、消泡剂、增稠剂、香精、pH缓冲盐；优选通过搅拌进行混合。
在本发明的第三方面，提供一种如上所述的本发明提供的塞来昔布口服制剂的用途，用于治疗轻度至中度的急性疼痛、轻度至中度的慢性疼痛或用于制备治疗轻度至中度的急性疼痛、轻度至中度的慢性疼痛的药物。
附图说明
本发明将进一步附图解释。所示附图不完全按比例绘制，其重点在于阐述本发明的核心要点。此外，附图可能放大一些局部特征，以突出本发明的特殊部分。
图1显示塞来昔布的化学结构。
图2A显示本发明的塞来昔布(湿法研磨前)粒径大小分布曲线；图2B则显示经湿法研磨后本发明塞来昔布混悬液中塞来昔布粒径大小分布曲线。
图3显示塞来昔布制剂的工艺，包括口服固体制剂如片剂、胶囊剂和颗粒，口服液体制剂如混悬剂。图4显示本发明一个实施例中，雄性和雌性比格犬单次给药后，零时刻至12小时的平均血药浓度曲线，包括塞来昔布制剂(50mg/胶囊)，塞来昔布制剂(25mg/胶囊)，和塞来昔布市售制剂西乐葆(100mg/胶囊)。
图5A图5B显示本发明同一个实施例的健康人给药后的平均药-时曲线。实验中，12名健康志愿者在空腹条件下按4个时序(A、B、C、D)试验分别给药；其中：A组:塞来昔布制剂AP2500,50mg/胶囊；B组:塞来昔布市售制剂西乐葆
Figure PCTCN2019093044-appb-000002
100mg/胶囊；C组:塞来昔布制剂AP2500,75mg/胶囊；D组:塞来昔布制剂AP2500,100mg/胶囊。图5A显示塞来昔布的平均血药浓度-时间曲线0-48小时；图5B显示塞来昔布的平均血药浓度-时间曲线0-12小时。
附图为本发明的一部分，包含本发明的一些实例，以更直观的方式阐释本发明的独创性。附图可能并未按照比例绘制，为方便理解，会放大一些部位，以突出其特殊性。另外，附图中所示的任何测量、说明等，均为示范性的，而非限制性的。因此，本发明公开的具体处方、工艺等细节不应被解读为限制范围，而仅仅是作为代表性示例，教导本领域技术人员以多种方式实施本发明。
具体实施方式
除前面已经披露的那些优点和改进外，结合附图的描述，本发明的其它优点也是明显的。在此，本文公开本发明的详细实施方案；然而，应当理解以各种形式呈现的实例仅仅为解释本发明。各种实例只是说明性的，而非限制性的。
除上下文另有说明外，在整个说明书和权利要求书中，所用术语采用以下定义。本发明中所使用的短语“在一个实例中”和“在一些实例中”可以指代相同的实例，也可以指代不同的实例。此外，如本发明所使用的短语“在另一实例中”和“在一些其它实例中”可以指代不同的实例，但也可以指代相同的实例。因此，如下所述，在不脱离本发明的范围或本意的情况下，可以容易地组合本发明的各种实例。
此外，除上下文另有说明外，本发明所使用的术语“或”是包括性的，并且等同于术语“和/或”。
术语解释
本发明所用的术语“AUC”(area under the curve)或“曲线下面积”，是指给药后血药浓度对时间曲线下面积或药-时曲线的积分，反映药物在人体中被吸收的程度。
本发明所用的术语“C max”(peak concentration)，是指给药后血浆中药物成分浓度峰值。
本发明所用的术语“T max”(time to peak concentration)，是指给药后血浆中药物达到最高浓度时的时间。
本发明所用的术语“生物利用度”，是指药物成分在生物系统中被利用的部分。
本文所用的术语“塞来昔布”是指化学品：4-[5-(4-甲基苯基)-3-(三氟甲基)-1氢-吡唑-1-基]苯磺酰胺，化学结构如图1所示。塞来昔布的分子量为381.4，是白色结晶性粉末，熔点为157-158℃。塞来昔布是选择性环氧化酶-2(“COX-2”)抑制剂，用于治疗骨关节炎(OA)、类风湿性关节炎(RA)、部分急性疼痛、月经疼痛等。
本发明所用的术语“参比制剂”是指西乐葆(英文名：
Figure PCTCN2019093044-appb-000003
)胶囊；其规格分别为：50mg、100mg、200mg或400mg。
本发明所用的术语“塞来昔布制剂”或“塞来昔布处方”或“塞来昔布口服制剂”或“低规格塞来昔布制剂”或“降剂量塞来昔布制剂”或“AP2500”，均是指本发明研发的制剂。塞来昔布制剂包括口服液体制剂(如：混悬剂)、口服固体制剂(如：胶囊剂、片剂、颗粒剂等)。AP2500特指塞来昔布的一种口服胶囊剂。
本发明中所用的“市售制剂”或“塞来昔布市售制剂”均是指西乐葆
Figure PCTCN2019093044-appb-000004
或与西乐葆同等规格并生物等效的仿制药产品，规格分别为：50mg、100mg、200mg或400mg；剂型是胶囊或片剂。
本发明所使用的术语“生物等效”是指：与市售制剂相比，本发明研发的降剂量的塞来昔布制剂在人体内的C max在同等水平(即在90％的置信区间，C max的几何平均值比率在80％-125％范围)、或AUC在同等水平(即在90％的置信区间，AUC的几何平均值比率在80％-125％范围)、或塞来昔布制剂在体内的C max和AUC均在同等水平(即在90％的置信区间，C max和AUC的几何平均值比率均在80％-125％范围)。
本发明所使用的“置信区间”是指由样本统计量所构造的总体参数的估计区间。在统计学中，一个概率样本的置信区间(confidence interval，“CV”)是对这个样本的某个总体参数的区间估计。置信区间展现的是这个参数的真实值有一定概率落在测量结果的周围的程度。置信区间给出的是被测量参数的测量值的可信程度，即前面所要求的"一个概率"。
本发明所使用的术语“溶出”是指药物从剂型例如胶囊或片剂中释放的过程。“溶出度”或“溶出率”是指药物的片剂等固体制剂在规定溶剂中溶出的速度和程度。
本发明所用“剂量”(dose)系指一次给药后产生药物治疗作用的量。本发明所用术语“有效剂量”(effective dose)，是指药物通过具体给药途径在 体内产生治疗效果的剂量。
本发明所使用的术语“规格”，是指某种剂型，如：一粒胶囊，一片片剂或单位体积悬浮剂中含有的药物总量。
本发明所使用的术语“非甾体类抗炎镇痛药物”或“NSAIDs”(non-steroidal anti-inflammatory drugs)，是指一类不含糖皮质激素而具有抗炎、解热、镇痛作用的药物。这类药物的化学结构中缺乏糖皮质激素所具有的甾环，而又具有解热、镇痛、抗炎等功效，因此被称为非甾体类抗炎药。非甾体类抗炎药是也是药物治疗骨关节炎的一线药物，同时也广泛地运用于其它骨关节疾病、风湿免疫性疾病和疼痛性疾病，以减轻上述疾病的疼痛、僵硬，改善骨关节功能。塞来昔布是NSAIDs药物的一种，可供病患者口服给药，也可用于急性镇痛。
本发明所使用的术语“急性疼痛”是指快速发作，可以是严重的、但持续相对较短的时间段的疼痛。本发明中，“轻度至中度急性疼痛”是指以数值“0”至“10”表示疼痛的不同程度时，测量他/她的疼痛小于数值“7”时的疼痛。轻度至中度急性疼痛可包括背部和颈部疼痛，偏头痛，手术后疼痛等。本文中，“慢性疼痛”是相对于“急性疼痛”而使用的术语，其持续时间超过6个月。慢性疼痛可以是轻微的或难以忍受的疼痛，间歇性的或连续的疼痛，可以是稍不便的或完全丧失能力的疼痛。最常见的疼痛来源是：风湿性关节炎疼痛，骨关节炎疼痛，损伤引起的疼痛，头痛、背痛等。其它类型的慢性疼痛包括肌腱炎，窦性疼痛，腕管综合征和身体特定部位的诱发性疼痛，例如肩痛，骨盆痛和颈痛。一般的肌肉或神经疼痛也可发展成慢性疼痛疾病。
本发明所使用的术语“受试者”或“个体”或“患者”可互换使用，是指哺乳动物(包括人)。
本发明所使用的术语
Figure PCTCN2019093044-appb-000005
是指先前曾用于其它实验的动物，例如药代动力学研究。本发明中，“非房室模型”是药代动力学研究分析中常用的一种计算方法。
本发明所使用的术语“粒径”用于描述药物纳米颗粒的重要生物物理性能即颗粒的大小。粒径的大小及稳定性直接影响到以纳米颗粒为基础的药物产品在人体的吸收、分布、药效和安全等性能。粒径分布，例如：D50和D90，也称d(0.5)和d(0.9)，可通过激光粒度仪测量。D50是指颗粒累计粒度分布百分数达到50％时所对应的粒度值，通常以D50数据代替平均粒径。类似地， D90是指颗粒累计粒度分布百分数达到90％时所对应的粒度值。
本发明中，“稳定性”是指在限定的储存条件下制剂的物理和化学稳定性。本发明中所指40℃/75％RH的储存条件是常用的稳定性研究实验条件，旨在评价加速储藏条件下塞来昔布制剂的物理和化学稳定性。储藏条件通常带有“时间段”(例如2周、1个月、3个月)，指制剂样品在特定储存条件下经历的实际时间。
本发明所使用的术语“药用辅料”或辅料都是指用于制剂的赋形剂和附加剂；是除活性成分以外，在安全性方面已进行了合理的评估、且包含在药物制剂中的物质。药用辅料有不同种类，根据制剂的不同有不同功能，如用于口服固体制剂，有：赋形、填充、粘合、崩解、助溶、助流、抗氧化等；如用于口服混悬剂，有：助悬、抗氧化、掩味、增甜、防腐、消泡、增稠、溶液pH缓冲盐等。药用辅料是药物制剂的重要组成部分；其选择和使用直接影响药品的安全性、有效性和产品稳定性。
本发明所使用的术语“湿法研磨”系指一种制备药物纳米混悬液的工艺方法：在研磨设备的研磨腔中，放置研磨介质(“研磨珠”)、含药物、表面活性剂、亲水性聚合物及其它药用辅料的混悬液；随后启动研磨腔中的搅拌棒高速转动，并以此带动研磨介质对水相中的药物颗粒进行撞击、剪切、研磨，使药物颗粒的粒径从常见的微米范围降至纳米范围(通常在20-1000纳米范围)。
本发明所使用的术语“载体”特指用于流化床干燥中置于底部的药用辅料。
低规格(即低剂量)的塞来昔布口服制剂
本发明提供一种低规格的(即低剂量的)、可用于治疗疼痛和炎症的塞来昔布口服制剂，以达到更安全使用的目的。
在一些实例中，本发明是一种塞来昔布制剂如胶囊剂、片剂、颗粒剂或混悬液；在健康人空腹的药代动力学研究中，其同塞来昔布市售制剂西乐葆
Figure PCTCN2019093044-appb-000006
相比，其在人体中的血浓峰值C max能达到生物等效，即在90％的置信区间，C max的几何平均值比率为80％-125％；或其在人体中的吸收AUC能达到生物等效，即在90％的置信区间，AUC的几何平均值比率为80％-125％； 或其在人体中的血浓峰值C max和AUC均达到生物等效，即在90％的置信区间，C max和AUC的几何平均值比率均为80％-125％；但本发明的塞来昔布制剂的剂量较之同规格市售制剂西乐葆则降低10-40％w/w。
塞来昔布市售制剂西乐葆
Figure PCTCN2019093044-appb-000007
或其仿制药的规格分别是：50mg、100mg、200mg、400mg。对应于上述四个规格，本发明的塞来昔布口服固体制剂如片剂、胶囊剂或颗粒剂，其规格降低10-40％，即制剂中塞来昔布的含量降低10-40％；如对等于市售制剂的50mg，可以是：30mg，30.5mg，31mg，31.5mg，32mg，32.5mg，33mg，33.5mg，34mg，34.5mg，35mg,35.5mg,36mg,36.5mg,37mg,37.5mg,38mg，38.5mg，39mg，39.5mg，40mg,40.5mg,41mg,41.5mg,42mg,42.5mg,43mg,43.5mg,44mg,44.5mg,45mg；如对等于市售制剂的100mg，可以是：60mg，61mg，62mg，63mg，64mg，65mg，66mg，67mg，68mg，69mg，70mg,71mg,72mg,73mg,74mg,75mg,76mg，77mg，78mg，79mg，80mg，81mg，82mg，83mg，84mg，85mg,86mg,87mg,88mg,89mg,90mg；如对等于市售制剂的200mg，可以是：120mg，122mg，124mg，126mg，128mg，130mg，132mg，134mg，136mg，138mg，140mg,142mg,144mg,146mg,148mg,150mg,152mg，154mg，156mg，158mg，160mg,162mg，164mg，166mg，168mg，170mg,172mg,174mg,176mg,178mg,180mg；如对等于市售制剂的400mg，可以是：240mg，244mg，248mg，252mg，256mg，260mg，264mg，268mg，272mg，276mg，280mg,284mg,288mg,292mg,296mg,300mg,304mg，308mg，312mg，316mg，320mg，324mg，328mg，332mg，336mg，340mg,344mg,348mg,352mg,356mg,360mg。
在一些实施例中，本发明所述的塞来昔布口服固体制剂，当其所含塞来昔布规格降低20％时，分别是：40mg，80mg，160mg，320mg；并分别对应于市售制剂规格：50mg，100mg，200mg，400mg。
在一些实施例中，塞来昔布口服固体制剂可以是下述中的任何一种：片剂、胶囊剂、颗粒剂、口崩片、舌下片。
在一些实施例中，塞来昔布制剂是口服混悬剂。
在一些实施例中，塞来昔布制剂的规格为分别为40mg和80mg的胶囊，在使用美国药典溶出方法I(USP Apparatus I，篮法，转速50rpm)时，其在溶出介质为pH 1.0时，塞来昔布溶出量在30分钟均不低于30％和在60分钟均不低于45％。
在一些实施例中，塞来昔布制剂的规格分别为40mg和80mg的胶囊，在使用美国药典溶出方法I(USP Apparatus I，篮法，转速50rpm)时，其在溶出介质为pH 6.1时，塞来昔布溶出量在30分钟均不低于30％和在60分钟均不低于45％。
制备塞来昔布口服制剂
在一些实施例中，本发明的塞来昔布口服固体制剂的制备主要经过下述四个步骤(见图3)：
步骤A：湿法研磨制备纳米混悬液
步骤B：添加糖类等辅料制备稳定的纳米混悬液
步骤C：流化床干燥除水制备载药颗粒
步骤D：制成塞来昔布固体制剂
本发明的塞来昔布纳米制备采用了两步制备工艺，即“步骤A+步骤B”，或称其为“先研磨、后稳定”。
步骤A：通过湿法研磨工艺制备纳米混悬液，即在水相中，加入药物塞来昔布、表面活性剂、亲水性聚合物并制成混悬液，随后启动研磨腔中的搅拌棒高速转动(2600-4500rpm)，并以此带动研磨腔内的研磨介质(“研磨珠”)在水相中对药物颗粒进行撞击、剪切、研磨，使药物颗粒的粒径从常见的微米范围(如：20-200μm)降至纳米范围(如：20-400nm)。
湿法研磨工艺对表面活性剂和亲水性聚合物的选择、组合、含量有较高的要求，是在工艺上保障塞来昔布药物颗粒的粒径能被研磨至纳米范围的关键。在研磨过程中，药物颗粒的粒径逐渐变小，但药物颗粒的表面积却迅速增大。研磨腔的大小取决于所需生产制备的规模。研磨腔的腔室容积通常为0.2升、0.5升、1升、2升、5升、10升；研磨腔可以外接2-20倍于研磨腔内混悬液的容器，用于从实验室、中试到规模生产的需要。研磨珠通过动态间隙分离器保持在研磨腔中。研磨珠通常由直径为0.1-0.5mm的经氧化钇稳定的氧化锆(YTZ)珠、或有高度交联度的聚苯乙烯球形树脂珠等组成。研磨温度通常被恒温控制在20-45℃的范围内。在本发明中，用于研磨的混悬液为全水相，不含有机溶媒。本发明也不使用任何高压均质技术。
每个药物都有其特定的晶型结构。塞来昔布也不例外。塞来昔布的研磨工艺需要评估多方面因素,以优化研磨液配方和研磨工艺参数，获得具稳定粒径及其它良好物理化学性能的塞来昔布纳米混悬液。研磨工艺的关键参数包 括：药物浓度、辅料的种类及浓度、研磨珠用量、研磨珠直径、研磨速度、研磨时间、物料温度以及蠕动泵流速等。
步骤B：在收集起的上述经湿法研磨制备的纳米混悬液中(完成步骤A)，添加辅料以制备稳定的纳米混悬液，并辅助以适当的机械搅拌。添加的辅料包括：一定量的单糖、或双糖、或多元醇等高亲水性辅料；同时继续添加一定量的表面活性剂和亲水性聚合物。
湿法研磨，即步骤A中所描述的，是在表面活性剂和亲水性聚合物存在的水相中，在研磨腔中转动研磨棒带动研磨珠，通过高速撞击、剪切、研磨等过程，将药物颗粒从微米范围降至纳米范围；并在此之后，通过流化床干燥或其它干燥除水的工艺、并与其它药用辅料混合等步骤，制备药物的纳米固体制剂。经湿法研磨制备纳米药物应达到下列要求：
1)药物粒径降至纳米范围，如:D50小于200nm；D90小于400nm；或更好：D50小于150nm，D90小于300nm；
2)研磨时，药物在混悬液中有较高的载药量，因此有较高的研磨效率；通常载药量应该高于5％、高于10％；对于规格较高的药物(如：50mg以上)，研磨液中的载药量应在15-25％w/w；
3)纳米混悬液应该足够稳定，以保障生产工艺的可操作性。在规模生产中，湿法研磨工艺和后续的制剂制备工艺通常有时间差–最低要求能稳定48-72小时，最好能稳定7天，即药物的化学和物理性能稳定，尤其是药物的纳米粒径无显著变化(粒径变化小于10％,或最优小于5％)；
4)纳米混悬液在除水并固化成颗粒或粉末的过程中和在固化后，药物的粒径应该维持稳定，即在所需要的纳米范围内(20-400nm)。这是最重要的；也就是说，在制备纳米固体制剂如片剂、胶囊剂或颗粒剂的生产过程中，当纳米混悬液的水分被除去后，药物颗粒能固化在辅料(在流化床干燥中，又称“载体”)上，并保持稳定的纳米粒径状态。因为只有这样，才能制成稳定的纳米制剂：药物在体内释放时,纳米药物能够起到它应该起到的作用：快溶解、高吸收。
本发明中对塞来昔布的纳米混悬液的制备采用了“先研磨、后稳定”，即“步骤A+步骤B”，有效地解决了塞来昔布纳米研磨的几个重要问题：
1)增加了研磨混悬液中的塞来昔布载量(从10％w/w提高至20％-25％w/w)。这对塞来昔布研磨制备的规模生产(或商业生产)至关重要。之前，塞来昔布在研磨混悬液中，如果载药量高于10％w/w，表面活性剂导致的泡 沫递增较快，混悬液粘度递增也较快，研磨腔的温度随之升高(至50℃-65℃)。这使得研磨制备十分困难甚至无法完成。但如果在研磨时，能使用表面活性剂的一部分和亲水性聚合物的一部分，则研磨混悬液粘度和泡沫均能在生产操作可控的范围；同时，研磨腔温度维持在合理范围(25℃-40℃)。如此，混悬液中的塞来昔布载量可随之增到20％-30％w/w。这极大地提高了塞来昔布的研磨效率；而且药物能在较短时间内(如：2-4个小时)，达到预期设定的纳米范围(即D50小于160nm，D90小于300nm)；
2)有效控制了塞来昔布粒径在纳米范围的稳定。在塞来昔布完成湿法研磨即药物粒径达到预设要求后，取出混悬液，加入糖类辅料并同时继续加入一定量的表面活性剂和一定量的亲水性聚合物；该过程辅以普通的机械搅拌。这些辅料的加入及时有效地稳定了塞来昔布在混悬液中的稳定性。尤其是糖类或多元醇等的辅料(如乳糖、甘露醇或蔗糖)的应用，能在随后的流化床干燥除水(即在热气流作用下与其它辅料混合的载药固化过程)中，使塞来昔布颗粒的粒径始终保持在纳米范围。这在后续的制剂溶出和稳定性研究中得到佐证。
步骤C：干燥除水并与其它药用辅料混合，制成载药粉末或载药微丸。流化床干燥除水是最常用的除水制粒工艺。两个途径分别是：
1)制备载药颗粒粉末：可以通过顶喷工艺或底喷工艺。其原理是：将塞来昔布纳米混悬液喷洒到事先放置在流化床锅体底部的药用辅料(置于锅底的这些药用辅料又称“载体”)。纳米混悬液和载体在流化床的腔体内经热气流作用，不断地剧烈混合、流动、除水、干燥，最后纳米颗粒附着在这些辅料表面形成干燥的载药颗粒粉末。
2)制备载药包衣微丸：通常采用底喷工艺。其原理是：将塞来昔布纳米混悬液喷洒到事先放置在流化床锅体底部的药用微丸丸芯上。同样，纳米混悬液和载体在流化床的腔体里经热气流作用，不断地剧烈混合、流动、除水、干燥，最后纳米颗粒附着在微丸表面形成载药包衣微丸(简称“载药微丸”)。
塞来昔布的纳米制剂的稳定性以及颗粒的流动性与下述因素直接相关：药用辅料的种类及用量，药物与这些辅料之间的比例，具体流化床设备(锅体积、喷嘴直径)，操作技术参数包括：进风温度、进风量、物料温度、雾化压力、喷液速度、干燥时间等。
在流化床干燥制备载药颗粒或载药微丸的工艺中，需要对用于喷雾的纳米混悬液添加合适的辅料，也需要对所使用的药用辅料或药用微丸丸芯进行 筛选优化。这些工作不仅有助于纳米药物颗粒固化后药物粒径的稳定，也有助于制备有良好流动性的载药颗粒粉末或载药微丸，以用于随后的制剂如胶囊或片剂或颗粒剂等的生产。使用的药用辅料(载体)中包含糖类，包括但不限于，单糖(如：葡萄糖、果糖、半乳糖、核糖、脱氧核糖)、双糖(如：蔗糖、麦芽糖、乳糖)、或多元醇(如：甘露醇、木糖醇、山梨醇)等；以经流化床干燥工艺制得的载药颗粒的总重量计，所述糖类的含量为30-70％w/w。使用的药用辅料(载体)也可以是微丸丸芯，包括但不限于：蔗糖丸芯、微晶纤维素丸芯、淀粉丸芯、酒石酸丸芯、乳糖丸芯等；以经流化床干燥工艺制得的载药颗粒的总重量计，所述微丸丸芯的含量为30-70％w/w。
除流化床干燥工艺外，步骤C也可以采用其它生产工艺来干燥除水制粒，包括：高效包衣机干燥、真空干燥、箱式干燥、喷雾包衣干燥。
步骤D：制备塞来昔布制剂：在完成流化床干燥制粒后，塞来昔布的载药粉末或载药微丸通常有较好的流动性，可以直接用来制备胶囊、片剂或颗粒剂；也可以结合步骤C或在完成步骤C后，与适当的药用辅料，包括：崩解剂、和/或粘合剂、和/或助流剂、和/或润滑剂等的充分混合，并按照不同制剂要求，填充胶囊、压片、或制成颗粒剂。
在一些实施例中，在塞来昔布湿法研磨(步骤A)及随后的制备稳定纳米混悬液(步骤B)中所需用到的表面活性剂，有非离子表面活性剂、阳离子表面活性剂、阴离子表面活性剂、两性离子表面活性剂，包括但不限于：十二烷基硫酸钠，硬脂基硫酸钠，十六烷基硫酸钠，十八烷基硫酸钠，琥珀酸二辛酯磺酸钠(DOSS)，脱氧胆酸钠，单油酸酯，单月桂酸酯，单棕榈酸酯，单硬脂酸酯或聚氧乙烯脱水山梨醇，磷脂，泊洛沙姆188，泊洛沙姆338，泊洛沙姆407，胆酸，胆酸钠，脱氧胆酸，牛磺胆酸钠，牛磺胆酸，牛磺脱氧胆酸盐，牛磺脱氧胆酸，大豆卵磷脂，酪蛋白，磷脂，泊洛沙姆，泊洛沙胺，聚山梨酯20，聚山梨酯40，聚山梨酯60，聚山梨酯80。在完成步骤A和B后，表面活性剂在混悬液中的总含量为0.5％-12％w/w，优选2-10％w/w，更优选4-8％w/w。
在一些实施例中，在塞来昔布湿法研磨(步骤A)及随后的制备稳定纳米混悬液(步骤B)中所需用到的表面活性剂，包括：十二烷基硫酸钠；其在混悬液中的总含量(即步骤A+步骤B)为4-8％w/w。
在一些实施例中，在湿法研磨(步骤A)及随后的制备稳定纳米混悬液(步骤B)中所需用到的亲水性聚合物，包括：聚乙烯吡咯烷酮(PVP)，聚乙烯吡咯烷酮/乙酸乙烯酯(PVP/VA)共聚物(如：PVP/VA 64、PVP/VA37)，羟甲基纤维素(HMC)，羟乙基纤维素(HEC)，羟丙基甲基纤维素(HPMC)，羟丙基纤维素(HPC)，甲基纤维素(MC)，乙基纤维素(EC)，羟甲基乙基纤维素(HEMC)，羟乙基纤维素乙基醚(EHEC)和羧甲基纤维素，聚乙二醇4000，聚乙二醇6000，聚乙二醇8000，聚乙二醇10000，聚乙二醇20000；在完成步骤A和B后，亲水性聚合物在塞来昔布混悬液中的总含量为0.5％-7％w/w，优选0.5-5％w/w，更优选0.5-3％w/w
在一些实施例中，在塞来昔布湿法研磨(步骤A)和在随后制备稳定纳米混悬液(步骤B)中所需用到的亲水性聚合物，包括：聚乙烯吡咯烷酮；其在塞来昔布混悬液中的总含量(即步骤A+步骤B)为0.5-3％w/w。
在一些实施例中，在制备塞来昔布稳定纳米混悬液(步骤B)中所需用到的糖类辅料包括：单糖(如：葡萄糖、果糖、半乳糖、核糖、脱氧核糖)、或双糖(如：蔗糖、麦芽糖、乳糖)、或多元醇(如：甘露醇、木糖醇、山梨醇)等高亲水性辅料；其在塞来昔布混悬液中的用量10-60％w/w，优选10-40％w/w，更优选10-30％w/w。
在一些实施例中，在塞来昔布制剂制备的步骤B(即稳定纳米混悬液)中所需用到的蔗糖，其在塞来昔布混悬液中的总含量为10-30％w/w。
在一些实施例中，在流化床干燥并制备塞来昔布载药颗粒中使用的药用辅料(用作流化床的锅底底料，又称“载体”)(步骤C)，包括下述的一种或数种以及这些辅料的任意组合：填充剂、粘合剂、崩解剂、润滑剂、助流剂、抗氧化剂。这些辅料在塞来昔布制剂中的总含量为5％-80％w/w。
在一些实施例中，用于塞来昔布在流化床干燥制粒以及随后混合的填充剂包括但不限于：单糖(如：葡萄糖、果糖、半乳糖、核糖、脱氧核糖)、双糖(如：蔗糖、麦芽糖、乳糖)、多元醇(如：甘露醇、木糖醇、山梨醇)；淀粉、纤维素(微晶纤维素、甲基纤维素、羧甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素)、硅化微晶纤维素(“SMCC”)、无水磷酸钙或磷酸二氢钙、碳酸钙、硫酸钙；微丸丸芯，如：蔗糖丸芯、微晶 纤维素丸芯、淀粉丸芯、酒石酸丸芯、乳糖丸芯、二氧化硅丸芯、羟丙甲纤维素丸芯、柠檬酸丸芯、酒石酸丸芯。上述微丸丸芯包括多种规格：0.212-0.355mm；0.3-0.5mm；0.3-0.425mm；0.425-0.5mm；0.425-0.6mm；0.5-0.6mm；0.5-0.71mm；0.6-0.71mm；0.71-0.85mm；0.71-0.9mm；0.8-0.9mm；0.85-1.0mm；0.9-1.12mm；1.0-1.18mm。填充剂在塞来昔布制剂中的总含量在20-80％w/w。
在一些实施例中，用于塞来昔布在流化床干燥制粒以及随后混合的粘合剂包括但不限于：阿拉伯胶、明胶、聚甲基丙烯酸酯，聚乙烯吡咯烷酮、淀粉、预胶化淀粉、黄蓍胶、黄原胶、藻酸盐、镁-铝硅酸盐、皂土等。
在一些实施例中，用于塞来昔布在流化床干燥制粒以及随后混合的崩解剂包括但不限于：淀粉、预胶化淀粉、羟丙基淀粉、羧甲淀粉钠、羧甲基纤维素钠、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮。
在一些实施例中，用于塞来昔布在流化床干燥制粒以及随后混合的润滑剂和/或助流剂包括但不限于：硬脂酸镁、硬脂酸钙、滑石粉、聚乙二醇、环氧乙烷聚合物、十二烷基硫酸钠、十二烷基硫酸镁、油酸钠、硬脂酸富马酸钠、硬脂酸、二氧化硅、微粉硅胶、硅胶。
在一些实施例中，用于塞来昔布在流化床干燥制粒以及随后混合的抗氧剂可以包括但不限于：自由基吸收剂(如：维生素E，类胡萝卜素)、氧清除剂(如：类胡萝卜素及其衍生物、抗坏血酸、抗坏血酸棕榈酸酯、异抗坏血酸、异抗坏血酸钠)、金属离子螯合剂(如：枸橼酸、EDTA和磷酸衍生物)、丁基羟基茴香醚(BHA)、二丁基羟基甲苯(BHT)。
在一些实施例中，塞来昔布制剂含有蔗糖；其含量在口服制剂中的总重量是10％-80％w/w，优选20-70％w/w，更优选30-70％w/w。
在一些实施例中，塞来昔布制剂含有蔗糖丸芯；其在制剂中的含量是10％-80％w/w，优选20-70％w/w，更优选30-70％w/w。
在一些实施例中，塞来昔布制剂含有微晶纤维素丸芯；其在制剂中的含量是10％-80％w/w，优选20-70％w/w，更优选30-70％w/w。
在一个实施例中，塞来昔布制剂包括一种防潮薄膜包衣；薄膜包衣材料通常由各种不同纤维素如羟丙甲基纤维素、乙基纤维素，以及二氧化钛、滑石粉等组成。通常使用的防潮薄膜包衣包括：欧巴代
Figure PCTCN2019093044-appb-000008
Ⅱ(“
Figure PCTCN2019093044-appb-000009
II”)。 其在口服固体制剂中的含量为1-5％w/w。
在一些实施例中，塞来昔布的口服固体制剂可以是下述制剂中的一种：胶囊剂、片剂、颗粒剂。
在一个实施例中，制备塞来昔布制剂，其规格是25mg胶囊；在一个实施例中，制备塞来昔布制剂，其规格是40mg胶囊；在一个实施例中，制备塞来昔布制剂，其规格是50mg胶囊；在一个实施例中，制备塞来昔布制剂，其规格是75mg胶囊；在一个实施例中，制备塞来昔布制剂，其规格是80mg胶囊；在一个实施例中，制备塞来昔布制剂，其规格是160mg胶囊；在一个实施例中，制备塞来昔布制剂，其规格是320mg胶囊
在一个实施例中，制备塞来昔布制剂，其规格是25mg片剂；在一个实施例中，制备塞来昔布制剂，其规格是40mg片剂；在一个实施例中，制备塞来昔布制剂，其规格是50mg片剂；在一个实施例中，制备塞来昔布制剂，其规格是80mg片剂；在一个实施例中，制备塞来昔布制剂，其规格是80mg片剂；在一个实施例中，制备塞来昔布制剂，其规格是160mg片剂；在一个实施例中，制备塞来昔布制剂，其规格是320mg片剂。
在一个实施例中，塞来昔布混悬剂的生产制备经过下述步骤(见图3)：步骤A：通过湿法研磨制备纳米混悬液；此步骤同上述口服固体制剂中的步骤A的湿法研磨，即在全水相中，加入药物塞来昔布、表面活性剂、亲水性聚合物并制成混悬液，随后启动研磨腔中的搅拌棒高速转动并以此带动研磨腔内的研磨介质在水相中对药物颗粒进行撞击、剪切、研磨，使药物颗粒的粒径从常见的微米范围降至纳米范围(如：100-300nm)；步骤B：添加糖类等辅料制备稳定的纳米混悬液。此步骤同上述口服固体制剂制备中的步骤B，即在获得的上述经湿法研磨制备的纳米混悬液中，添加一定量的单糖、或双糖、或多元醇等高亲水性辅料，以及一定量的表面活性剂和亲水性聚合物；优选通过机械搅拌进行混合；步骤E:在步骤B的基础上，继续添加一定量的下述辅料的一种或两种以上，包括：助悬剂、抗氧剂、掩味剂、增甜剂、防腐剂、消泡剂、增稠剂、溶液pH缓冲盐；优选通过机械搅拌进行混合。以制剂的总重量计，含有塞来昔布0.5-5％(w/v)，优选0.5-3％(w/v)，更优选1-2％(w/v)；含有十二烷基硫酸钠0.1-2％(w/v)，优选0.1-1.5％(w/v)，更优选0.1-1％(w/v)；含有聚乙烯吡咯烷酮0.05-2％(w/v)，优选0.05-1％(w/v)，更优选0.05-0.5％(w/v)；含有蔗糖0.5-30％(w/v)，优选0.5-20％ (w/v)，更优选0.5-10％(w/v)。在完成上述的步骤A、步骤B、步骤E后，仍需要完成除菌、装瓶等口服混悬液通常需要的生产步骤，最后制成塞来昔布口服混悬剂。
本发明提供的塞来昔布口服制剂可用于治疗轻度至中度的急性疼痛、轻度至中度的慢性疼痛或用于制备治疗轻度至中度的急性疼痛、轻度至中度的慢性疼痛的药物。
在一个实施例中，受试者是哺乳动物(比格犬)。
在一个实施例中，受试者是健康人。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。本发明中的重量体积百分比中的单位是本领域技术人员所熟知的，例如是指在100毫升的溶液中溶质的重量。除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1
塞来昔布湿法研磨
表1-1列举了塞来昔布湿法研磨的部分处方筛选。在该发明中使用的高速湿法研磨机包括：
Figure PCTCN2019093044-appb-000010
Mill ResearchLab、Multi-Lab；研磨的技术参数及范围：研磨腔容积：75-600ml；转速：2600-4200rpm(转/分钟)；研磨时间：1-3小时；研磨珠：0.3-0.5mm YTZ研磨珠(即通过氧化钇稳定的氧化锆珠)；混悬液进样速度：10±5ml/min。粒径检测：Malvern2000激光粒度检测仪用于检测药物粒径分布(D50、D90)；Leica光学显微镜用于观察粒度的分散性。表1-1的研究表明：混悬液6和混悬液7有良好的粒径分布。注意：此处的混悬液指湿法研磨的处方，非指制剂的混悬剂。
图2A-2B是一个具有代表性批次的塞来昔布混悬液在研磨前后的药物粒径分布曲线。
图2A展现了本发明所使用的塞来昔布原料药具代表性的某批次的粒径 分布图：D50：7.7μm,D90：104.7μm。图2B则展现了塞来昔布经湿法研磨后的研磨处方“混悬液10”的粒径分布图：D50：122nm；D90：250nm。注意：D50即为d(0.5)；D90即为d(0.9)。
表1-1塞来昔布湿法研磨及纳米混悬液的处方筛选
Figure PCTCN2019093044-appb-000011
*：SLS：十二烷基硫酸钠；HPMC：羟丙甲基纤维素；PVP：聚乙烯吡咯烷酮；DOSS：磺基琥珀酸二辛酯钠(又称：多库酯钠)；Poloxamer：泊洛沙姆，即：(环氧乙烷)-聚(环氧丙烷)嵌段共聚物
表1-2塞来昔布纳米混悬液的制备及稳定性研究
Figure PCTCN2019093044-appb-000012
混悬液中的载药量是塞来昔布纳米制备效率的一个重要指标。表1-2中的纳米混悬液9和混悬液10是对混悬液6-7的进一步研究，即提高在混悬液中载药量的研究，也就是提高药物研磨效率的研究。表1-2列出了部分研究结果，即增加混悬液中的塞来昔布载药量从10％w/w至20％w/w：混悬液9中的药物粒径大幅度增加。这表明：表面活性剂SLS(“十二烷基硫酸钠”)和亲水性聚合物HPMC(“羟丙甲基纤维素”)的联合使用仅适用于低载药量的研磨，而不适用于高载药量研磨。同时，由于制备纳米药物的需要而相应增加的SLS和HPMC的用量，直接导致了混悬液流动性下降(粘稠度增加)、泡沫增加、研磨腔温度明显升高(50-65℃)。混悬液9的处方组合随之放弃。
混悬液10(见表1-2)：塞来昔布在增加载药量后，其粒径仍保持稳定，表明SLS和PVP(“聚乙烯吡咯烷酮”)系良好组合，可供继续优化以适用于规模生产。继续研究混悬液10发现，SLS和PVP K30虽是良好组合，但粒径不够稳定：在室温下的第3天，粒径即有明显增长。在规模生产中，这是一个不确定因素。药物在湿法研磨后和在流化床干燥处理前，有一个时间差。生产工艺需要该纳米混悬液能保持足够的稳定性。
表1-2中，混悬液11则是采用了两步制备工艺，即“先研磨、后稳定”的工艺：在完成湿法研磨(步骤A)后，在收集起的纳米混悬液中继续添加 表面活性剂(SLS，至5.4％w/w)和亲水性聚合物(聚乙烯吡咯烷酮，至1.4％w/w)(即：步骤B)。这一步骤可通过机械搅拌(非湿法研磨)进行。从随后该混悬液的稳定性研究来看，塞来昔布的粒径能够保持高度稳定。值得指出的是，如果在研磨高载量塞来昔布(20％w/w)的一开始就使用较高浓度的表面活性剂(如混悬液11：SLS：5.4％w/w)和亲水性聚合物(聚乙烯吡咯烷酮:1.4％w/w)，则研磨很快导致混悬液粘度增加，过量表面活性剂产生大量泡沫，研磨腔的温度也随之增高至50-65℃(数据未列出)。这些都会严重影响研磨机的正常运行。
表1-2中的混悬液12类同混悬液11，采用了两步制备工艺，即在收集起来的纳米混悬液10里，通过机械搅拌(非湿法研磨)继续添加SLS 5％w/w和PVP K30 1％w/w，并同时添加蔗糖20％w/w(即“步骤B”)。这使得SLS、PVP K30和蔗糖在纳米混悬液中的最终浓度分别为：5.4％和1.4％和20％w/w。研究结果表明：加入蔗糖后的混悬液12的粒径稳定性与混悬液11相似。但蔗糖加入的重要意义不只在此：其是在制备固体纳米制剂时，在混悬液的水分除去后，帮助纳米药物颗粒迅速固化在辅料上并能保持稳定的纳米粒径(见塞来昔布制剂的溶出稳定性研究：表2-1、表3-1、表3-2)。
实施例2
制备塞来昔布制剂
一、塞来昔布制剂(胶囊)的处方及工艺
表2-1展示了部分塞来昔布制剂(胶囊)的处方及工艺。这些是用来制备规格为40mg的塞来昔布制剂的胶囊(装量160mg；3号胶囊)。处方1和处方2系流化床顶喷制备载药颗粒而成；所使用的流化床干燥的设备及工艺参数：德国Diosna Minilab-XP流化床干燥制粒机；进风温度：65±5℃；物料温度：45±5℃；进风量：25±5m 3/h；进样速度：10±5ml/min。处方3和处方4系流化床底喷制备载药微丸而成；流化床干燥制粒的工艺系通过常州创志机电科技公司生产的FLZB-0.5流化床制备而成；主要技术参数如下：进风温度：60±5℃；物料温度：40±5℃；进风量：15±5m 3/h；进样速度：7±2ml/min。
塞来昔布制剂(胶囊)的生产制备工艺见图3。
表2-1部分塞来昔布制剂(胶囊)的处方及工艺(规格：40mg)
Figure PCTCN2019093044-appb-000013
*：SLS：十二烷基硫酸钠；HPMC：羟丙甲基纤维素；PVP：聚乙烯吡咯烷酮；CCS:(croscamelose sodium)：交联羧甲基纤维素钠
二、制备塞来昔布制剂(混悬剂)的处方及工艺
塞来昔布制剂(混悬剂)的生产制备经过下述步骤：
步骤A：通过湿法研磨制备纳米混悬液；步骤B：添加糖类等辅料制备稳定的纳米混悬液，以及一定量的表面活性剂和亲水性聚合物；优选通过机械搅拌进行混合。步骤E:继续添加一定量的下述辅料的一种或两种以上，包括：助悬剂、抗氧剂、掩味剂、增甜剂、防腐剂、消泡剂、增稠剂、溶液pH缓冲盐；优选通过机械搅拌进行混合。塞来昔布制剂(混悬剂)的生产制备工艺过程见图3。
表2-2列出了塞来昔布制剂(混悬剂)的一代表性处方；其规格：16mg/ml， 60ml/瓶。
表2-2塞来昔布制剂(混悬剂)的处方(规格：16mg/ml，60ml/瓶)
Figure PCTCN2019093044-appb-000014
实施例3
塞来昔布制剂(胶囊)的溶出度检测
表3-1与表3-2列举了部分塞来昔布制剂(胶囊；具体处方组成及工艺见表2-1)的加速稳定性研究(40℃/75％RH)下药物溶出速率在0、1、2、3个月的变化。这里的溶出条件是非漏槽条件，即药物不完全溶出；主要是用来比较不同纳米制剂处方及制备工艺可能对制剂稳定性(主要是溶出稳定性)的影响。如：处方1和处方3均使用了蔗糖作为“步骤B”中用于制备稳定纳米混悬液的重要辅料，但处方2和处方4则没有。药物溶出度的稳定性直接关系到研判塞来昔布纳米粒径是否稳定，即是否产生聚集并使粒径增大、导致溶出下降。药物的溶出稳定对纳米制剂的体内吸收至关重要。表3-1和3-2显示：处方1的溶出及稳定性明显优于处方2；处方3则优于处方4。
表3-1塞来昔布制剂(处方1-4；40mg胶囊)和西乐葆
Figure PCTCN2019093044-appb-000015
胶囊50mg的溶出率数据(稳定性研究：40℃/75％RH；0、1、2、3个月；溶出条件：篮法，50rpm，900ml，pH 1.0稀盐酸溶液，37℃)
Figure PCTCN2019093044-appb-000016
表3-2塞来昔布制剂(处方1-4；40mg胶囊)和西乐葆
Figure PCTCN2019093044-appb-000017
胶囊50mg的溶出率数据(稳定性研究：40℃/75％RH；0、1、2、3个月；溶出条件：篮法，50rpm，900ml，pH 6.1磷酸盐缓冲溶液，37℃)
Figure PCTCN2019093044-appb-000018
实施例4
塞来昔布制剂和西乐葆在比格犬上的比较研究
通过分别对
Figure PCTCN2019093044-appb-000019
(即先前使用过的)雄性和雌性比格犬给药，来研究塞来昔布的药代动力学；给药方式：口服单次；分三组给药，分别是：塞来昔布制剂(50mg/胶囊)；塞来昔布制剂(25mg/胶囊)；市售制剂西乐葆
Figure PCTCN2019093044-appb-000020
(100mg/胶囊)；通过研究给药后的药代动力学参数，以评价塞来昔布制剂在体内吸收并同参比制剂
Figure PCTCN2019093044-appb-000021
进行比较。该实验中塞来昔布制剂的处方与表2-1中的处方1一致，但胶囊尺寸和装量均按比例做了适当调整。
实验设计：实验使用了两只雄性和两只雌性的
Figure PCTCN2019093044-appb-000022
比格犬，体重在9-11kg。每只动物耳朵上都会标有独特的纹身号码。四只动物按以下顺序口服给药：塞来昔布制剂(50mg/胶囊/比格犬)，
Figure PCTCN2019093044-appb-000023
(100mg/胶囊/比格犬)，塞来昔布制剂(25mg/胶囊/比格犬)。每个动物按同样的时间点采集血液样品。
药品准备和给药：所有用于给药的动物都预先称重，并记录在案。
样品采集和处理：分别给药3个制剂后，在比格犬外周血管收集一系列取样时间点的血液样品。取样时间点分别为10，20，30，45分钟，1,1.25,1.5,2,3,4,6,12,48小时，每个取样点的血液样品中都含有大约0.5ml K 2EDTA的抗凝剂。血液样品收集于取样试管后，轻轻倒置几次试管，在2-8℃条件下，在3000g条件下离心10分钟，取出后立即放置于湿冰上。取0.2ml血浆转移至预先写好标签的小瓶中，并存储在-60℃或更低的环境中。送样分析时，需用干冰转移。
实验观察：每天两次(大约9:30a.m.和4:00p.m.)在笼外对动物进行一般健康情况和外观的观察。动物在实验研究开始前已经进行过健康检查。在给药当天，实验动物在每个取样点前后都会被观察。动物的一般情况、行为、活动、排泄、呼吸或其他不寻常的地方都会书面记录。
样品分析：实验中比格犬的取样血液中经过蛋白质沉淀后，采用经过验证的LC-MS/MS分析方法，测定血浆中塞来昔布含量。其检测的最低定量限为1.00ng/ml，最高定量限为3000ng/ml。
药代动力学参数分析：检测的血浆中塞来昔布药物浓度数据将使用WinNonlin Version 6.2.1(Pharsight,Mountain View,CA)软件进行分析。血药浓度峰(C max)和相应的达峰时间(T max)可以在血药浓度对时间曲线上直接读出。
药代动力学参数：半衰期(t 1/2),平均滞留时间0到无穷大(MRT 0-inf)，平均滞留时间(MRT 0-last)，血浓-时间曲线下面积(AUC 0-inf)和血浓时间曲线下面积(AUC 0-last)，都会通过软件计算给出。所有的药代动力学参数，比如C max，T max，AUC，t 1/2和MRT值都会保留3位有效数字。样品血液在给药后第一个小时内采集的取样点，采集时间会在±1分钟之内完成，余下的取样点都会在预定时间的5％内进行采集。因此，通常采用理论取样时间来计算，药代动力学参数结果都会存在一定偏差。
表4展示了通过单次口服给药塞来昔布制剂和参比制剂西乐葆予
Figure PCTCN2019093044-appb-000024
比格犬得到的主要药代动力学参数的均值，如C max，T max，AUC 0-last，AUC 0-inf，AUC Extrap(％)，t 1/2，MRT 0-last和MRT 0-inf。
在本次研究中，塞来昔布制剂两个剂量25mg和50mg是通过口服方式分别给药于两只雄性比格犬和两只雌性比格犬，剂量为100mg的塞来昔布市售制剂西乐葆
Figure PCTCN2019093044-appb-000025
胶囊也同样单次给药于以上的这四只比格犬。每组制剂实验的安排时间之间会有一周的药物排空期。各组安排的给药顺序如下：
第一组：塞来昔布制剂(50mg/胶囊/比格犬)
第二组：市售制剂
Figure PCTCN2019093044-appb-000026
胶囊(100mg/胶囊/比格犬)
第三组：塞来昔布制剂(25mg/胶囊/比格犬)
表4塞来昔布制剂与西乐葆通过单次口服给药给比格犬的药代动力学研究
Figure PCTCN2019093044-appb-000027
图5展示了本发明案例的平均血药浓度曲线图(放大曲线：0-12小时)，由通过分别单次口服给药塞来昔布制剂(50mg/胶囊/比格犬)，塞来昔布制 剂(25mg/胶囊/比格犬)和市售制剂
Figure PCTCN2019093044-appb-000028
(100mg/胶囊/比格犬)于雄性和雌性比格犬而得到的。
表4中数据显示，塞来昔布制剂同市售制剂
Figure PCTCN2019093044-appb-000029
胶囊比较，单位剂量的药物吸收(C max,，AUC)有显著增长：塞来昔布制剂(50mg/胶囊)，塞来昔布制剂(25mg/胶囊)和市售制剂
Figure PCTCN2019093044-appb-000030
(100mg/胶囊)的C max分别为1131ng/ml，915ng/ml和662ng/ml；AUC 0-inf分别为7797ng/mL·hr，5187ng/mL·hr和5337ng/mL·hr
以上数据表明：塞来昔布制剂(25mg/胶囊)的C max和AUC的几何平均值与市售制剂
Figure PCTCN2019093044-appb-000031
(100mg/胶囊)比较，比率分别为1.38与0.97，但给药剂量市售制剂
Figure PCTCN2019093044-appb-000032
(100mg/胶囊)为塞来昔布制剂(25mg/胶囊)的4倍。
接下来，塞来昔布制剂(50mg/胶囊)相比塞来昔布制剂(25mg/胶囊)，AUC 0-inf和C max也相应的增加了1.50倍和1.24倍，仍呈增长趋势，虽然没有完全按比例增长。
实施例5
塞来昔布制剂AP2500与西乐葆在健康人中的药代动力学研究
塞来昔布制剂(AP2500)的三个剂量(50mg，75mg，100mg)与塞来昔布参比制剂西乐葆
Figure PCTCN2019093044-appb-000033
(100mg)在健康受试者中的药代动力学研究：采用随机开放的单中心、空腹、单剂量、四周期、自身对照四交叉(4×4)试验设计。该实验中的塞来昔布制剂同表2-1中的处方1一致，但胶囊尺寸和装量均按比例做了适当调整。选择健康受试者12例，随机分成A、B、C、D四组，每组3例，每个周期受试者于试验前一天进清淡饮食，在过夜禁食(不禁水)至少10h后按受试者照随机表和给药方法空腹以240mL温水送服如下研究药物：
受试制剂1(T 1)：塞来昔布制剂AP2500胶囊50mg
受试制剂2(T 2)：塞来昔布制剂AP2500胶囊75mg
受试制剂3(T 3)：塞来昔布制剂AP2500胶囊100mg
参比制剂(R)：西乐葆
Figure PCTCN2019093044-appb-000034
胶囊100mg
清洗期为1周。
给药方法：受试者于试验前一天进清淡饮食，并禁食10小时、不禁水 过夜，试验当天分别照随机表,空腹以240mL温水送服如下研究药物：
受试制剂1(T 1)：塞来昔布制剂AP2500；50mg胶囊
受试制剂2(T 2)：塞来昔布制剂AP2500；75mg胶囊
受试制剂3(T 3)：塞来昔布制剂AP2500；100mg胶囊
参比制剂(R)：西乐葆
Figure PCTCN2019093044-appb-000035
100mg胶囊
服药周期见表6。服药前1小时至服药后1小时内禁止饮水，其他时间可自由饮水；服药后4小时内禁食，每个试验周期受试者应在相同的特定时间点(给药后4小时和10小时)用标准餐。
研究期间需要受试者配合的其他事项：受试者在服药后应避免剧烈活动，亦不得长时间卧床。在研究期间受试者的饮食和作息时间统一安排。禁服任何含酒精和黄嘌呤的食品和饮料：巧克力、茶、咖啡及可乐等，并禁止吸烟，禁止饮用葡萄柚(西柚)汁或包含葡萄柚的产品。受试者应遵守试验方案，不使用任何药物(包括清洗期)。除非在治疗突发疾病时必须用药，并应及时告知。
表5塞来昔布制剂AP2500的服药周期表
Figure PCTCN2019093044-appb-000036
血样采集与处理：A、B、C、D四组分别于服药前(0小时)及服药后0.5，1，1.5，2，2.5，3，3.5，4，5，6，8，12，24，36，48小时采集静脉血4mL(置EDTA抗凝管中)，总计16个点；血样采集后，3000转/分离心10分钟，取血浆置-70℃以下储存备用。
样品分析测试：HPLC-MS/MS法测定血浆中塞来昔布的药物浓度。
数据处理：采用WINNONLIN程序计算主要药动学参数并作等效分析。 药动学参数以实际采血时间计算。
结果见表6。
表6健康人AP2500与参比制剂的单次空腹口服给药的药代动力学研究
Figure PCTCN2019093044-appb-000037
NA:不适用
aA组T1的一名受试者在取血12小时后自愿退出了试验
b
Figure PCTCN2019093044-appb-000038
表6中数据显示，AP2500在50mg-100mg剂量PK参数与剂量基本成正比，有线性动力学趋势。与参比制剂西乐葆(
Figure PCTCN2019093044-appb-000039
100mg)相比，塞来昔布制剂T 1组AP2500(50mg)，血药浓度-时间曲线下面积(AUC 0-t与AUC 0-∞) 为53.52％与53.59％，血药浓度峰值为(77.07％)。塞来昔布制剂T 2组AP2500(75mg)，血药浓度-时间曲线下面积(AUC 0-t与AUC 0-∞)为83.71％与83.93％，血药浓度峰值为94.58％。塞来昔布制剂T 3组AP2500(100mg)，血药浓度-时间曲线下面积(AUC 0-t与AUC 0-∞)为113.56％与111.39％，血药浓度峰值为138％。
等同性
本发明披露了用于治疗轻度至中度急性疼痛和慢性疼痛的新的塞来昔布制剂处方和制备方法。列举了一些具体实施例，旨在举例说明而并非限制权利要求。在阅读后，本领域技术人员能轻易实施，并作一些变化。本发明所覆盖的全部范围由权利要求说明书所限定。
参考说明
尽管已经描述了本发明的多个实例，但是应当理解，这些实例仅是说明性的，而非限制性的，并且许多变动对于本领域普通技术人员来说是显而易见的。此外，各步骤可以以任何合理的顺序执行(并且可以添加任何可预见的步骤和/或可以消除任何可预见的步骤)。

Claims (20)

  1. 一种塞来昔布口服制剂，其特征在于，所述制剂的规格为塞来昔布市售制剂规格的60-90％；且所述制剂与对应规格的塞来昔布市售制剂生物等效。
  2. 如权利要求1所述的制剂，其特征在于，所述制剂的剂型包括：片剂、胶囊剂、颗粒剂、混悬剂。
  3. 如权利要求1所述的制剂，其特征在于，所述制剂中塞来昔布的粒径D50不大于160nm，D90不大于300nm。
  4. 如权利要求1所述的制剂，其特征在于，所述制剂为片剂、胶囊或颗粒剂时，以制剂的总重量计，含有十二烷基硫酸钠0.5-12％w/w，优选2-10％w/w，更优选4-8％w/w。
  5. 如权利要求1所述的制剂，其特征在于，所述制剂为片剂、胶囊或颗粒剂时，以制剂的总重量计，含有聚乙烯吡咯烷酮0.5-7％w/w，优选0.5-5％w/w，更优选0.5-3％w/w。
  6. 如权利要求5所述的制剂，其特征在于，所述制剂为片剂、胶囊或颗粒剂时，以制剂的总重量计，含有蔗糖10-70％w/w，优选10-50％w/w，更优选10-30％w/w。
  7. 如权利要求1所述的制剂，其特征在于，所述制剂为片剂、胶囊或颗粒剂时，所述制剂规格包括：40mg、80mg、160mg、320mg；其分别对应于塞来昔布市售制剂的规格为：50mg、100mg、200mg、400mg。
  8. 如权利要求1所述的制剂，其特征在于，所述制剂为片剂、胶囊或颗粒剂时，所述制剂中的药用辅料还包括下述的一种或两种以上：填充剂、崩解剂、粘合剂、助流剂、润滑剂。
  9. 如权利要求1所述的制剂，其特征在于，所述制剂为片剂、胶囊或颗粒剂、且规格是40-80mg时，使用美国药典溶出方法I，其在溶出介质为pH1.0或pH 6.1时并在转速50rpm下测定的塞来昔布的溶出量在30分钟不低于30％和在60分钟不低于45％。
  10. 如权利要求1所述的制剂，其特征在于，所述制剂为混悬剂时，以制剂的总重量计，含有塞来昔布0.5-5％(w/v)，优选0.5-3％(w/v)，更优选1-2％(w/v)。
  11. 如权利要求1所述的制剂，其特征在于，所述制剂为混悬剂时，以制剂的总重量计，含有十二烷基硫酸钠0.1-2％(w/v)，优选0.1-1.5％(w/v)， 更优选0.1-1％(w/v)。
  12. 如权利要求1所述的制剂，其特征在于，所述制剂为混悬剂时，以制剂的总重量计，含有聚乙烯吡咯烷酮0.05-2％(w/v)，优选0.05-1％(w/v)，更优选0.05-0.5％(w/v)。
  13. 如权利要求1所述的制剂，其特征在于，所述制剂为混悬剂时，以制剂的总重量计，含有蔗糖0.5-30％(w/v)，优选0.5-20％(w/v)，更优选0.5-10％(w/v)。
  14. 一种如权利要求1-9任一项所述塞来昔布口服制剂的制备方法，其特征在于，所述制剂为片剂、胶囊剂或颗粒剂，所述方法包括步骤：
    步骤A：将塞来昔布经全水相湿法研磨制成纳米颗粒混悬液；其中使用十二烷基硫酸钠为表面活性剂，使用聚乙烯吡咯烷酮为亲水性聚合物；
    步骤B：在步骤A得到的纳米颗粒混悬液中加入糖类，并继续加入十二烷基硫酸钠和聚乙烯吡咯烷酮进行混合得到纳米混悬液；所述糖类为单糖、双糖、和多元醇中的一种或两种以上；优选为乳糖、蔗糖、果糖、甘露醇、和山梨醇中的一种或两种以上；优选通过搅拌进行混合；
    步骤C：将步骤B得到的纳米混悬液经流化床喷雾干燥得到载药颗粒或载药微丸；
    步骤D：将载药颗粒或载药微丸制成口服固体制剂包括片剂、胶囊剂、颗粒剂。
  15. 如权利要求14所述的制备方法，其特征在于，步骤A所述的湿法研磨中，以获得的纳米颗粒混悬液的总重量计，其中含有超过10％w/w的塞来昔布，优选10-35％w/w，更优选15-25％w/w。
  16. 如权利要求14所述的制备方法，其特征在于，以步骤B所获得的纳米混悬液的总重量计：十二烷基硫酸钠的用量0.5-12％w/w，优选2-10％w/w，更优选4-8％w/w；聚乙烯吡咯烷酮的用量为0.5-7％w/w，优选0.5-5％w/w，更优选0.5-3％w/w；糖类的用量为10-70％w/w，优选10-50％w/w，更优选10-30％w/w。
  17. 如权利要求14所述的制备方法，其特征在于，用于步骤C的载体包括填充剂；所述填充剂包括糖类和100-1000μm的微丸丸芯；所述糖类为单糖、双糖、和多元醇中的一种或两种以上；所述微丸丸芯选自蔗糖丸芯、微晶纤维素丸芯、淀粉丸芯、酒石酸丸芯、乳糖丸芯、二氧化硅丸芯、羟丙甲 纤维素丸芯、柠檬酸丸芯、或酒石酸丸芯。
  18. 如权利要求17所述的制备方法，其特征在于，所述载体还包括崩解剂、粘合剂、助流剂、润滑剂、和抗氧剂中的一种或两种以上。
  19. 一种如权利要求1-3、10-13任一项所述塞来昔布口服制剂的制备方法，其特征在于，所述制剂为混悬剂，所述方法包括步骤A、步骤B和步骤E：
    步骤A：将塞来昔布经全水相湿法研磨制成纳米颗粒混悬液；其中使用十二烷基硫酸钠为表面活性剂，使用聚乙烯吡咯烷酮为亲水性聚合物；
    步骤B：在步骤A得到的纳米颗粒混悬液中加入糖类，并继续加入十二烷基硫酸钠和聚乙烯吡咯烷酮进行混合得到纳米混悬液；所述糖类为单糖、双糖、和多元醇中的一种或两种以上；优选为乳糖、蔗糖、果糖、甘露醇、和山梨醇中的一种或两种以上；优选通过搅拌进行混合；
    步骤E:在步骤B得到的纳米混悬液中加入一种或两种以上下述辅料：助悬剂、抗氧剂、掩味剂、增甜剂、防腐剂、消泡剂、增稠剂、香精、pH缓冲盐；优选通过搅拌进行混合。
  20. 一种如权利要求1-13任一项所述塞来昔布口服制剂的用途，用于治疗轻度至中度的急性疼痛、轻度至中度的慢性疼痛或用于制备治疗轻度至中度的急性疼痛、轻度至中度的慢性疼痛的药物。
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