WO2015003479A2 - 一种适用于婴幼儿及儿童的口服固体颗粒及其制备方法 - Google Patents

一种适用于婴幼儿及儿童的口服固体颗粒及其制备方法 Download PDF

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WO2015003479A2
WO2015003479A2 PCT/CN2014/000836 CN2014000836W WO2015003479A2 WO 2015003479 A2 WO2015003479 A2 WO 2015003479A2 CN 2014000836 W CN2014000836 W CN 2014000836W WO 2015003479 A2 WO2015003479 A2 WO 2015003479A2
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pellets
drug
pellet
oseltamivir
coating
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PCT/CN2014/000836
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English (en)
French (fr)
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WO2015003479A3 (zh
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孙卫东
任逢晓
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Sun Weidong
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Publication of WO2015003479A2 publication Critical patent/WO2015003479A2/zh
Publication of WO2015003479A3 publication Critical patent/WO2015003479A3/zh
Priority to US14/992,038 priority Critical patent/US9585845B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—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
    • A61K9/5078—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 with drug-free core
    • 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
    • A61K9/0087—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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • 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
    • A61K9/5026—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
    • 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

Definitions

  • the invention relates to a preparation method of a pharmaceutical preparation in the field of pharmacy, in particular to an oral solid granule suitable for infants and children and a preparation method thereof using oseltamivir as a main medicine.
  • Pellets are small spherical oral dosage forms having a diameter of less than 2.5 mm.
  • the sustained-release and controlled-release pellets prepared by mixing the main drug with a retarder or the like, or the pellet core, and the sustained release and controlled release film coating are prepared by a dose dispersion type preparation, and the single dose has a plurality of units.
  • the combination of pellets can achieve the desired release rate, achieve the desired blood concentration, and can maintain a longer duration of action, avoiding adverse reactions such as stimulation of the gastric mucosa; the release behavior is to form a plurality of pellets at a dose.
  • composition of the compound has a good reproducibility in the body; the drug is rarely affected by changes in gastric emptying function in the body, and the absorption in the body has good reproducibility; the safety factor is high; Pill is one of the most suitable slow-release and controlled-release dosage forms, and it is the current development direction of slow-release and controlled-release preparations.
  • the oseltamivir that is now on the market is a common capsule that needs to be swallowed or swallowed, but it is not or unwilling to complete the swallowing action for infants and children, and does not understand the necessity of treatment, and because of oseltamivir. It has a strong bitter taste and often does not cooperate with treatment, which brings great difficulties to the treatment of diseases. Therefore, improving patient compliance is especially important for infants and children.
  • a large amount of sweetener is needed to cover up the bitterness of the drug, but a large amount of sweetener is added. Even if the human body feels sweet, it then feels bitter. The main reason is that the sensitive part of the human body feels bitter is the root of the tongue, and the tongue root is sensitive to bitterness.
  • the solid particles prepared by the method have small particle size (and can cover bitterness, and the compliance of infants and children is good, and can be further prepared into capsules, orally disintegrating tablets, chewable tablets, suspensions, granules.
  • the preparation method of the invention is simple, the medicine is stable, the reproducibility is high, and the mass production is easy.
  • the object of the present invention is to provide a granule of coated micropellets containing oseltamivir and a preparation method thereof.
  • the pellets are odorless and tasteless, and the particle size can be prepared into a dosage form suitable for children, especially infants, for children, especially infants. Prevention and treatment of childhood flu.
  • An oral pharmaceutical pellet composition comprising a drug-containing pellet core and a coating layer, wherein the drug in the drug-containing pellet core is oseltamivir or a pharmaceutically acceptable salt thereof, which accounts for 10% by weight of the total weight of the pellets - 40 %, the material used for the coating layer is polyacrylic resin IV, which accounts for 1%-50% of the total weight of the pellets, and the pellet diameter is 0.10-0.50 mm.
  • oseltamivir described in the present invention refers to oseltamivir phosphate unless otherwise stated.
  • composition of the present invention wherein the drug-containing pellet core is prepared by blank pellets, a drug, a filler, a binder and an anti-adhesive agent, and the percentage of each component in the total weight of the pellets is as follows, and the drug is 10% to 40%. , blank pellets 20%-60%, filler 0%-50%, binder 1%-20%, anti-adherent 0.5%-5%.
  • the blank pellets may be selected from the group consisting of sucrose pellets, microcrystalline cellulose pellets, starch pellets, lactose-microcrystalline cellulose pellets, starch-microcrystalline cellulose pellets, and sucrose-starch pellets. Or more than one;
  • the filler may be selected from one or more of sucrose, lactose, mannitol, starch, microcrystalline cellulose, seaweed polysaccharide, and chitosan;
  • the binder may be one or more selected from the group consisting of water, ethanol, hypromellose, polyacrylic acid resin, hydroxypropyl cellulose, povidone, polyvinyl alcohol, sodium carboxymethyl cellulose;
  • the anti-adhesive agent in the pharmaceutical composition pellet is one or more of talc, colloidal silica, magnesium stearate, calcium stearate, magnesium silicate, and glyceryl monostearate. .
  • the blank pellets are sucrose pellets; the filler is lactose and/or mannitol; the binder is hypromellose; the anti-adhesive agent is talcum powder.
  • the percentage of each component in the total weight of the pellets is as follows, oseltamivir 10%-30% (w/w), polyacrylic resin IV5%-50%, sucrose pellets 20 %-60%, lactose and/or mannitol 0%-50%, hypromellose 1%-20%, talc 0.5%-5%.
  • the percentage of each component in the total weight of the pellets is as follows, oseltamivir 23.8% (w / w), polyacrylic resin IV 16.7%, sucrose pellets 49.6%, hydroxypropyl Cellulose was 7.9% and talc was 2.0%.
  • the oral pharmaceutical composition pellet of the present invention is characterized in that the pharmaceutical composition pellet can be further prepared into a capsule, a tablet, a pellet, a granule, and a suspension.
  • the oral pharmaceutical composition pellet of the present invention characterized in that the preparation method comprises the following steps:
  • the required raw materials are pulverized through a 120 mesh screen, and the required auxiliary materials are pulverized through an 80 mesh sieve, and oseltamivir, a filler and an anti-adhesive agent are added to the binder solution under stirring to form a drug-loading layer.
  • a suspension of the material the preferred suspension is applied to a fluidized bed or a coating pan, and the drug carrier material is atomized under a suitable pressure and sprayed into the fluidized bed at a certain temperature.
  • the drug layer material forms a drug layer attached to the blank pellets. At a certain fluidization speed, the blank pellets can obtain drug-loaded pellets with uniform content and uniform particle size.
  • the particle size of the drug-loaded pellets can be controlled in the range of 0.10 to 0.50 mm, and the particle diameter of the drug is preferably controlled to be in the range of 0.25 ⁇ 0.10 mm.
  • the acrylic resin IV solution is atomized at a suitable pressure and sprayed into the fluidized bed at a certain temperature.
  • the coating material forms a coating film attached to the pellets, that is, it is obtained.
  • the binder solution is prepared by mixing water with a binder, and the amount of water added is 5-100 times of the weight of the binder; and the coating liquid is prepared by mixing polyacrylic acid resin IV with ethanol solution.
  • the ethanol solution is 50-99% ethanol, and the amount of ethanol added is 5-100 times the weight of the polyacrylic resin IV.
  • pellets (containing oseltamivir 30 mg) prepared in Examples 1-6 and Comparative Examples 1-3 were taken, and the appropriate amount of pellets (containing oseltamivir 30 mg) was taken to taste the taste.
  • Test 2 examining the effect of the composition of the invention on the vomiting model of the pigeon
  • Experimental animals Healthy domestic pigeons, both male and female, weighing 350 ⁇ 50g, common grade, purchased from breeding base.
  • 70 healthy pigeons were randomly divided into 7 groups. Adaptive feeding for 1 week before the experiment, drinking water during normal feeding during the feeding period, fasting for 4 hours before the experiment, keeping the temperature at 22 to 24 °C, keeping it clean and well ventilated. Each of the following test groups was administered in the same amount as 30 mg of oseltamivir/kg of animal body weight, or the same amount. Polyacrylic resin IV. Close observation of each indicator, normal intake of water after 8h.
  • Test groups 1-3, 3 which are the oseltamivir pharmaceutical compositions of Examples 1, 2, and 3, respectively, in an amount calculated as 30 mg of oseltamivir/kg of animal body weight.
  • Control group A group 1, oseltamivir drug substance, the dose was 30 mg oseltamivir / kg animal body weight.
  • Control group B 1 group, polyacrylic resin IV, the dosage was 30 mg polyacrylic resin IV/kg animal body weight.
  • Control group C 1 group, a physical mixture of polyacrylic resin IV and oseltamivir 1:1, administered in a mixture of 30 mg of oseltamivir/kg of animal body weight.
  • Control group D group 1, commercially available oseltamivir capsules, manufacturer Roche, administered in capsule contents/kg animal body weight calculated as 30 mg oseltamivir.
  • the pellet of the pharmaceutical composition of the present invention causes less vomiting animals, a longer incubation period and less frequent vomiting and vomiting.
  • a large number of drug-containing pellets were prepared, and the same prescription polyacrylic acid resin IV ethanol solution was prepared to test the taste-masking effect of different amounts of polyacrylic acid resin IV ethanol solution.
  • the test results show that, under the same circumstances, when the ratio of the polyacrylic resin IV of the taste-masking coating material is 16.7%, the taste-masking effect can meet the demand.
  • the ratio of the polyacrylic resin IV is 20%, the taste-masking effect and ratio are 16.7% is slightly better, but the difference is not big, and the ratio of polyacrylic resin IV is 20%.
  • the pellet coating takes time and labor and wastes energy. Therefore, we choose the polyacrylic resin IV ratio of 16.7% for the optimized process prescription.
  • the drug-containing layer suspension needs to adhere to a carrier of a certain particle size, and the most commonly used blank carrier in industrial production is obtained by using certain pharmaceutical excipients.
  • Blank spherical pellets ie blank pellets. According to the different pharmaceutical excipients used, it can be divided into sucrose pellets, microcrystalline cellulose pellets, starch pellets, lactose-microcrystalline cellulose pellets, starch-microcrystalline cellulose pellets, and sucrose-starch pellets. Wait.
  • Sucrose pellets are the most commonly used blank pellets, which have the advantages of easy disintegration, low friability, small particle size deviation, high roundness and narrow particle size distribution. After testing, they can satisfy our requirements for blank pellets. Demand, so we choose sucrose pellets.
  • Hypromellose is a white or yellowish powder, odorless, tasteless, stable to light, heat and humidity, soluble in water at any pH below 60 °C, and ethanol, propanol or isomeric at a concentration below 70%.
  • ethanol a mixed solvent of propanol and dichloromethane (1:1)
  • a low viscosity grade 5 cPa.s
  • talcum powder that meets the Chinese Pharmacopoeia 2010 edition standard as an anti-adhesive agent.
  • the talc powder is white or off-white, fine, sand-free powder, and the hand feels greasy. Odorless, tasteless. It does not dissolve in water, dilute mineral acid or dilute alkali hydroxide solution. Widely used as a pharmaceutical excipient, it has non-toxic, odorless, high whiteness, good compatibility, strong gloss, soft taste and strong smoothness. The pH value is 7-9, which will not change due to degradation. Product characteristics.
  • the oseltamivir fine pellet prepared by the technical scheme of the invention has no toxic and side effects, is convenient for long-term treatment of the patient, and improves the compliance of the medication.
  • the pellets are odorless and tasteless, have good roundness, are not irritating to the oral cavity, and can be prepared into a dosage form suitable for children, especially infants and young children, for the prevention and treatment of influenza in children, especially infants and young children.
  • the auxiliary materials and preparation methods for the oseltamivir pellets prepared by the technical scheme of the invention are all feasible and suitable for expanding industrial production, and the method adopted has good reproducibility, and the pellets of different specifications have the same Prescriptions and processes, only need to change the filling amount of the pellets to get different specifications.
  • the preferred formulation and preparation method of the present invention is the best solution obtained through screening, and the optimized prescription is adopted, and the pellets are prepared by the fluidized bed method, which is odorless and tasteless, and can achieve good release performance of the dosage form in the body. And can At the same time, the preparation of different specifications of the pellets to meet the needs of different weight groups.
  • the effective dosage of the oseltamivir pellets of the present invention is between 10 and 75 mg, and has a plurality of different specifications, and different specifications correspond to different body weights, when the dosage level is 1.0 to 4.0 mg/kg.
  • In vivo experiments showed that the in vivo pharmacokinetic parameters of different specifications of oseltamivir pellets were the same, which was consistent with the demand for blood concentration in patient treatment.
  • the various different specifications of oseltamivir pellets of the present invention are prepared from the same sustained-release pellets, and the total weight of the loaded oseltamivir pellets is adjusted without changing the prescription composition and ratio.
  • the physical stability characteristics of oseltamivir fine pellets prepared by the technical scheme of the present invention can be adapted to the pharmacokinetic characteristics of human body, and can be different according to different population characteristics and required doses.
  • Different oral preparations such as tablets, capsules, dry suspensions and the like are prepared.
  • Different dosage forms and specifications have the same in vitro release characteristics of the oseltamivir fine pellets, and the preparation process is stable.
  • the product of the invention oseltamivir micropellets
  • the preparation process is simple and easy, can be carried out in fluidized bed pharmaceutical process, centrifugal granulation, the yield is more than 90%, high productivity, in line with the requirements of large production,
  • 10,000 to 30,000 units of amplified production can be completed, and the production efficiency is high.
  • the release of the pellets under various conditions in vitro is consistent with the listed capsules, and the in vivo pharmacokinetic study shows that The capsules that have been marketed have bioavailability equivalence. According to the relevant principles of ICH research, it can be used for marketing purposes without clinical trial verification.
  • the oseltamivir micropels of the invention have been tested by accelerated stability test, and the traits are stable, the drug content and related substances are within a controllable range within 12 months, and are suitable for industrial production.
  • the drug-loading pellet core was prepared by using the blank pellet core medicine, and then the masking pellet was prepared by coating the drug-loaded pellet core, and the oseltamivir pellet was obtained.
  • Drug-loaded pellets core group blank sugar pellet core (particle size: 0.10 ⁇ 0.20mm) 150.0g, oseltamivir phosphate 82.0g, hypromellose 28.0g, purified water 500.0g.
  • the taste-masking pellets side 260.0 g of drug-loaded pellet core, 39 g of polyacrylic resin IV, and 390 ml of 95% (by mass) ethanol.
  • Preparation process Weigh the prescribed amount of polyacrylic resin IV, add 95% ethanol solution to dissolve to clarify, make a coating liquid, and set aside.
  • the weight percentage of each component in the oseltamivir phosphate pellets in this example is:
  • the oseltamivir phosphate was 27.4%, the polyacrylic resin IV was 13.0%, the blank sugar pellet core was 50.2%, and the adhesive hypromellose was 9.4%.
  • Example 2 oseltamivir composition pellet and preparation method thereof
  • the drug-loading pellet core was prepared by using the blank pellet core medicine, and then the masking pellet was prepared by coating the drug-loaded pellet core, and the oseltamivir pellet was obtained.
  • Drug-loaded pellets core group blank sugar pellet core (particle size: 0.15 ⁇ 0.25mm) 100.0g, oseltamivir 48.0g, hypromellose 16.0g, talc powder 4.0g, purified water 384.0g.
  • Preparation process Adding 16.0 g of hypromellose to 384.0 g of purified water under stirring, dissolving until clarification, adding 48.0 g of oseltamivir and 4.0 g of talc, stirring for 1 h, passing through a 40 mesh screen, and containing Liquid medicine.
  • the taste-masking pellets were prepared: 168.0 g of drug-loaded pellet core, 33.6 g of polyacrylic resin IV, and 336 ml of 95% (by mass) ethanol.
  • the purified water and ethanol added in this embodiment are subjected to a preparation method, and finally dried to obtain a product, and the purified water and ethanol added are all evaporated;
  • the weight percentage of each component in the oseltamivir pellets in this example is:
  • Example 3 oseltamivir phosphate composition pellet and preparation method thereof
  • the drug-loading pellet core was prepared by using the blank pellet core medicine, and then the masking pellet was prepared by coating the drug-loaded pellet core, and the oseltamivir pellet was obtained.
  • Drug-loaded pellets core group blank microcrystalline cellulose pellet core (particle size: 0.15 ⁇ 0.25mm) 136.0g, 76.2 g of oseltamivir phosphate, 19.3 g of hydroxypropylcellulose, 5.0 g of magnesium stearate, 35.0 g of mannitol, and 677.5 g of purified water.
  • the taste-masking pellets were prepared: 271.5 g of drug-loaded pellet core, 62.7 g of polyacrylic resin IV, and 627 ml of 97% (by mass) ethanol.
  • the weight percentage of each component in the oseltamivir phosphate pellets in this example is:
  • Example 4 oseltamivir composition pellets and preparation method thereof
  • the drug-loading pellet core was prepared by using the blank pellet core medicine, and then the masking pellet was prepared by coating the drug-loaded pellet core, and the oseltamivir pellet was obtained.
  • Drug-loaded pellets core group blank starch pellet core (particle size: 0.10 ⁇ 0.15mm) 153.0g, oseltamivir 40.0g, povidone 12.0g, purified water 265.0g.
  • Preparation process 12.0 g of povidone was added to 265.0 g of purified water under stirring, dissolved to clarification, and 40.0 g of oseltamivir was added thereto, and stirring was continued for 1 hour, and the sieve was passed through a 40 mesh screen to obtain a drug solution.
  • Taste-masking pellets 205.0 g of drug-loaded pellet core, 100 g of polyacrylic resin IV, and 900 ml of 97% (by mass) acetone.
  • Preparation process Weigh the prescribed amount of polyacrylic resin IV, add 97% acetone solution to dissolve to clarify, make a coating liquid, and set aside.
  • the weight percentage of each component in the oseltamivir pellets in this example is:
  • the oseltamivir was 13.1%, the polyacrylic resin IV was 32.8%, the blank starch pellet core was 50.2%, and the binder povidone was 3.9%.
  • Example 5 oseltamivir phosphate composition pellet and preparation method thereof
  • the drug-loaded pellet core was prepared by using a centrifugal coating pan according to the formula, and then the taste-preserving pellet was prepared by coating the drug-loaded pellets with a pellet, thereby obtaining oseltamivir pellets.
  • the drug-loaded pellets core group 100.0 g of microcrystalline cellulose, 80.0 g of oseltamivir phosphate, 16.0 g of hydroxypropylcellulose, and 400.0 g of purified water.
  • Preparation process Weigh the prescribed amount of polyacrylic resin IV, add 97% ethanol solution to dissolve to clarify, make a coating liquid, and set aside.
  • the purified water and ethanol added in this embodiment are subjected to a preparation method, and finally dried to obtain a product, and the purified water and ethanol added are all evaporated;
  • the oseltamivir phosphate was 23.1%, the polyacrylic resin IV was 43.4%, the filler microcrystalline cellulose was 28.9%, and the binder hydroxypropylcellulose was 4.6%.
  • the drug-loaded pellet core was prepared by using a centrifugal coating pan according to the formula, and then the taste-preserving pellet was prepared by coating the drug-loaded pellets with a pellet, thereby obtaining oseltamivir pellets.
  • the drug-loaded pellets core group starch 150.0 g, oseltamivir phosphate 150.0 g, 75% (mass ratio) ethanol 300.0 g.
  • Taste-masking pellets 240.0 g of drug-loaded pellets, 80 g of polyacrylic resin IV, and 720 ml of 90% (by mass) ethanol.
  • Preparation process Weigh a prescribed amount of polyacrylic resin IV, add 90% ethanol solution to dissolve to clarify, make a coating liquid, and set aside.
  • the purified water and ethanol added in this embodiment are subjected to a preparation method, and finally dried to obtain a product, and the purified water and ethanol added are all evaporated;
  • the weight percentage of each component in the oseltamivir phosphate pellets in this example is:
  • Example 7 oseltamivir phosphate composition pellet and preparation method thereof
  • the drug-loaded pellets were prepared by extrusion and rounding according to the formula, and then the pellets were prepared by coating the pellets with the drug-loaded pellets, thereby obtaining oseltamivir pellets.
  • the drug-loaded pellets core group 200.0 g of microcrystalline cellulose, 194.0 g of oseltamivir phosphate, 6.0 g of hypromellose, and 200.0 g of purified water.
  • Preparation process 6.0 g of hypromellose was added to 200.0 g of purified water under stirring, and dissolved to be clarified to obtain a binder solution.
  • Strips were prepared by extrusion of a 0.25 mm aperture sieve. After the preparation of the strips, they were placed in a shearing drum and cut into a circular shape. After the rounding was completed, the strips were taken out and placed in an oven at 60 ° C for 4 hours to take out a particle size of 0.10. The pellets of ⁇ 0.30 mm are inspected, that is, the pellets of the drug-loaded pellets are obtained.
  • Preparation process Weigh the prescribed amount of polyacrylic resin IV, add 95% ethanol solution to dissolve to clarify, make a coating liquid, and set aside.
  • the purified water and ethanol added in this embodiment are subjected to a preparation method, and finally dried to obtain a product, and the purified water and ethanol added are all evaporated;
  • the weight percentage of each component in the oseltamivir phosphate pellets in this example is:
  • Oseltamivir phosphate pellet A core group blank sugar pellet core (particle size: 0.10 ⁇ 0.20mm) 150.0g, oseltamivir phosphate 82.0g, hypromellose 28.0g, purified water 500.0g.
  • Preparation process 28.0 g of hypromellose was added to 500.0 g of purified water under stirring, dissolved to clarification, and 82.0 g of oseltamivir phosphate was added thereto, and stirring was continued for 1 hour, and the sieve was passed through a 40 mesh screen to obtain a drug solution.
  • the drug-loaded pellet core was prepared by using the blank pellet core according to the formula, and the oseltamivir phosphate pellet B was prepared from the drug-loaded pellet core.
  • Drug-loaded pellets core group blank sugar pellet core (particle size: 0.10 ⁇ 0.20mm) 150.0g, oseltamivir phosphate 82.0g, hypromellose 28.0g, purified water 500.0g.
  • Preparation process 28.0 g of hypromellose was added to 500.0 g of purified water under stirring, dissolved to clarification, and 82.0 g of oseltamivir phosphate was added thereto, and stirring was continued for 1 hour, and the sieve was passed through a 40 mesh screen to obtain a drug solution.
  • Group B of oseltamivir phosphate pellets 260.0 g of drug-loaded pellet core, 52 g of hypromellose, and 520 g of deionized water.
  • Preparation process Weigh the prescribed amount of hypromellose, add deionized water to dissolve to clarify, make a coating liquid, and set aside.
  • the drug-loaded pellet core was prepared according to the formula, and the oseltamivir phosphate pellet C was prepared from the drug-loaded pellet core.
  • the drug-loaded pellets core group 100.0 g of microcrystalline cellulose, 80.0 g of oseltamivir phosphate, 16.0 g of hydroxypropylcellulose, and 400.0 g of purified water.
  • Preparation process 16.0 g of hydroxypropylcellulose was added to 400.0 g of purified water under stirring, and dissolved to clarify to obtain a binder solution.
  • Group C of oseltamivir phosphate pellets 196.0 g of drug-loaded pellets, 100 g of Opadry, and 1000 g of deionized water.
  • Preparation process Weigh the prescribed amount of Opadry, add deionized water, stir for 1 hour, and then pass through a 40 mesh screen to prepare a coating liquid, and set aside.

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Abstract

本发明涉及一种适用于婴幼儿及儿童的口服固体颗粒及其制备方法，本发明的口服固体颗粒，由含药丸芯和包衣层组成，含药丸芯中的药物为奥司他韦或其药学上可接受的盐，其占微丸总重量的10％-40％，包衣层所用材料为聚丙烯酸树脂IV，其占微丸总重量的1％-50％，微丸粒径为0.10-0.50mm。

Description

一种适用于婴幼儿及儿童的口服固体颗粒及其制备方法 技术领域
本发明涉及制药领域关于药物制剂的制备方法，具体地说，涉及一种以奥司他韦为主药的适用于婴幼儿及儿童的口服固体颗粒及制备方法。
技术背景
奥司他韦(Oseltamivir)作为一种最新研制的神经氨酸酶抑制剂，广泛应用于临床，其化学名为(3R，4R，5S)-4-乙酰胺-5-氨基-3(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯，结构式如下：
Figure PCTCN2014000836-appb-000001
奥司他韦可作用于流感病毒表面糖蛋白-神经氨酸酶(NA)，从而抑制病毒复制及在呼吸道中的传播，是一种高选择性流感病毒NA抑制剂。奥司他韦于1999年在瑞士上市，上市后的大量临床实践证实奥司他韦具有对A、B型流感病毒具有效、不易耐药和患者耐受性好、安全性高等优点，是一种非常安全、有效的流感预防和治疗用药，也是目前国际上公认的抗禽流感病毒、甲型H1N1流感病毒最有效的药物。1999年奥司他韦上市时仅批准用于成人甲型和以乙型流感的治疗。经过以后长期的临床实践，到2012年12月，经FDA批准，奥司他韦可用于2周龄以上的婴幼儿及儿童使用。AAP、WHO一致推荐刚出生的新生儿即可用药。
微丸是指直径小于2.5mm的小球状口服剂型。将主药与阻滞剂等混合制丸或先制成丸芯后包缓、控释膜衣而制备的缓释与控释微丸，由于属剂量分散型制剂，一次剂量有多个单元组成，于单剂量剂型相比具有许多优点：能提高药物与胃肠道的接触面积，使药物吸收完全，从而提高生物利用度；通过几种不同释药速度 的小丸组合，可获得理想的释药速率，取得预期的血药浓度，并能维持较长的作用时间，避免对胃粘膜的刺激等不良反映；其释药行为是组成一个剂量的多个小丸组成复方影响，在体内的吸收具有良好的重现性；药物在体内很少受到胃排空功能变化的影响，在体内的吸收具有良好得重现性；安全系数高；因此缓、控释微丸是目前认为较理想的缓、控释剂型之一，是目前缓、控释制剂发展的方向。
现在已上市的奥司他韦为普通胶囊剂，需要吞服或者送水吞服，但对于婴幼儿及儿童不能或者不愿自主完成吞咽动作，且不懂得治疗的必要性，同时由于奥司他韦具有很强烈的苦味，往往不配合治疗，对于疾病的治疗带来了很大的困难。因此，改善病人的依从性，这对于婴幼儿及儿童尤为重要。一般需加入大量的甜味剂来掩盖药物的苦味，但添入大量的甜味剂即使人体感觉开始甜但随后感觉苦，主要原因在于人体感觉苦味的敏感部位在于舌根，而且舌根对苦味的敏感性很强，同时大量服用矫味剂对身体有害。因此，有很多研究者采用包裹技术如物理化学法制备含药微囊，物理法如流化床包衣法制备微丸或颗粒，喷雾干燥法制备含药微囊和微球，制备得到苦味药物的颗粒来掩味，这些方法中物理化学的方法在实验研究中应用较多，但其不能完全包封药物，依旧可产生一定的不良口味，并且生产可行性差；物理方法大生产较为可行，但流化床制得的颗粒粒径较大；喷雾干燥的方法制得的粒径较小，但载药量和包封率较低。
为解决这一问题，我们采用了新的处方组合以奥司他韦为主药，在保证发挥药效和安全的前提下，制备了适用于婴幼儿及儿童的口服固体颗粒且对处方和工艺进行了进一步优化，该方法制备的固体颗粒粒径较小(且又能掩盖苦味，婴幼儿及儿童的顺应性好，可进一步制成胶囊剂、口崩片、咀嚼片、混悬剂、颗粒剂。同时，本发明的制备方法简单、药物稳定好、重现性高、易于大规模生产。
发明内容
本发明的目的在于提供一种含有奥司他韦的包衣细微丸的颗粒及制备方法，该微丸无嗅无味，粒度可以制备适合儿童尤其是婴幼儿服用的剂型，用于儿童尤其是婴幼儿流感的预防和治疗。
本发明的另一个目的是提供一种以奥司他韦为活性成分的新的处方组合，该组合适用于我们选定的流化床层积包衣工艺中，能够提供一种工艺简单、药物稳定、重现性高的制剂中间体，可进一步制成胶囊剂、口崩片、咀嚼片、混悬剂、 颗粒剂。
本发明采用的技术方案为：
一种口服药物微丸组合物，由含药丸芯和包衣层组成，含药丸芯中的药物为奥司他韦或其药学上可接受的盐，其占微丸总重量的10％-40％，包衣层所用材料为聚丙烯酸树脂IV，其占微丸总重量的1％-50％，微丸粒径为0.10-0.50mm。
优选的，微丸粒径为0.15-0.35mm，包衣层占微丸总重量的5％-50％；奥司他韦的盐为磷酸奥司他韦。
本发明文中所述奥司他韦，若无特别声明均指磷酸奥司他韦。
本发明的组合物，其中含药丸芯中由空白微丸、药物，填充剂、粘合剂和抗粘剂制备而成，各组分占微丸总重量的百分比如下，药物10％-40％、空白微丸20％-60％、填充剂0％-50％、粘合剂1％-20％、抗粘剂0.5％-5％。
本发明的组合物，
其中，空白微丸可选用蔗糖微丸、微晶纤维素微丸、淀粉微丸、乳糖-微晶纤维素微丸、淀粉-微晶纤维素微丸、蔗糖-淀粉微丸中的一种或者或一种以上；
填充剂可选用蔗糖、乳糖、甘露醇、淀粉、微晶纤维素、海藻多糖、壳聚糖中的一种或一种以上；
粘合剂可选用水、乙醇、羟丙甲纤维素、聚丙烯酸树酯、羟丙基纤维素、聚维酮、聚乙烯醇、羧甲基纤维素钠中的一种或一种以上；
所述药物组合物微丸中的抗粘剂为滑石粉、胶态二氧化硅、硬脂酸镁、硬脂酸钙、硅酸镁、单硬脂酸甘油酯中的一种或一种以上。
优选的，本发明的组合物，空白微丸为蔗糖微丸；所述的填充剂为乳糖和/或甘露醇；所述的粘合剂为羟丙甲纤维素；所述的抗粘剂为滑石粉。
更优选的，本发明的组合物，各组分占微丸总重量的百分比如下，奥司他韦10％-30％(w/w)、聚丙烯酸树脂IV5％-50％、蔗糖微丸20％-60％、乳糖和/或甘露醇0％-50％、羟丙甲纤维素1％-20％、滑石粉0.5％-5％。
最优选的，本发明的组合物，各组分占微丸总重量的百分比如下，奥司他韦23.8％(w/w)、聚丙烯酸树脂IV16.7％、蔗糖微丸49.6％、羟丙甲纤维素7.9％、滑石粉2.0％。
本发明的口服药物组合物微丸，其特征在于：该药物组合物微丸可进一步制成胶囊剂、片剂、微丸、颗粒剂、混悬剂。
本发明的口服药物组合物微丸，其特征在于，所述制备方法包括以下步骤：
a、将所需原料粉碎过120目筛网，所需辅料粉碎过80目筛网，将奥司他韦、填充剂和抗粘剂在搅拌状态下加入粘合剂溶液中，形成载药层材料混悬液，将优选的混悬液采用流化床上药或包衣锅上药，载药层材料在一个适合的压力下雾化后喷射至流化床中，在一定温度下，载药层材料形成药层附着于空白微丸上。空白微丸在一定的流化速度下，可获得含量均匀、粒径均一的载药微丸。根据刚开始采用的空白微丸的粒径和相应的处方工艺，载药微丸粒径可控制在0.10至0.50mm的范围中，经过优选控制载药的粒径在0.25±0.10mm范围内。
b、将聚丙烯酸树脂IV加入乙醇溶液中，采用流化床包衣或包衣锅包衣，聚
丙烯酸树脂IV溶液在一个适合的压力下雾化后喷射至流化床中，在一定温度
下，包衣材料形成衣膜附着于微丸上，即得。
制备方法中，所述粘合剂溶液是由粘合剂加水混合制备而成，加水量为粘合剂重量的5-100倍；所述包衣液是聚丙烯酸树脂IV加乙醇溶液混合制备而成，乙醇溶液为50-99％的乙醇，加乙醇量为聚丙烯酸树脂IV重量的5-100倍。
以下通过实验数据进一步说明本发明的有益效果：
试验一、口感评价
采用实施例1-6以及对比例1-3所制得的微丸(含奥司他韦30mg)，取微丸适量(含奥司他韦30mg)，品尝口感。
结果，实施例1-6的各样品均无明显不良口感，无涩感，而对比例1-3的样品均存在明显的涩感。
试验二、考察本发明组合物对家鸽呕吐模型的影响
1、实验动物：健康家鸽，雌雄兼用，体重350±50g，普通级，购于养殖基地。
2、实验药物及给药量：
健康家鸽70只，随机分成7组。实验前适应性饲养1周，饲养期间正常饮食饮水，实验前禁食4h，室温保持22～24℃，保持清洁，通风良好。分别按下面各试药组给药，给药量均相同于30mg奥司他韦/kg动物体重，或者与其相同的量 的聚丙烯酸树脂IV。密切观察各个指标，8h后正常进食进水。
(1)试验组1-3，3组，分别为实施例1、2、和3的奥司他韦药物组合物，给药量为以30mg奥司他韦计算的组合物/kg动物体重。
(2)对照组A，1组，奥司他韦原料药，给药量为30mg奥司他韦/kg动物体重。
(3)对照组B，1组，聚丙烯酸树脂IV，给药量为30mg聚丙烯酸树脂IV/kg动物体重。
(4)对照组C，1组，聚丙烯酸树脂IV与奥司他韦1∶1的物理混合物，给药量为以30mg奥司他韦计算的混合物/kg动物体重。
(5)对照组D，1组，市售磷酸奥司他韦胶囊，生产厂家罗氏，给药量为以30mg奥司他韦计算的胶囊内容物/kg动物体重。
3、实验方法：
观察指标：家鸽发生呕吐潜伏期(指给药后至发生第一次呕吐的时间)，呕吐次数(指给药后发生每一阵呕吐的次数，其中一阵呕吐指从家鸽发生伸脖、张口、耸肩、腹部收缩到家鸽恢复平静计为1次呕吐)和呕吐频率(指每阵呕吐中家鸽发生伸脖、张口、耸肩、腹部收缩的次数)。
按以上分组经灌胃给予每只动物药液30mg奥司他韦/kg动物体重，记录每只动物灌胃后呕吐潜伏期(min)，同时记录每只动物自灌胃开始起5小时内的呕吐次数和呕吐频率。
在每组内，统计出现呕吐的动物数(n)，对于出现呕吐(包括有呕吐物的呕吐和无呕吐物的干呕的总和)的动物计算它们的潜伏期
Figure PCTCN2014000836-appb-000002
平均呕吐次数和平均呕吐频率。结果见下表：
表1家鸽动物实验呕吐情况比较
Figure PCTCN2014000836-appb-000003
Figure PCTCN2014000836-appb-000004
Figure PCTCN2014000836-appb-000005
可见，本发明药物组合物微丸所造成的呕吐动物少，潜伏期长并且呕吐次数和呕吐频率少。
试验三、最优选的配方筛选
本发明最优选的配方筛选如下：
(1)聚丙烯酸树脂IV
奥司他韦具有很强烈的苦味，但我们服药时，如果奥司他韦直接接触口腔黏膜，我们能明显感受到苦味，为了掩盖药物的苦味，减少刺激性，本发明的含药微丸外面需要加入一层隔离层，我们在甲基纤维素、聚丙烯酸树脂IV、羟丙甲纤维素、羟丙基纤维素、聚维酮、及乙基纤维素进行了筛选，最终选用聚丙烯酸树脂IV作为掩味包衣层材料。聚丙烯酸树脂IV常用做掩味包衣层材料，我们选择不同的聚丙烯酸树脂IV层厚度，即不同的聚丙烯酸树脂IV比例，考察其掩味效果的影响。
制备一大批含药微丸，配制同一处方的聚丙烯酸树脂IV乙醇溶液，试验不同量的聚丙烯酸树脂IV乙醇溶液的掩味效果。由试验结果表明：在相同的情况下，掩味包衣层材料聚丙烯酸树脂IV比例为16.7％时，掩味效果能够满足需求，聚丙烯酸树脂IV比例为20％时，掩味效果与比例为16.7％稍好，但区别不大，而聚丙烯酸树脂IV比例为20％的情况下微丸包衣费时费工、浪费能源，所以我们选择聚丙烯酸树脂IV比例为16.7％为优化的工艺处方。
(2)空白微丸
采用流化床上药或包衣锅上药时，含药层混悬液需要粘附到一定粒径的载体上，工业化生产中最常用的空白载体就是使用一定的药用辅料制备而得到的空白球形小丸，即空白微丸。根据使用的药用辅料的不同，可以分为蔗糖微丸、微晶纤维素微丸、淀粉微丸、乳糖-微晶纤维素微丸、淀粉-微晶纤维素微丸、蔗糖-淀粉微丸等。蔗糖微丸为最常用的空白微丸，其具有易崩解、脆碎度低、粒度偏差小、圆整度高，粒径分布范围窄等优点，经过试验，能够满足我们对空白微丸的需求，故我们选择蔗糖微丸。
(3)粘合剂
为了使原料药能够粘附于空白微丸之上，需要加入一定量的粘合剂。羟丙甲纤维素为白色或微黄色粉末，无臭，无味，对光、热、湿均稳定，能溶于60℃以下任何pH的水中，以及浓度为70％以下的乙醇、丙醇或异丙醇和二氯甲烷的混合溶剂(1∶1)中，为目前应用最广泛的粘合剂。我们选用低粘度级别(5cPa.s)，在本处方中作为制备含药微丸的粘合剂。
我们对不同的羟丙甲纤维素的量进行筛选，采用相同的包衣参数，以上药后所得含药微丸中主药的回收率以及上药后对药物溶出的影响为考察指标进行处分筛选。试验结果表明：在相同的情况下，粘合剂羟丙甲纤维素比例为7.9％时，含药微丸中主药的回收率达到97.8％，同时对微丸中主药的溶出也没有影响。
(4)抗粘剂
由于奥司他韦在上药包衣过程中，含药微丸容易相互粘连，聚集成团。故需要加入一定的粘合剂，我们选用符合中国药典2010版标准的滑石粉作为抗粘剂。滑石粉为白色或类白色、微细、无砂性的粉末，手摸有油腻感。无臭，无味。在水、稀矿酸或稀氢氧化碱溶液中均不溶解。用途广泛，作为药用辅料，具有无毒、无味、白色度高，可容性好、光泽度强、口味柔软、光滑度强特点，pH值为7-9，不会因为降解而改变原有产品的特性。
试验结果表明：在相同的情况下，加入2.0％的滑石粉即能明显改善含药微丸容易相互粘连，聚集成团情况，满足我们的要求。
本发明的积极有益效果：
1、利用本发明技术方案制备的奥司他韦细微丸无毒副作用，便于患者长期治疗，并改善了用药的依从性。该微丸无嗅无味，具有良好的圆整度，对口腔无砂物明刺激，粒度可以制备适合儿童尤其是婴幼儿服用的剂型，用于儿童尤其是婴幼儿流感的预防和治疗。
2、本发明技术方案制备的奥司他韦微丸所选用的辅料与制备方法均易得可行，适宜扩大工业化生产，所采用的方法具有良好的重现性，不同规格的微丸具有相同的处方和工艺，仅需改变微丸的填充量即可得到不同的规格。特别是本发明优选的配方和制备方法，是经过筛选获得的最佳方案，选用优化的处方，采用流化床上药法制备微丸，无嗅无味，可实现该剂型在体内良好的释放性能，并能 同时制备不同规格的微丸适应不同的体重人群的需要。
3、本发明的奥司他韦微丸的有效剂量在10～75mg之间，具有多个不同的规格，不同规格对应不同体重的用药对象，当给药水平在1.0～4.0mg/kg时，体内实验表明不同规格的奥司他韦微丸的体内药动学的各个参数相同，符合病患治疗对血药浓度的需求。本发明的多种不同的规格的奥司他韦微丸均由同一种缓释微丸制备而成，无需更改处方组成和比例，只需调节装入的奥司他韦微丸的总重量即可得到不同规格的奥司他韦微丸处方，可减少申报更改药品剂量中的申报手续和资料。同时，由于采用同一种微丸制备而成，不同规格的奥司他韦微丸之间体外释放度和体内药动学参数差异极小，不同释放条件下均F2大于90，提高了用药安全性。
4、本发明技术方案制备的奥司他韦细微丸粒度、圆整度、稳定性等物理稳定性特性均能适合人体内药代动力学特征，可以根据不同的人群特征和所需剂量的不同制备出不同的口服制剂，比如：片剂、胶囊剂、干混悬剂等。不同剂型和规格均以该奥司他韦细微丸体外释放特征相同，制剂上工艺为稳定。
5、本发明产品奥司他韦微丸，制备过程工艺简单易行，可采用流化床上药法工艺、离心造粒，产率达到90％以上，产效高，符合大生产的要求，在实验室规模下，已能完成10000～30000单位的放大生产，生产效率高；同时，该微丸在体外多个条件下释放与已上市胶囊剂一致，经体内药代动力学研究表明，与已上市胶囊剂具有生物利用度等效性。依照ICH研究有关原则，无需临床试验验证即可达上市目的。
6、本发明产品奥司他韦微丸，经加速稳定性试验考察，12个月内性状稳定、药物含量、有关物质均在可控范围内，适宜工业化生产。
具体实施方式
以下为本发明的具体实施方式，实施例是为进一步描述本发明而不是限制本发明。凡与本发明等效的技术方案均属于本发明的保护范围内。
实施例1磷酸奥司他韦组合物微丸及其制备方法
先按配方用空白丸芯上药制备出载药微丸丸芯，再由载药微丸丸芯包衣制得掩味微丸，即得奥司他韦微丸。
(1)磷酸奥司他韦载药微丸丸芯制备过程
载药微丸丸芯组方：空白糖丸丸芯(粒径：0.10～0.20mm)150.0g，磷酸奥司他韦82.0g，羟丙甲纤维素28.0g，纯化水500.0g。
制备过程：在搅拌下向纯化水500.0g中加入羟丙甲纤维素28.0g，溶解至澄清，加入磷酸奥司他韦82.0g，继续搅拌1h，过40目筛网，得含药液。
取空白糖丸丸芯(粒径：0.10～0.20mm)150.0g放入流化床内，调节流化温度至50℃，调整进风量50m3*h-1，将配制好的含药层包衣液用蠕动泵通过底喷方式以2ml/min的流速加入至雾化室雾化包衣，雾化压力为1.2bar，逐渐提高供液速率到6ml/min，直至，包衣结束后，继续在流化床内流化干燥30min，即得载药微丸丸芯。(该部分为上药过程，叙述中不要用包衣表述，以免与下一步包衣过程产生混淆)
(2)掩味微丸制备过程
掩味微丸组方：载药微丸丸芯260.0g，聚丙烯酸树脂IV 39g，95％(质量比)的乙醇390ml。
制备过程：称取处方量的聚丙烯酸树脂IV，加入95％乙醇溶液溶解至澄清，制成包衣液，备用。
取载药微丸丸芯260.0g，调节流化温度至35℃、干燥空气流量60m3*h-1，取上述掩味包衣液，用蠕动泵以底喷方式2ml/min的流速泵入雾化室雾化包衣，雾化压力为1.0bar，逐步提高泵入速率到10ml/min至包衣液用完，提高流化温度到50℃，继续在流化床中流化干燥30min后取出，选取粒径0.10～0.30mm之间微丸，检查合格后即为掩味微丸。
说明：本实施例加入的纯化水和乙醇经过制备方法，最终经干燥得到产品，其加入的纯化水和乙醇全部蒸发；
经核算，本例中磷酸奥司他韦微丸中各组分的重量百分比为：
磷酸奥司他韦27.4％，聚丙烯酸树脂IV 13.0％，空白糖丸丸芯50.2％，粘合剂羟丙甲纤维素9.4％。
实施例2奥司他韦组合物微丸及其制备方法
先按配方用空白丸芯上药制备出载药微丸丸芯，再由载药微丸丸芯包衣制得掩味微丸，即得奥司他韦微丸。
(1)载药微丸丸芯制备过程
载药微丸丸芯组方：空白糖丸丸芯(粒径：0.15～0.25mm)100.0g，奥司他韦48.0g，羟丙甲纤维素16.0g，滑石粉4.0g，纯化水384.0g。
制备过程：在搅拌下向纯化水384.0g中加入羟丙甲纤维素16.0g，溶解至澄清，加入奥司他韦48.0g和滑石粉4.0g，继续搅拌1h，过40目筛网，得含药液。
取空白糖丸丸芯(粒径：0.15～0.25mm)100.0g放入流化床内，调节流化温度至50℃，调整进风量50m3*h-1，将配制好的含药层包衣液用蠕动泵通过底喷方式以2ml/min的流速加入至雾化室雾化包衣，雾化压力为1.0bar，逐渐提高供液速率到5ml/min，直至包衣液包完，包衣结束后，继续在流化床内流化干燥30min，即得载药微丸丸芯。
(2)掩味微丸制备过程
掩味微丸组方：载药微丸丸芯168.0g，聚丙烯酸树脂IV 33.6g，95％(质量比)的乙醇336ml。
制备过程：称取处方量的聚丙烯酸树脂IV，加入95％乙醇溶液溶解至澄清，制成包衣液，备用。
取载药微丸丸芯168.0g，调节流化温度至35℃、干燥空气流量60m3*h-1，取上述掩味包衣液，用蠕动泵以底喷方式2ml/min的流速泵入雾化室雾化包衣，雾化压力为1.0bar，逐步提高泵入速率到8ml/min至包衣液用完，提高流化温度到50℃，继续在流化床中流化干燥30分钟后取出，选取粒径0.15～0.35mm之间微丸，检查合格后即为掩味微丸。
说明：本实施例加入的纯化水和乙醇经过制备方法，最终经干燥得到产品，其加入的纯化水和乙醇全部蒸发；
经核算，本例中奥司他韦微丸中各组分的重量百分比为：
奥司他韦23.8％，聚丙烯酸树脂IV 16.7％，空白糖丸丸芯49.6％，粘合剂羟丙甲纤维素7.9％，抗粘剂滑石粉2.0％。
实施例3磷酸奥司他韦组合物微丸及其制备方法
先按配方用空白丸芯上药制备出载药微丸丸芯，再由载药微丸丸芯包衣制得掩味微丸，即得奥司他韦微丸。
(1)载药微丸丸芯制备过程
载药微丸丸芯组方：空白微晶纤维素丸芯(粒径：0.15～0.25mm)136.0g， 磷酸奥司他韦76.2g，羟丙基纤维素19.3g，硬脂酸镁5.0g，甘露醇35.0g，纯化水677.5g。
制备过程：在搅拌下向纯化水677.5g中加入羟丙基纤维素19.3g和甘露醇35.0g，溶解至澄清，加入磷酸奥司他韦76.2g和硬脂酸镁5.0g，继续搅拌1h，过40目筛网，得含药液。
取空白微晶纤维素丸芯(粒径：0.15～0.25mm)136.0g放入流化床内，调节流化温度至45℃，调整进风量50m3*h-1，将配制好的含药层包衣液用蠕动泵通过底喷方式以2ml/min的流速加入至雾化室雾化包衣，雾化压力为1.4bar，逐渐提高供液速率到8ml/min，直至包衣液包完，包衣结束后，继续在流化床内流化干燥30min，即得载药微丸丸芯。
(2)掩味微丸制备过程
掩味微丸组方：载药微丸丸芯271.5g，聚丙烯酸树脂IV 62.7g，97％(质量比)的乙醇627ml。
制备过程：称取处方量的聚丙烯酸树脂IV，加入97％乙醇溶液溶解至澄清，制成包衣液，备用。
取载药微丸丸芯271.5g，调节流化温度至35℃、干燥空气流量60m3*h-1，取上述掩味包衣液，用蠕动泵以底喷方式2ml/min的流速泵入雾化室雾化包衣，雾化压力为1.2bar，逐步提高泵入速率到10ml/min至包衣液用完，提高流化温度到50℃，继续在流化床中流化干燥30min后取出，选取粒径0.15～0.35mm之间微丸，检查合格后即为掩味微丸。
说明：本实施例加入的纯化水和乙醇经过制备方法，最终经干燥得到产品，其加入的纯化水和乙醇全部蒸发；
经核算，本例中磷酸奥司他韦微丸中各组分的重量百分比为：
磷酸奥司他韦22.8％，聚丙烯酸树脂IV 18.8％，空白微晶纤维素丸芯40.7％，填充剂甘露醇10.5％，粘合剂羟丙基纤维素5.8％，抗粘剂硬脂酸镁1.5％。
实施例4奥司他韦组合物微丸及其制备方法
先按配方用空白丸芯上药制备出载药微丸丸芯，再由载药微丸丸芯包衣制得掩味微丸，即得奥司他韦微丸。
(1)载药微丸丸芯制备过程
载药微丸丸芯组方：空白淀粉丸芯(粒径：0.10～0.15mm)153.0g，奥司他韦40.0g，聚维酮12.0g，纯化水265.0g。
制备过程：在搅拌下向纯化水265.0g中加入聚维酮12.0g，溶解至澄清，加入奥司他韦40.0g，继续搅拌1h，过40目筛网，得含药液。
取空白淀粉丸芯(粒径：0.10～0.15mm)153.0g放入流化床内，调节流化温度至45℃，调整进风量50m3*h-1，将配制好的含药层包衣液用蠕动泵通过底喷方式以1.5ml/min的流速加入至雾化室雾化包衣，雾化压力为1.0bar，逐渐提高供液速率到5ml/min，直至包衣液包完，包衣结束后，继续在流化床内流化干燥30min，即得载药微丸丸芯。
(2)掩味微丸制备过程
掩味微丸组方：载药微丸丸芯205.0g，聚丙烯酸树脂IV 100g，97％(质量比)的丙酮900ml。
制备过程：称取处方量的聚丙烯酸树脂IV，加入97％丙酮溶液溶解至澄清，制成包衣液，备用。
取载药微丸丸芯205.0g，调节流化温度至30℃、干燥空气流量65m3*h-1，取上述掩味包衣液，用蠕动泵以底喷方式2ml/min的流速泵入雾化室雾化包衣，雾化压力为1.2bar，逐步提高泵入速率到12ml/min至包衣液用完，提高流化温度到50℃，继续在流化床中流化干燥30min后取出，选取粒径0.10～0.25mm之间微丸，检查合格后即为掩味微丸。
说明：本实施例加入的纯化水和乙醇经过制备方法，最终经干燥得到产品，其加入的纯化水和丙酮全部蒸发；
经核算，本例中奥司他韦微丸中各组分的重量百分比为：
奥司他韦13.1％，聚丙烯酸树脂IV 32.8％，空白淀粉丸芯50.2％，粘合剂聚维酮3.9％。
实施例5磷酸奥司他韦组合物微丸及其制备方法
先按配方用离心包衣锅制备出载药微丸丸芯，再由载药微丸丸芯包衣制得掩味微丸，即得奥司他韦微丸。
(1)磷酸奥司他韦载药微丸丸芯制备过程
载药微丸丸芯组方：微晶纤维素100.0g，磷酸奥司他韦80.0g，羟丙基纤维素16.0g，纯化水400.0g。
制备过程：在搅拌下向纯化水400.0g中加入羟丙基纤维素16.0g，溶解至澄清，得粘合剂溶液。
取微晶纤维素100.0g和磷酸奥司他韦80.0g放入离心包衣锅内，调节离心包衣锅温度至55℃，调整进风量70m3*h-1，将配制好的粘合剂溶液用蠕动泵以4ml/min的流速加入至离心包衣锅内包衣，雾化压力为1.5bar，逐渐提高供液速率到8ml/min，直至粘合剂溶液喷完，包衣结束后，继续在离心包衣锅内干燥30min，即得载药微丸丸芯。
(2)掩味微丸制备过程
掩味微丸组方：载药微丸丸芯196.0g，聚丙烯酸树脂IV 150g，97％(质量比)的乙醇1350ml。
制备过程：称取处方量的聚丙烯酸树脂IV，加入97％乙醇溶液溶解至澄清，制成包衣液，备用。
取载药微丸丸芯196.0g放入离心包衣锅内，调节离心包衣锅温度至40℃，调整进风量90m3*h-1，将配制好的掩味包衣液用蠕动泵以3ml/min的流速加入至离心包衣锅内包衣，雾化压力为1.2bar，逐渐提高供液速率到10ml/min，直至粘合剂溶液喷完，包衣结束后，提高流化温度到50℃，继续在离心包衣锅中流化干燥30min后取出，选取粒径0.10～0.30mm之间微丸，检查合格后即为掩味微丸。
说明：本实施例加入的纯化水和乙醇经过制备方法，最终经干燥得到产品，其加入的纯化水和乙醇全部蒸发；
经核算，本例中磷酸奥司他韦微丸中各组分的重量百分比为：
磷酸奥司他韦23.1％，聚丙烯酸树脂IV 43.4％，填充剂微晶纤维素28.9％，粘合剂羟丙基纤维素4.6％。
实施例6磷酸奥司他韦组合物微丸及其制备方法
先按配方用离心包衣锅制备出载药微丸丸芯，再由载药微丸丸芯包衣制得掩味微丸，即得奥司他韦微丸。
(1)磷酸奥司他韦载药微丸丸芯制备过程
载药微丸丸芯组方：淀粉150.0g，磷酸奥司他韦150.0g，75％(质量比)乙醇300.0g。
制备过程：
取淀粉150.0g和磷酸奥司他韦150.0g放入离心包衣锅内，调节离心包衣锅温度至45℃，调整进风量65m3*h-1，将75％(质量比)乙醇300.0g用蠕动泵以3ml/min的流速加入至离心包衣锅内包衣，雾化压力为1.0bar，逐渐提高供液速率到6ml/min，直至粘合剂溶液喷完，包衣结束后，继续在离心包衣锅内干燥30min，即得载药微丸丸芯。
(2)掩味微丸制备过程
掩味微丸组方：载药微丸丸芯240.0g，聚丙烯酸树脂IV 80g，90％(质量比)的乙醇720ml。
制备过程：称取处方量的聚丙烯酸树脂IV，加入90％乙醇溶液溶解至澄清，制成包衣液，备用。
取载药微丸丸芯240.0g放入离心包衣锅内，调节离心包衣锅温度至40℃，调整进风量70m3*h-1，将配制好的掩味包衣液用蠕动泵以2ml/min的流速加入至离心包衣锅内包衣，雾化压力为1.4bar，逐渐提高供液速率到6ml/min，直至粘合剂溶液喷完，包衣结束后，提高流化温度到45℃，继续在离心包衣锅中流化干燥30分钟后取出，选取粒径0.10～0.25mm之间微丸，检查合格后即为掩味微丸。
说明：本实施例加入的纯化水和乙醇经过制备方法，最终经干燥得到产品，其加入的纯化水和乙醇全部蒸发；
经核算，本例中磷酸奥司他韦微丸中各组分的重量百分比为：
磷酸奥司他韦37.5％，聚丙烯酸树脂IV 25.0％，填充剂淀粉37.5％。
实施例7磷酸奥司他韦组合物微丸及其制备方法
先按配方挤出滚圆制备出载药微丸丸芯，再由载药微丸丸芯包衣制得掩味微丸，即得奥司他韦微丸。
(1)磷酸奥司他韦载药微丸丸芯制备过程
载药微丸丸芯组方：微晶纤维素200.0g，磷酸奥司他韦194.0g，羟丙甲纤维素6.0g，纯化水200.0g。
制备过程：在搅拌下向纯化水200.0g中加入羟丙甲纤维素6.0g，溶解至澄清，得粘合剂溶液。
取微晶纤维素200.0g和磷酸奥司他韦194.0g，混合均匀，用上述粘合剂制备软材；打开低温制冷机，温度控制在3～15℃，将软材放进料槽中用0.25mm孔径的筛板挤出制备条状物，条状物制备完成后放进剪切滚圆桶中剪切滚圆，滚圆完成后取出，放置到烘箱中60℃干燥4小时取出，取粒径0.10～0.30mm的微丸进行检查，即得载药微丸丸芯。
(2)掩味微丸制备过程
掩味微丸组方：载药微丸丸芯400.0g，聚丙烯酸树脂IV 100g，95％(质量比)的乙醇900ml。
制备过程：称取处方量的聚丙烯酸树脂IV，加入95％乙醇溶液溶解至澄清，制成包衣液，备用。
取载药微丸丸芯400.0g，调节流化温度至35℃、干燥空气流量65m3*h-1，取上述掩味包衣液，用蠕动泵以底喷方式3ml/min的流速泵入雾化室雾化包衣，雾化压力为1.2bar，逐步提高泵入速率到12ml/min至包衣液用完，提高流化温度到50℃，继续在流化床中流化干燥30min后取出，选取粒径0.10～0.30mm之间微丸，检查合格后即为掩味微丸。
说明：本实施例加入的纯化水和乙醇经过制备方法，最终经干燥得到产品，其加入的纯化水和乙醇全部蒸发；
经核算，本例中磷酸奥司他韦微丸中各组分的重量百分比为：
磷酸奥司他韦38.8％，聚丙烯酸树脂IV 20.0％，填充剂微晶纤维素40.0％，粘合剂羟丙甲纤维素1.2％。
比较例1磷酸奥司他韦微丸A及其制备方法
磷酸奥司他韦微丸A丸芯组方：空白糖丸丸芯(粒径：0.10～0.20mm)150.0g，磷酸奥司他韦82.0g，羟丙甲纤维素28.0g，纯化水500.0g。
制备过程：在搅拌下向纯化水500.0g中加入羟丙甲纤维素28.0g，溶解至澄清，加入磷酸奥司他韦82.0g，继续搅拌1h，过40目筛网，得含药液。
取空白糖丸丸芯(粒径：0.10～0.20mm)150.0g放入流化床内，调节流化温度至50℃，调整进风量50m3*h-1，将配制好的含药层包衣液用蠕动泵通过底喷 方式以2ml/min的流速加入至雾化室雾化包衣，雾化压力为1.2bar，逐渐提高供液速率到6ml/min，直至包衣液包完，包衣结束后，继续在流化床内流化干燥30min，即得磷酸奥司他韦微丸A。
比较例2磷酸奥司他韦微丸B及其制备方法
先按配方用空白丸芯上药制备出载药微丸丸芯，再由载药微丸丸芯制备磷酸奥司他韦微丸B。
(1)磷酸奥司他韦载药微丸丸芯制备过程
载药微丸丸芯组方：空白糖丸丸芯(粒径：0.10～0.20mm)150.0g，磷酸奥司他韦82.0g，羟丙甲纤维素28.0g，纯化水500.0g。
制备过程：在搅拌下向纯化水500.0g中加入羟丙甲纤维素28.0g，溶解至澄清，加入磷酸奥司他韦82.0g，继续搅拌1h，过40目筛网，得含药液。
取空白糖丸丸芯(粒径：0.10～0.20mm)150.0g放入流化床内，调节流化温度至50℃，调整进风量50m3*h-1，将配制好的含药层包衣液用蠕动泵通过底喷方式以2ml/min的流速加入至雾化室雾化包衣，雾化压力为1.2bar，逐渐提高供液速率到6ml/min，直至包衣液包完，包衣结束后，继续在流化床内流化干燥30min，即得载药微丸丸芯。
(2)磷酸奥司他韦微丸B制备过程
磷酸奥司他韦微丸B组方：载药微丸丸芯260.0g，羟丙甲纤维素52g，去离子水520g。
制备过程：称取处方量的羟丙甲纤维素，加入去离子水溶解至澄清，制成包衣液，备用。
取载药微丸丸芯260.0g，调节流化温度至50℃、干燥空气流量60m3*h-1，取上述掩味包衣液，用蠕动泵以底喷方式2ml/min的流速泵入雾化室雾化包衣，雾化压力为1.4bar，逐步提高泵入速率到8ml/min至包衣液用完，提高流化温度到60℃，继续在流化床中流化干燥30min后取出，选取粒径0.10～0.30mm之间微丸，检查合格后即为磷酸奥司他韦微丸B。
比较例3磷酸奥司他韦微丸C及其制备方法
先按配方制备出载药微丸丸芯，再由载药微丸丸芯制备磷酸奥司他韦微丸C。
(1)磷酸奥司他韦载药微丸丸芯制备过程
载药微丸丸芯组方：微晶纤维素100.0g，磷酸奥司他韦80.0g，羟丙基纤维素16.0g，纯化水400.0g。
制备过程：在搅拌下向纯化水400.0g中加入羟丙基纤维素16.0g，溶解至澄清，得粘合剂溶液。
取微晶纤维素100.0g和磷酸奥司他韦80.0g放入离心包衣锅内，调节离心包衣锅温度至55℃，调整进风量70m3*h-1，将配制好的粘合剂溶液用蠕动泵以4ml/min的流速加入至离心包衣锅内包衣，雾化压力为1.5bar，逐渐提高供液速率到8ml/min，直至粘合剂溶液喷完，包衣结束后，继续在离心包衣锅内干燥30min，即得载药微丸丸芯。
(2)磷酸奥司他韦微丸C制备过程
磷酸奥司他韦微丸C组方：载药微丸丸芯196.0g，欧巴代100g，去离子水1000g。
制备过程：称取处方量的欧巴代，加入去离子水，搅拌1h后，过40目筛网，制成包衣液，备用。
取载药微丸丸芯196.0g放入离心包衣锅内，调节离心包衣锅温度至45℃，调整进风量90m3*h-1，将配制好的掩味包衣液用蠕动泵以3ml/min的流速加入至离心包衣锅内包衣，雾化压力为1.4bar，逐渐提高供液速率到12ml/min，直至粘合剂溶液喷完，包衣结束后，提高流化温度到50℃，继续在离心包衣锅中流化干燥30min后取出，选取粒径0.10～0.30mm之间微丸，检查合格后即为磷酸奥司他韦微丸C。

Claims (10)

  1. 一种口服药物微丸组合物，由含药丸芯和包衣层组成，含药丸芯中的药物为奥司他韦或其药学上可接受的盐，其占微丸总重量的10％-40％，包衣层所用材料为聚丙烯酸树脂IV，其占微丸总重量的1％-50％，微丸粒径为0.10-0.50mm。
  2. 根据权利要求1所述的组合物，其特征在于：微丸粒径为0.15-0.35mm，包衣层占微丸总重量的5％-50％；奥司他韦的盐为磷酸奥司他韦。
  3. 根据权利要求1所述的组合物，其特征在于：含药丸芯由空白微丸、药物，填充剂、粘合剂和抗粘剂制备而成，各组分占微丸总重量的百分比如下，药物10％-40％、空白微丸20％-60％、填充剂0％-50％、粘合剂1％-20％、抗粘剂0.5％-5％。
  4. 根据权利要求3所述的组合物，其特征在于：
    所述空白微丸选自：蔗糖微丸、微晶纤维素微丸、淀粉微丸、乳糖-微晶纤维素微丸、淀粉-微晶纤维素微丸、蔗糖-淀粉微丸中的一种或者或一种以上；
    所述填充剂选自：蔗糖、乳糖、甘露醇、淀粉、微晶纤维素、海藻多糖、壳聚糖中的一种或一种以上；
    所述粘合剂选自：水、乙醇、羟丙甲纤维素、聚丙烯酸树酯、羟丙基纤维素、聚维酮、聚乙烯醇、羧甲基纤维素钠中的一种或一种以上；
    所述抗粘剂选自：滑石粉、胶态二氧化硅、硬脂酸镁、硬脂酸钙、硅酸镁、单硬脂酸甘油酯中的一种或一种以上。
  5. 根据权利要求4所述的组合物，其特征在于：所述的空白微丸为蔗糖微丸；所述的填充剂为乳糖和/或甘露醇；所述的粘合剂为羟丙甲纤维素；所述的抗粘剂为滑石粉。
  6. 根据权利要求5所述的组合物，其特征在于：各组分占微丸总重量的百分比如下，奥司他韦10％-30％、聚丙烯酸树脂IV 5％-50％、蔗糖微丸20％-60％、 乳糖和/或甘露醇0％-50％、羟丙甲纤维素1％-20％、滑石粉0.5％-5％。
  7. 根据权利要求6所述的组合物，其特征在于：各组分占微丸总重量的百分比如下，奥司他韦23.8％、聚丙烯酸树脂IV 16.7％、蔗糖微丸49.6％、羟丙甲纤维素7.9％、滑石粉2.0％。
  8. 根据权利要求1所述的组合物，其特征在于：可进一步制成胶囊剂、片剂、微丸、颗粒剂、混悬剂。
  9. 一种权利要求1所述的组合物的制备方法，其特征在于，包括以下步骤：
    a、将药物、填充剂和抗粘剂在搅拌状态下加入粘合剂溶液中，形成混悬液，将混悬液包裹在空白微丸上，包裹采用流化床上药或包衣锅上药，载药微丸粒径控制在0.10至0.50mm的范围中；
    b、将聚丙烯酸树脂IV加入乙醇溶液中，制备成包衣液，采用流化床包衣或包衣锅包衣，形成包衣膜附着于丸芯上，即得包衣微丸。
  10. 根据权利要求9所述的制备方法，其特征在于，所述粘合剂溶液是由粘合剂加水混合制备而成，加水量为粘合剂重量的5-100倍；所述包衣液是聚丙烯酸树脂IV加乙醇溶液混合制备而成，乙醇溶液为50-99％的乙醇，加乙醇量为聚丙烯酸树脂IV重量的5-100倍。
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