WO2008018561A1 - Procédé de production de granulé sphérique contenant une substance légèrement hydrosoluble - Google Patents
Procédé de production de granulé sphérique contenant une substance légèrement hydrosoluble Download PDFInfo
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- WO2008018561A1 WO2008018561A1 PCT/JP2007/065654 JP2007065654W WO2008018561A1 WO 2008018561 A1 WO2008018561 A1 WO 2008018561A1 JP 2007065654 W JP2007065654 W JP 2007065654W WO 2008018561 A1 WO2008018561 A1 WO 2008018561A1
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- poorly water
- soluble drug
- drug
- layering solution
- layering
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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]
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
-
- 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
Definitions
- the present invention relates to a method for producing spherical elementary granules containing a poorly water-soluble drug.
- Solid pharmaceutical preparations are film coatings such as sustained release, enteric properties, bitterness masks, etc. for the purpose of reducing side effects, reducing the number of doses, improving the effect of drugs, suppressing bitterness, stabilizing drugs, etc. Ting may be given.
- film coatings such as sustained release, enteric properties, bitterness masks, etc.
- Such spherical granules containing a drug which is a dosage form suitable for film coating are called spherical granules!
- the layering method is a method of producing granules by coating spherical core particles with a coating layer by spraying a layering solution containing a drug, a binder, or the like onto the spherical core particles.
- a method of supplying and coating a drug powder and an aqueous binder solution simultaneously there are a method of supplying and coating a suspension of drug particles, and a method of supplying and coating a drug aqueous solution.
- the layering method spherical particles having a high sphericity and a narrow particle size distribution can be obtained by using spherical core particles having a high sphericity and a narrow particle size distribution. Therefore, the layering method is suitable as a method for producing spherical elementary granules for film coating.
- the drug contained in the layering solution is a low water-soluble drug or a drug (poorly water-soluble drug)
- the foam was vigorously foamed and it was necessary to remove the foam.
- drug particles precipitate over time.
- the layering solution must always be stirred and mixed to keep the suspension homogeneous. Still, settling during movement from layering fluid tank to spray nozzle There remains a risk of agglomeration and blockage of the tube and spray nozzle.
- the drug particles are large, the risk increases and the adhesion to the spherical core particles decreases, leading to a decrease in the recovery rate and an increase in the aggregation rate due to rolling inhibition. If the drug particles are made smaller, the suspension stability and recovery rate of the layering solution can be improved, and a powder particle (or grinding) treatment process is required.
- Patent Document 2 It is known that various additives are added to the layering solution for the purpose of preventing peeling of the coated drug, adjusting the dissolution rate of the drug, or stabilizing (for example, Patent Document 2, 3 and 4).
- Patent Documents 2 to 4 do not describe the use of microcrystalline cellulose and an emulsifier in combination.
- Patent Document 5 discloses a technique for coating spherical core particles with a poorly water-soluble drug, an emulsifier, and the like by a layering method.
- the technique specifically disclosed supplies a drug powder and an aqueous binder solution simultaneously.
- Patent Document 5 there is no description regarding improvement in suspendability when a poorly water-soluble drug is added to the layering solution.
- Patent Document 1 Japanese Patent Laid-Open No. 63-301816
- Patent Document 2 JP-A-9 165329
- Patent Document 3 Japanese Patent Laid-Open No. 9 67247
- Patent Document 4 Japanese Translation of Special Publication 2005—536527
- Patent Document 5 International Publication 2005/044240 Pamphlet
- the present invention provides a method for producing poorly water-soluble drug-containing spheroid granules having improved production efficiency by using a poorly water-soluble drug-containing layering solution having good suspension stability and suppressed foaming.
- the purpose is to do.
- the present inventors have blended finely divided crystalline cellulose and an emulsifier into a layering solution, so that the layer can be formed without any special pulverization treatment of the drug.
- the suspension stability of the ring solution is improved and foaming is also suppressed.
- the present invention has been found and the present invention has been made. That is, the present invention is as follows.
- a method of producing spherical elementary granules in which a layering solution is sprayed onto pharmaceutically inert spherical core particles and coated with a drug-containing layer,
- a process for producing a poorly water-soluble drug-containing spherical elementary granule comprising:
- the spherical core particles used in the present invention are pharmaceutically inert. That is, it does not contain drugs.
- the “drug” means a device that is used for treatment, prevention, or diagnosis of a human or animal disease and is not a device “machine”.
- the spherical core particles can contain one or more pharmaceutical additives.
- pharmaceutical additives include, for example, excipients such as lactose, sucrose, D-mannitol, corn starch, powdered cellulose, calcium hydrogen phosphate, calcium carbonate; low-substituted hydroxypropyl cellulose, carmellose calcium , Partially alpha-ized Disintegrants such as starch, croscarmellose sodium, crospovidone, carboxymethyl starch; binders such as hydroxypropylcellulose, povidone (polybutyrrolidone), xanthan gum; hypromellose (hydroxypropylmethylcellulose), methacrylic acid Copolymer LD, coating solution of ethyl cellulose dispersion, emulsifier such as sucrose fatty acid ester, glycerin fatty acid ester, sodium lauryl sulfate, polysorbate 60; talc , Magnesium stearate,
- Preferable formulation examples include sucrose alone, sucrose 70% by mass and corn starch 30% by mass, crystalline cellulose 30% by mass or more and other pharmaceutical additives, crystalline cellulose only, mannitol only, and the like.
- Spherical nuclei containing 30% by mass or more of crystalline cellulose are preferable because they have high strength and water retention. More preferred are those containing 70% by mass or more of crystalline cellulose, and even more preferred are spherical core particles consisting only of crystalline cellulose. Most preferably, the spherical core particles are composed only of microcrystalline cellulose.
- the sphericity is preferably 0.9 or more.
- spherical core particles having an average particle size of about 50 to about 1000 m can be used. A sharper particle size distribution is preferred.
- the bulk density is preferably about 0.5 to 2. Og / cm 3 . In the case of spherical core particles composed only of crystalline cellulose, it is usually about 0.5 to 1. Og / cm 3 . Higher mechanical strength is preferred.
- poorly water-soluble drug particles blended in the layering solution of the present invention will be described.
- “poorly water-soluble” means that it is hardly soluble in water, and its solubility in lcm 3 of water at 20 ° C. is not more than 0.0OOlg.
- Examples of poorly water-soluble drugs include amsinonide, ibuprofen, indomethacin, ethenzamide, erythromycin, cefotiam hexetyl hydrochloride, dicardipine hydrochloride, omeprazole, prednisolone valerate acetate, diflucortron valerate, dexamethasone valerate, betamethasone valerate , Clarithromycin, griseofulvin, chromazepam, chloramphenicol, synthetic peptide compounds, cortisone acetate, diflorazone acetate, dexamethasone acetate, triamcinolone acetate, parameterzone acetate, hydrocortisone acetate, flurocortisone acetate, methylprednisolone acetate, dizepam, digitoxin, digoxin , Diflu prednate, beclomethasone dipropionate, betamethasone di
- the smaller water-soluble drug particles preferably have smaller maximum lengths of 30% or less of the average minor axis of the spherical core particles, and the maximum minor axes of 12% or less of the average minor axis of the spherical core particles.
- each value is larger than the specified value, the drug particles are likely to peel off and the recovery rate of the spherical granules decreases.
- exfoliated drug particles inhibit the rolling of spherical core particles, and as a result, aggregation of spherical elementary granules increases.
- the maximum major axis is 20% or less of the average minor axis of the spherical core particles, and the maximum minor axis is 10% or less.
- the poorly water-soluble drug particles are mixed in the layering solution in an amount of 0.0; If it is less than 0.01 mass%, it will be necessary to carry out layering for a long time in order to carry the required amount of drug. If it exceeds 50% by mass, the viscosity of the layering solution is too high, which hinders spraying. Preferably it is 1-30 mass%, More preferably, it is 5-20 mass%.
- the refined crystal cellulose blended in the layering solution of the present invention has an average particle diameter measured in water. It means crystalline cellulose of 12 m or less. More preferably, it is 9 ⁇ m or less.
- crystalline cellulose means “crystalline cellulose” of the 14th revision Japanese Pharmacopoeia, 7th edition food additive official document “microcrystalline cellulose”, “2003 It means what meets any standard of “carmellose sodium”.
- the refined crystalline cellulose includes those obtained by dry or wet pulverization of ordinary crystalline cellulose, and those obtained by dispersing crystalline cellulose.carmellose sodium in water. Crystalline cellulose 'Carmellose sodium is preferable because it is easy to prepare a layering solution to which it is added, has high strength, and has high suspension stability. .
- the refined crystalline cellulose is blended in the layering solution in an amount of 0.; If it is less than 0.1% by mass, sufficient suspension stabilizing effect cannot be obtained. If it exceeds 2 mass%, the viscosity of the layering solution will be too high, which will hinder spraying.
- Preferably 0.5 2 ;! wt%, good Ri preferably 0.3 to 0.8 mass 0/0.
- the suspension stability of the poorly water-soluble drug particles in the layering solution is improved, and the blockage of the spray nozzle as well as the tube is eliminated. Furthermore, since the adhesion of poorly water-soluble drug particles to spherical core particles is improved, the effect of increasing the recovery rate and reducing the aggregation rate can also be obtained.
- the emulsifier blended in the layering solution means a substance having a milking function for pharmaceutical preparations.
- the emulsifier examples include sucrose fatty acid ester, glycerin fatty acid ester, sodium lauryl sulfate, polysorbate, polyoxyethylene hydrogenated castor oil, carmellose sodium, xanthan gum and the like.
- the emulsifier must be selected appropriately according to the physical properties of the drug particles! /.
- the polyoxyethylene hydrogenated castor oil 60 is more preferable because the effect of suppressing foaming is higher!
- polyoxyethylene hydrogenated castor oil 60 is a nonionic surfactant obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, which is obtained by adding hydrogen to castor oil.
- the average number of moles added is about 60! /, And its CAS number is 61788-85-0.
- the average added mole number of ethylene oxide in the polyoxyethylene hydrogenated castor oil 60 is preferably 52 to 68, and more preferably 55 to 65.
- the emulsifier is blended in the layering solution in an amount of 0 ⁇ 0; If it is less than 01% by mass, the affinity of drug particles with water will not be improved sufficiently. There is no upper limit. However, the effect is not improved as expected. More preferably, it is 0.05-0.8 mass%.
- binder examples include hydroxypropylcellulose, povidone, hypromellose (hydroxypropylmethylcellulose) and the like.
- a fluidized bed coating apparatus can be used to coat the spherical core particles with a poorly water-soluble drug-containing layer.
- the fluidized bed coating apparatus includes a spouted bed type having a guide tube (Worster one-force ram) inside, a rolling fluidized bed type having a rotating mechanism at the bottom.
- the layering solution can be supplied by selecting a method suitable for each apparatus such as top spray, bottom spray, side spray, tangential spray, etc. Are intermittently sprayed onto the spherical core particles. After spraying, the spherical granules are dried. At this time, the spherical elementary granules can be dried as they are without taking out the sample or by appropriately adjusting the air volume and temperature.
- the coating amount of the drug layer is determined by the formulation design capability such as a single dose and the size of the formulation. For example, it is about 0.5 to 200% by mass with respect to the spherical core particles.
- microcrystalline cellulose is dispersed in water and subjected to a micronization treatment using a Menton's goolin type homogenizer. Although it is processed as many times as necessary at high pressure, for example, 5 passes are processed at 50 MPa.
- Fine crystalline cellulose for example, “Ceras” Cream FP-03, manufactured by Asahi Kasei Chemicals Corporation, solid content 10% by mass, average particle size of about 4 111
- crystalline cellulose “carmellose sodium for example,“ Ceras ”
- a rotary type disperser in order to make the micronized crystalline cellulose sufficiently small and blend with other components.
- the disperser include “Kai. ⁇ . Homomixer 1” manufactured by Tokushu Kika Kogyo Co., Ltd. and “Ultra Turrax” manufactured by IK A.
- a stirrer having a weak stirring force such as a propeller stirrer is not so preferable.
- the co-synthesis may be sequentially dispersed.
- Spherical granules obtained according to the present invention are sized according to need, coated with a film such as sustained release, enteric, bitterness mask, etc., and used as granules, capsules, tablets, etc. Can be used.
- Samples of the shape digital microscope (VH- 7000, (Ltd.) manufactured by Keyence) taken with (using 50-fold or 100 fold the lens), an image analyzer (Im a geHyp er, (Ltd.) inter- Quest) Measure the short diameter (D) and long diameter (L) of 50 particles.
- the minor axis and the major axis are defined as the short side of the circumscribed rectangle having the smallest area circumscribed on the boundary pixel of the particle and the long side as the major axis.
- the sphericity is the ratio of minor axis to major axis (the average value of D / U. ⁇ Average minor axis of spherical core particles [m]>
- the average minor axis is the value at 50% of the cumulative minor axis (D) obtained in the same way as the sphericity measurement method.
- Tapping apparent density [g / cm 3 ] 30 [g] / Tapping volume [cm 3 ]
- a layering solution is dropped on a slide glass, and a cover glass is placed thereon to prepare a sample.
- the sample is photographed with an optical microscope (using a 40 ⁇ lens), and the major axis and minor axis of 50 drug particles are measured from the photograph to determine the maximum major axis m] and the maximum minor axis m].
- the microcrystalline cellulose is dispersed in pure water, and a laser diffraction / scattering type particle size distribution analyzer (LA-910, manufactured by Horiba, Ltd.) is used. Set the relative refractive index 1.20 to obtain the median diameter m]. This operation is repeated twice and the average value is adopted.
- LA-910 laser diffraction / scattering type particle size distribution analyzer
- Recovery [mass%] ⁇ recovered amount [g] / total amount of raw material [g] ⁇ X 100
- Spherical granules are dispersed on paper, and the number of particles (a [pieces]) and the number of single particles (b [pieces]) constituting the agglomerated granules are visually counted, and the following formula is calculated.
- This layering solution had significantly higher suspension stability compared to Comparative Example 1 described later, in which the drug was not separated or foamed after dispersion.
- Worster type coating equipment (“Multiplex” MP-01 type, Wurster power ram Spherical core particles made of 100% crystalline cellulose ("Selfia” CP-203, manufactured by Asahi Kasei Chemicals Co., Ltd., sphericity 0.9, tapping bulk density 0.98 g / cm @ 3, an average 0. 3 kg were charged minor 165), a spray air pressure of 0. 16 MPa, sPRAY air flow rate 40L / min, inlet air temperature 65 to 70 ° C, exhaust temperature 40 ° C, air volume 40 m 3 / h, in terms of layering liquid spray rate of 3 g / min, and layering until 12. 8 mass% relative to the spherical core particles (5 as drug 0 mass 0/0).
- the layering solution was always propeller-stirred at 150 rpm. After stopping the spraying of the layering liquid, dry under the same conditions until the exhaust temperature rises to 42 ° C, and then turn off the heater of the supply air to bring the supply air temperature to 40 ° C. Cool until
- Example 1 Using the layering solution prepared in Example 1, 0.6 kg of the same spherical core particles as in Example 1 were charged into a tumbling fluidized coating apparatus (“Multiplex” MP-01 type, manufactured by Baurec Co., Ltd.) using tangential bottom spray, spray air pressure 0. 16 MPa, spray Reea flow 40L / min, inlet air temperature 75 ° C, exhaust temperature 41 ° C, air volume 35m 3 / h, the rotary plate rotation speed 400 rpm, layering liquid under the conditions of spray rate 5. Og / min, and layering until against the spherical core particles 12.8 mass 0/0 (5 ⁇ 0 weight 0/0 as a drug). The layering solution was always stirred with a propeller at 150 rpm.
- a tumbling fluidized coating apparatus (“Multiplex” MP-01 type, manufactured by Baurec Co., Ltd.) using tangential bottom spray, spray air pressure 0. 16 MPa, spray Reea flow 40L / min, inlet air temperature 75
- the rotating plate rotation speed is set to 200 rpm, drying is performed until the exhaust temperature rises to 42 ° C, then the heater for supplying air is turned off, and the supply air temperature is reduced. Cooled to 40 ° C.
- the powdered drug not adhering to the spherical core particles had a low recovery rate of 94.6% and an aggregation rate of 1.2%, both of which were good results.
- the results are shown in Table 1.
- Example 2 Layering was performed in the same manner as in Example 1 except that the supply air temperature was 70 to 78 ° C and the propeller stirring of the layering solution was 300 rpm.
- the drug did not adhere to the spherical core particles, and the powdered drug adhered to the bag filter at the top of the device, resulting in a decrease in the recovery rate. Furthermore, the obtained spherical elementary granules contained many agglomerated particles. The results are shown in Table 1.
- Example 1 which used a layering solution containing #tatacrystalline cellulose and an emulsifier, the wisteria granules had less wrinkles and a higher recovery rate.
- Comparative Example 1 using a layering solution that does not contain Gyodai ⁇ crystalline cellulose and 3 ⁇ 4ft ⁇ J, the spherical opening granule is aggregated due to foaming of the layering solution.
- the resulting layering solution was a uniform, thick and cloudy suspension with no foaming or drug particle settling.
- Figure 1 shows the appearance.
- Table 2 shows the appearance observation results.
- Figure 2 shows the appearance.
- Table 2 shows the appearance observation results.
- a layering solution was prepared in the same manner as in Reference Comparative Example 1 except that the amount of povidone added was 15 g, and the state of separation was observed. The amount of drug present in the lower layer from Reference Comparative Example 1 increased. The foamed drug layer in the upper part of 1S was almost unchanged.
- Figure 3 shows the appearance.
- Table 2 shows the appearance observation results.
- the resulting layering solution was separated into three layers, with bubbles in the upper 23% and a precipitated drug layer in the lower 23%.
- Figure 4 shows the appearance.
- Table 2 shows the appearance observation results.
- a layering solution was prepared in the same manner as in Reference Comparative Example 3, except that 0.3 g of polyoxyethylene hydrogenated castor oil was added to 89.7 g of water.
- the lower drug sedimentation layer was 11%, which was slightly improved from Reference Comparative Example 3, but the three-layer separation was not improved. Table 2 shows the appearance observation results.
- a layering solution was prepared in the same manner as in Reference Comparative Example 5, except that 2.2 g of the same crystalline cellulose 'carmellose sodium as in Example 1 was added to 87.8 g of water.
- the layering solution in the reference example using a combination of crystallite cellulose and emulsifier is a uniform paint.
- the layering solution containing neither totalized crystalline cellulose nor 3 ⁇ 4 ⁇ ⁇ was separated into ii (Reference Comparative Examples 1 and 2). Further, the layering solution containing only milk t3 ⁇ 4 was severely foamed and separated into three layers (Reference Comparative Examples 3 and 4). On the other hand, the layering solution containing only W ⁇ crystalline cellulose has a reduced foaming force S, and the separation is also eliminated.
- the production method of the present invention can be suitably used in the field of production of pharmaceutical granules coated with a film.
- FIG. 5 Appearance of the layering solution prepared in Reference Comparative Example 6.
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/310,067 US9095512B2 (en) | 2006-08-11 | 2007-08-09 | Method for producing spherical base granules comprising hardly water-soluble drug |
EP07792304.3A EP2050439B1 (en) | 2006-08-11 | 2007-08-09 | Process for production of spherical granule containing slightly water-soluble substance |
CN2007800293602A CN101500541B (zh) | 2006-08-11 | 2007-08-09 | 含有水难溶性药物的球状素颗粒的制造方法 |
JP2008528886A JP5171626B2 (ja) | 2006-08-11 | 2007-08-09 | 水難溶性薬物含有球形素顆粒の製造方法 |
Applications Claiming Priority (2)
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JP2006220247 | 2006-08-11 | ||
JP2006-220247 | 2006-08-11 |
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WO2008018561A1 true WO2008018561A1 (fr) | 2008-02-14 |
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PCT/JP2007/065654 WO2008018561A1 (fr) | 2006-08-11 | 2007-08-09 | Procédé de production de granulé sphérique contenant une substance légèrement hydrosoluble |
Country Status (5)
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US (1) | US9095512B2 (ja) |
EP (1) | EP2050439B1 (ja) |
JP (1) | JP5171626B2 (ja) |
CN (1) | CN101500541B (ja) |
WO (1) | WO2008018561A1 (ja) |
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WO2015198304A1 (en) | 2014-06-22 | 2015-12-30 | Dexcel Pharma Technologies Ltd. | Pharmaceutical compositions comprising ferric citrate and methods for the production thereof |
CN105496970A (zh) * | 2015-12-18 | 2016-04-20 | 北京华禧联合科技发展有限公司 | 含有利格列汀的组合物及其制备方法 |
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JPH0967247A (ja) | 1995-08-31 | 1997-03-11 | Taisho Pharmaceut Co Ltd | 均一な微粒子製剤の製造方法 |
JPH09165329A (ja) | 1995-10-12 | 1997-06-24 | Asahi Chem Ind Co Ltd | フィルムコーティング顆粒およびその製造方法 |
JP2005044240A (ja) | 2003-07-24 | 2005-02-17 | Nec Engineering Ltd | パソコンのユーザサポートシステム |
JP2005536527A (ja) | 2002-08-02 | 2005-12-02 | ラティオファルム ゲー・エム・ベー・ハー | 微結晶セルロースと混合したベンズイミダゾール化合物を含有する医薬製剤およびその製造方法 |
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US4902792A (en) * | 1985-04-19 | 1990-02-20 | Kanebo Ltd. | Fine cellulose particles and process for production thereof |
US5026560A (en) * | 1987-01-29 | 1991-06-25 | Takeda Chemical Industries, Ltd. | Spherical granules having core and their production |
CA1338596C (en) * | 1988-09-27 | 1996-09-17 | Hiroyoshi Koyama | Granules having core and their production |
JPH0725765A (ja) * | 1993-07-07 | 1995-01-27 | Mitsubishi Chem Corp | 眼疾患用薬剤 |
US6379688B2 (en) * | 1997-02-28 | 2002-04-30 | Senju Pharmaceutical Co., Ltd. | Preservative for emulsion and emulsion containing same |
US6156771A (en) * | 1997-08-28 | 2000-12-05 | Rubin; Walter | Method for alleviation of lower gastrointestinal disorders in a human patient |
JPH11171769A (ja) * | 1997-12-05 | 1999-06-29 | Nichiko Pharmaceutical Co Ltd | 3−イソブチリル−2−イソプロピルピラゾロ〔1,5−a〕ピリジンの徐放性製剤及びその製法 |
US6228400B1 (en) * | 1999-09-28 | 2001-05-08 | Carlsbad Technology, Inc. | Orally administered pharmaceutical formulations of benzimidazole derivatives and the method of preparing the same |
CA2359812C (en) * | 2000-11-20 | 2004-02-10 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures |
US7737133B2 (en) * | 2003-09-03 | 2010-06-15 | Agi Therapeutics Ltd. | Formulations and methods of treating inflammatory bowel disease |
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2007
- 2007-08-09 JP JP2008528886A patent/JP5171626B2/ja active Active
- 2007-08-09 WO PCT/JP2007/065654 patent/WO2008018561A1/ja active Application Filing
- 2007-08-09 EP EP07792304.3A patent/EP2050439B1/en active Active
- 2007-08-09 CN CN2007800293602A patent/CN101500541B/zh active Active
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JPS63301816A (ja) | 1987-01-29 | 1988-12-08 | Takeda Chem Ind Ltd | 有核顆粒およびその製造法 |
JPH0967247A (ja) | 1995-08-31 | 1997-03-11 | Taisho Pharmaceut Co Ltd | 均一な微粒子製剤の製造方法 |
JPH09165329A (ja) | 1995-10-12 | 1997-06-24 | Asahi Chem Ind Co Ltd | フィルムコーティング顆粒およびその製造方法 |
JP2005536527A (ja) | 2002-08-02 | 2005-12-02 | ラティオファルム ゲー・エム・ベー・ハー | 微結晶セルロースと混合したベンズイミダゾール化合物を含有する医薬製剤およびその製造方法 |
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Non-Patent Citations (1)
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Also Published As
Publication number | Publication date |
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CN101500541A (zh) | 2009-08-05 |
JPWO2008018561A1 (ja) | 2010-01-07 |
US9095512B2 (en) | 2015-08-04 |
EP2050439B1 (en) | 2016-11-23 |
CN101500541B (zh) | 2011-06-15 |
US20090324802A1 (en) | 2009-12-31 |
JP5171626B2 (ja) | 2013-03-27 |
EP2050439A1 (en) | 2009-04-22 |
EP2050439A4 (en) | 2011-09-07 |
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