WO2009101656A1 - Préparation à libération retardée - Google Patents

Préparation à libération retardée Download PDF

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Publication number
WO2009101656A1
WO2009101656A1 PCT/JP2008/001705 JP2008001705W WO2009101656A1 WO 2009101656 A1 WO2009101656 A1 WO 2009101656A1 JP 2008001705 W JP2008001705 W JP 2008001705W WO 2009101656 A1 WO2009101656 A1 WO 2009101656A1
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Prior art keywords
time
water
drug
mass
release preparation
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PCT/JP2008/001705
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English (en)
Japanese (ja)
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Hideyoshi Kanbe
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Ssp Co., Ltd.
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Publication of WO2009101656A1 publication Critical patent/WO2009101656A1/fr

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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
    • A61K9/5005—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a time-release preparation capable of freely adjusting the time at which a drug starts to be released from the preparation and the drug release rate after the start of drug release.
  • timed release control technology that can precisely control the starting time of the main drug release after taking is required.
  • methods such as (i) membrane disruption type, (ii) membrane detachment type, (iii) membrane dissolution type, and (iv) membrane permeation type have been proposed, but are still in practical use. Has not reached.
  • asthma attacks are said to concentrate from midnight to early morning, when respiratory function is most reduced. Even if regular preparations or sustained-release preparations are taken at bedtime, the effective plasma concentration range will be less than or equal to the effective plasma concentration range from midnight to early morning when seizures occur, but by taking a timed release preparation at midnight The plasma concentration can be maximized early in the morning.
  • the time-release preparation can be administered in advance while avoiding a time zone in which it is difficult to take.
  • myocardial infarction, depression, and seizures are also time-dependent.
  • the drug can be administered to the lower part of the small intestine or the large intestine, and by setting the release start time to several minutes, it can be used for masking drugs having an unpleasant taste. Furthermore, it can also be used to avoid drug interactions between drugs that interfere with each other's efficacy when taken simultaneously.
  • a time-release preparation is a preparation in which a water-swellable substance and a drug are attached around the core particles and coated with a mixed film of ethyl cellulose and talc. In which the drug is destroyed and the drug is released (Patent Documents 1 and 2).
  • a film of a preparation for obtaining a lag time until the start of release uses a water-repellent salt such as a metal salt of a fatty acid such as magnesium stearate and calcium stearate and an acrylic acid polymer (Patent Document 3), or Eudragit RS The thing (patent document 4) etc. which utilized the interaction of (made by Degussa Japan) and an organic acid are proposed.
  • these preparations are achieved by producing a multi-layered granule having a drug layer, a swelling agent layer, a controlled release layer, etc. on a lactose isospherical granule (for example, Nonparel 101; manufactured by Freund Sangyo Co., Ltd.). Therefore, advanced formulation techniques are required to produce these timed release formulations. In addition, it has been extremely difficult to accurately control the lag time (the time during which no drug is released) and the drug release after the lag time. Therefore, there has been a strong demand for a time-release preparation that does not require advanced preparation techniques and is easy to manufacture.
  • a lactose isospherical granule for example, Nonparel 101; manufactured by Freund Sangyo Co., Ltd.
  • an object of the present invention is to provide a time-release preparation capable of freely adjusting the time when the drug starts to be released from the preparation and the drug release rate after the start of the drug release.
  • the present invention provides a time-release preparation characterized in that the central core containing a drug and a water swelling substance is coated with a film containing one or more water-insoluble polymers.
  • the time at which the drug starts to be released from the preparation and the drug can be obtained by coating only one layer containing one or more water-insoluble polymers on the central core containing the drug and the water-swellable substance. It is possible to provide a time-release preparation capable of freely adjusting the drug release rate after the start of release. In particular, by changing the composition of the film, the coating amount, and the blending ratio of the water-swellable substance in the central core, it becomes possible to control the drug release start time and the drug release rate more precisely.
  • Fig. 1 shows the calculation method of lag time (time when drug is not released), T 80% (time when elution amount reaches 80%), T 80% -lag time (release of time-release preparation) from the dissolution curve. It is a figure for demonstrating.
  • 2 is a diagram showing an elution curve of the preparation obtained in Example 1.
  • FIG. 3 is a diagram showing an elution curve of the preparation obtained in Example 2.
  • FIG. 4 is a view showing an elution curve of the preparation obtained in Example 3.
  • FIG. 5 is a diagram showing an elution curve of the preparation obtained in Example 4.
  • FIG. 6 is a diagram showing an elution curve of the preparation obtained in Example 5.
  • FIG. 7 is a view showing an elution curve of the preparation obtained in Comparative Example 1.
  • FIG. 8 is a view showing an elution curve of the preparation obtained in Comparative Example 2.
  • FIG. 9 is a diagram showing an elution curve of the preparation obtained in Example 6.
  • 10 is a diagram showing an elution curve of the preparation obtained in Example 7.
  • FIG. 11 is a view showing an elution curve of the preparation obtained in Example 8.
  • FIG. 12 is a view showing an elution curve of the preparation obtained in Example 9.
  • FIG. 13 shows the elution curve of the preparation obtained in Example 10.
  • the time-release preparation of the present invention adopts a two-layer structure composed of a central core and a film covering the outer surface of the central core, the central core contains a drug and a water-swellable substance, and the film is highly water-insoluble. It is characterized by containing one or more molecules.
  • the drug applied to the present invention is not particularly limited as long as it can be administered orally.
  • Such drugs include, for example, chemotherapeutic agents, respiratory accelerators, antineoplastic agents, autonomic nerve agents, psychiatric agents, local anesthetics, muscle relaxants, digestive organ agents, addiction treatments, hypnotic sedatives As vasodilators, antilipidemic agents, nourishing tonics, anticoagulants, liver agents, hypoglycemic agents, antihypertensive agents, anticolitis agents, peptides, proteins, as well as bitterness drugs, Antibiotics (eg, tarampicillin hydrochloride, bacampicillin hydrochloride, cefaclor, erythromycin), antitussives (eg, noscapine hydrochloride, carbetapentane citrate, dextromethorphan hydrobromide, isoaminyl citrate, dimemorphan phosphate), antihistamines (For example, chlorpheniramine maleate, di
  • the content of the drug can be appropriately determined according to the purpose. However, from the viewpoint of the release property of the drug after the lag time and the lag time, the content of the drug is 85% by mass or less, and further 70% by mass. % Or less, and particularly preferably 60% by mass or less.
  • the lower limit of the drug content is preferably 3% by mass, particularly 5% by mass from the viewpoint of pharmacological effects.
  • water-swellable substance constituting the central core examples include, for example, low-substituted hydroxypropylcellulose, carmellose or a salt thereof, croscarmellose sodium, sodium carboxymethyl starch, cros polyvinylpyrrolidone, crystalline cellulose, crystalline cellulose / carmellose sodium, etc. Is mentioned.
  • low-substituted hydroxypropyl cellulose is particularly preferable, and the low-substituted hydroxypropyl cellulose has a hydroxypropoxyl group of about 7.0 to 16.0% by mass, preferably about 10 to 12.9% by mass.
  • the average particle size is preferably 30 ⁇ m or less, particularly preferably 20 ⁇ m or less.
  • the water-swellable substance can be used alone or in combination of two or more, and the content thereof is preferably 15% by mass or more, more preferably 30% by mass or more, particularly 40% by mass or more in the central core.
  • the upper limit of the content of the water-swellable substance is preferably 97% by mass, particularly 95% by mass from the viewpoint of drug content.
  • the central core may be blended with various additives usually used in this field, such as excipients, binders, lubricants, anti-aggregation agents, and solubilizing agents for pharmaceutical compounds.
  • excipients include saccharides such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, calcium sulfate, etc.
  • binders include, for example, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid.
  • examples of the lubricant and the aggregation inhibitor include talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, waxes, hardened oil, polyethylene glycols, sodium benzoate and the like.
  • examples of the solubilizing agent for the pharmaceutical compound include organic acids such as fumaric acid, succinic acid, malic acid, and adipic acid. The content of these additives can be appropriately determined according to the type of the drug.
  • the water-insoluble polymer constituting the film is not particularly limited as long as it is a water-insoluble polymer compound.
  • ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl terpolymer examples include ethyl cellulose, enteric polymer, and low pH soluble polymer.
  • the enteric polymer refers to a polymer that does not dissolve in the stomach in an acidic environment but dissolves in the neutral to basic small intestine, such as a methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methacrylic acid.
  • (Meth) acrylic binary copolymers such as acid methyl copolymer, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate.
  • the low pH-soluble polymer means a polymer that dissolves in the acidic region of pH 1 to 5 but does not dissolve in the neutral to alkaline region having a higher pH than that. Specific examples include polyvinyl acetal diethylaminoacetate, methyl methacrylate / dimethylaminoethyl methacrylate copolymer, and the like.
  • ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl terpolymer ethyl cellulose, methacrylic acid / methyl methacrylate copolymer, and hydroxypropyl methylcellulose acetate succinate are preferred.
  • the mass ratio of ethyl acrylate, methyl methacrylate and ethyl trimethylammonium methacrylate constituting the terpolymer is preferably 1: 2: 0.1 to 1: 2: 0.2.
  • Eudragit RS for example, RSPO, RS100, RS30D
  • Eudragit RL for example, RLPO, RL100, RL30D
  • Eudragit RS has a trimethylammonium chloride group content of 4.48 to 6.77% by mass
  • Eudragit RL has a trimethylammonium chloride group content of 8.85 to 11.96% by mass.
  • the ratio of methacrylic acid and methacrylic acid alkyl ester constituting the binary copolymer is preferably 1: 1 to 1: 2.
  • Eudragit L for example, L100
  • S for example, S100
  • Water-insoluble polymers can be used alone or in combination of two or more.
  • (a) two ternary copolymers having different trimethylammonium chloride group contents are used, or (b) ternary copolymer and ethyl cellulose, It is preferable to use a combination of a binary copolymer or hydroxypropyl methylcellulose acetate succinate.
  • the ratio of each compounding component (RS: RL) is preferably 9.8: 0.20 to 5: 5, more preferably 9.8: 0. 20 to 7.0: 3.0, particularly 9.75: 0.25 to 8.5: 1.5 is preferable.
  • the proportion of each blending component is 2: 8 by mass ratio. Is preferably 9: 1, more preferably 3: 7 to 8.5: 1.5, and particularly preferably 7: 3 to 8.5: 1.5.
  • the content (solid content) of the water-insoluble polymer in the film is preferably 80% by mass or more, more preferably 90% by mass or more, and particularly preferably 95% by mass or more, and the film may be composed of only the water-insoluble polymer.
  • additives such as wax, stearic acid, a hiding agent, a coloring agent, a fragrance, a lubricant, and an anti-aggregation agent can be blended.
  • the amount of these additives used can be appropriately determined according to the type of the drug.
  • the preparation of the present invention can be suitably produced, for example, as follows. First, if necessary, additives are added to the drug and water-swellable substance, and after mixing with a mixer such as a vertical granulator (manufactured by POWREC Co., Ltd.), purified water or hydrous alcohol is added. Knead to obtain a swollen state.
  • a mixer such as a vertical granulator (manufactured by POWREC Co., Ltd.)
  • purified water or hydrous alcohol is added. Knead to obtain a swollen state.
  • the alcohol in the hydrous alcohol include pharmaceuticals such as ethyl alcohol, methyl alcohol, and isopropyl alcohol, or those that can be used in the production thereof.
  • the alcohol concentration is preferably 50% by mass or less, particularly preferably 30% by mass or less, and the lower limit thereof is preferably 5% by mass, particularly 10% by mass.
  • Water or hydrous alcohol is used as a kneading solvent for wet granulation to make the water-swellable substance swell.
  • the amount used is preferably 2 to 5 times, more preferably 2 to 3 times the weight of the water-swellable substance.
  • Additives that can be used normally in pharmaceuticals such as sweeteners, sugars such as refined sucrose, sugar alcohols such as D-mannitol, polymers dissolved or dispersed in water, etc., in the kneading solvent of water or hydrous alcohol May be added.
  • the central core is preferably produced by wet granulation, but the method applied to wet granulation is not particularly limited as long as it is stirred granulation, fluidized bed granulation and extrusion granulation.
  • extrusion granulation is preferable, and it is particularly preferable to perform spheronization with a Malmerizer after extrusion granulation.
  • a kneaded product in a swollen state is extruded and granulated by, for example, a twin dome gran (produced by Fuji Powder Co., Ltd.) equipped with a screen having a diameter of 0.3 to 1.0 mm.
  • the preparation of the present invention can be produced by coating the obtained core and the water-swellable substance with a coating solution containing one or more water-insoluble polymers. At this time, you may mix
  • the solvent for dissolving and dispersing the coating base include water, alcohols such as methanol and ethanol, ketones such as acetone, halogenated hydrocarbons such as methylene chloride and chloroform, and mixtures thereof.
  • the alcohol concentration of the aqueous alcohol solution can be appropriately determined according to the purpose, but by setting it to less than 80% by mass, particularly 20 to 60% by mass, the lag time is within 5 minutes, 10 minutes or 15 minutes, and It is possible to obtain a time-release preparation capable of releasing 80% by mass or more of the drug contained in the preparation within 12 minutes, 15 minutes or 20 minutes after the lag time. Furthermore, it can be set as the masking type
  • a coating method of the film a method commonly used in pharmaceutical technology such as fluidized bed coating method, pan coating method, rolling fluidized bed coating method, etc. can be adopted. It can be carried out by spray coating the core material at a suitable speed from the spray gun nozzle while flowing by air pressure in the apparatus.
  • the concentration of the coating base in the coating solution is not particularly limited, but is preferably 5 to 30% by mass in consideration of the film forming ability and workability.
  • the thus obtained preparation of the present invention may be administered as it is in the above-mentioned dosage form, filled in capsules or the like, and further may be a tablet. If necessary, a sugar coating layer or the like may be further coated.
  • the coating amount of the film is preferably 20% by mass or more, more preferably 30% by mass or more, and particularly preferably 50% by mass or more with respect to the total mass of the central core from the viewpoint of lag time and drug release after the lag time.
  • the upper limit of the coating amount is preferably 300% by mass, particularly preferably 250% by mass.
  • a method of extruding and granulating in a swollen state and forming spherical granules with a malmerizer is preferably employed.
  • shrinking the water-swellable substance a central core of spherical particles smaller than the extrusion screen diameter can be obtained.
  • the core of non-parrel 103 average particle size: 840 to 350 ⁇ m, manufactured by Freund Sangyo Co., Ltd.
  • a conventional centrifugal rolling granulator such as a CF granulator (manufactured by Freund Sangyo Co., Ltd.).
  • a spherical central core containing the drug and water-swellable substance is produced without requiring advanced pharmaceutical technology. be able to.
  • the water-swellable substance is extruded in a swollen state.
  • the main drug release mechanism of the preparation according to the present invention is as follows.
  • the preparation of the present invention administered orally absorbs water in the digestive tract through the film, and the water-swellable substance in the central core gradually swells. Then, after a certain time, the film increases in volume due to the swelling of the water-swellable substance in the central core, and the film is destroyed by the swelling force. As a result, the entire amount of drug is instantaneously released. This time becomes the lag time.
  • This lag time can be freely adjusted by changing the composition ratio of the film containing one or more water-insoluble polymers, the coating amount, and the blending ratio of the water-swellable substance in the central core.
  • a porous film with high water permeability can be formed by adjusting the ethanol concentration in the aqueous alcohol solution used during film formation to 20 to 60% by mass.
  • the lag time and the release property after the lag time can be accelerated, and the lag time (time when the drug is not released) is within 5 minutes, 10 minutes, or 15 minutes, and 12 minutes after the lag time.
  • a time-release preparation capable of releasing 80% by mass or more of the drug in the preparation within 15 minutes or 20 minutes can be produced.
  • Example 1 100 g of theophylline (manufactured by Shiratori Pharmaceutical Co., Ltd.) and 900 g of low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) are mixed with a vertical granulator FM-VG-25 (manufactured by Paulec Co., Ltd.). Then, 2900 g of 10% ethanol aqueous solution was added and kneaded.
  • L-HPC LH31 low-substituted hydroxypropylcellulose
  • This kneaded product was extruded and granulated with Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.8 mm screen, and spherical granules were formed with Malmerizer Q400 (Fuji Paudal Co., Ltd.). did. Thereafter, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with 20 (840 ⁇ m) and 30 (500 ⁇ m) mesh sieves, and 20-30 mesh (840-500 ⁇ m) theophylline. Spherical granules containing 10% were produced.
  • 3500 g, 4500 g, and 5000 g of the coating liquid shown in Table 1 are sprayed onto 500 g of the spherical granules using a fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and the coating liquid (solid content) is sprayed on the granules. 75%, 90% and 100% coated formulations were prepared.
  • Example 2 300 g of theophylline (manufactured by Shiratori Pharmaceutical Co., Ltd.) and 700 g of low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) are mixed with a vertical granulator FM-VG-25 (manufactured by Paulec Co., Ltd.). Then, 2100 g of 10% ethanol aqueous solution was added and kneaded.
  • L-HPC LH31 low-substituted hydroxypropylcellulose
  • This kneaded product was extruded and granulated with Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.8 mm screen, and spherical granules were formed with Malmerizer Q400 (Fuji Paudal Co., Ltd.). did. Thereafter, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with 20 (840 ⁇ m) and 30 (500 ⁇ m) mesh sieves, and 20-30 mesh (840-500 ⁇ m) theophylline. Spherical granules containing 30% were produced.
  • Example 3 500 g of theophylline (manufactured by Shiratori Pharmaceutical Co., Ltd.) and 500 g of low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) are mixed with a vertical granulator FM-VG-25 (manufactured by Paulec Co., Ltd.). Thereafter, 1500 g of 10% ethanol aqueous solution was added and kneaded.
  • L-HPC LH31 low-substituted hydroxypropylcellulose
  • This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.6 mm screen, and spherical granules were formed with a Malmerizer Q400 (Fuji Paudal Co., Ltd.). did. Thereafter, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with a sieve of 20 (840 ⁇ m) and 30 (500 ⁇ m) mesh, and 20-30 mesh (840-500 ⁇ m) of theophylline. Spherical granules containing 50% were produced.
  • Test example 1 The preparations produced in Examples 1 to 3 were subjected to a dissolution test according to the following test method.
  • Dissolution test method JP 15 Dissolution test method (2) Second method (paddle method)
  • Test solution A formulation having a theophylline content of 60 mg was placed in 900 mL of water and stirred at a rotational speed of 100 rpm / min. The elution amount of theophylline at this time was measured by the UV method (wavelength: 267 nm). And the elution amount with respect to the theophylline quantity mix
  • An elution curve as shown in FIG. 1 was prepared for each preparation, and each measured value when the elution amount was 20 to 80% was subjected to correlation analysis. That is, the correlation coefficient and the slope of the straight line are obtained, the point where the straight line is in contact with the horizontal axis (time axis) is defined as the lag time (the time during which the drug is not released), and the time until the elution amount reaches 80% is defined as T 80% . T 80% -Lag time was calculated as the release of the controlled release start time formulation, respectively.
  • the analysis results of each preparation are shown in Table 4 (Example 1), Table 5 (Example 2), and Table 6 (Example 3).
  • Example 4 500 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 500 g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) are used with a vertical granulator FM-VG-25 (manufactured by Paulec Co., Ltd.). After mixing, 1500 g of a 10% ethanol aqueous solution was added and kneaded.
  • L-HPC LH31 low-substituted hydroxypropyl cellulose
  • This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.6 mm screen, and with a melmerizer Q400 (Fuji Paudal Co., Ltd.) did. Thereafter, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with a sieve of 20 (840 ⁇ m) and 30 (500 ⁇ m) mesh, and 20-30 mesh (840-500 ⁇ m) of diphenhydramine hydrochloride. A spherical granule containing 50% was produced.
  • Example 5 500 g of 50% diphenhydramine-containing granules (20 to 30 mesh) produced in Example 4 were sprayed in the same manner as in Example 1 with 3750 g of the coating liquids (1) to (4) shown in Table 8 to form a coating liquid ( A formulation coated with 75% solids) was produced.
  • Nonparel 103 (30-42 mesh, manufactured by Freund Sangyo Co., Ltd.) 5000 g was placed in a centrifugal fluid granulator (CF-3601) and rolled, and 20 g of hydroxypropylcellulose (HPC-L manufactured by Nippon Tanka Co., Ltd.) was added. While spraying a solution dissolved in 500 g of a water-ethanol (1: 1) mixture, a mixture of 1250 g of diphenhydramine hydrochloride and 730 g of lactose was gradually added to cover the periphery of the non-parrel, and 20-30 mesh diphenhydramine hydrochloride 50% Containing spherical granules were produced.
  • CF-3601 centrifugal fluid granulator
  • Comparative Example 2 Similar to Comparative Example 1, spherical granules containing 50% of 20-30 mesh diphenhydramine hydrochloride were produced. Next, 500 g of this spherical granule was sprayed with 1500 ⁇ g, 2000 g, 2500 g, 3000 g and 3500 g of the coating solution of (3) shown in Table 8 using a fluidized bed coating apparatus MP-01 (manufactured by Pauleck Co., Ltd.). On the other hand, preparations with 30%, 40%, 50%, 60% and 70% coating solution (solid content) were prepared.
  • Example 4 From Example 4 and Example 5, by adding an enteric water-insoluble polymer (Eudragit L100, S100) to the water-insoluble polymer (Eudragit RSPO), the release of the lag time and the drug after the lag time can be freely set. It was confirmed that it was possible to adjust. On the other hand, it was confirmed from Comparative Examples 1 and 2 that even when the same water-insoluble polymer was coated on normal granules, no lag time was generated and a time-release preparation could not be obtained.
  • an enteric water-insoluble polymer Eudragit L100, S100
  • Test example 3 Dissolution tests were performed on the preparations produced in Examples 6 to 7 in the same manner as in Test Example 1. 9 to 10 show elution curves. Tables 13 to 14 show the lag time and T 80% calculated from the elution curve.

Abstract

L'invention concerne une préparation à libération retardée, caractérisée en ce qu'elle comprend : un noyau comprenant un médicament et une substance gonflant à l'eau ; et un film qui comprend un ou plusieurs polymères insolubles dans l'eau et avec lequel le noyau est revêtu. Cette préparation à libération retardée peut être contrôlée à volonté en ce qui concerne le moment auquel le médicament commence à être libéré de la préparation et la vitesse de libération du médicament après l'initiation de la libération du médicament.
PCT/JP2008/001705 2008-02-15 2008-06-30 Préparation à libération retardée WO2009101656A1 (fr)

Applications Claiming Priority (2)

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JP2008-035055 2008-02-15
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JP2011207851A (ja) * 2010-03-30 2011-10-20 Asahi Kasei Chemicals Corp 膨潤性の球状核
US20120251588A1 (en) 2011-03-30 2012-10-04 Miyuki Fukasawa Coating Composition, Solid Preparation Coated Therewith, and Method for Preparing Solid Preparation
KR101597004B1 (ko) * 2013-07-25 2016-02-23 씨제이헬스케어 주식회사 서방형 메트포르민과 속방형 HMG-CoA 환원효소 억제제를 포함하는 복합제제
KR101642193B1 (ko) * 2014-10-13 2016-07-25 씨제이헬스케어 주식회사 메트포르민 서방성 제제 및 그의 제조방법
PL3398587T3 (pl) * 2015-12-28 2024-01-22 Ssp Co., Ltd., Japan Skompaktowany preparat farmaceutyczny
JP7336187B2 (ja) * 2017-11-30 2023-08-31 日本ケミファ株式会社 多層構造を有する粒子状医薬組成物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07188057A (ja) * 1993-12-27 1995-07-25 Ss Pharmaceut Co Ltd 粒状製剤の製造法
JPH09208458A (ja) * 1996-02-02 1997-08-12 Ss Pharmaceut Co Ltd 不快な味がマスキングされた製剤
JP2000128779A (ja) * 1998-10-20 2000-05-09 Mitsui Chemicals Inc 薬物放出制御型製剤
WO2002066004A1 (fr) * 2001-02-23 2002-08-29 Mitsubishi Pharma Corporation Compositions a liberation controlee de medicament
WO2005092336A1 (fr) * 2004-03-26 2005-10-06 Eisai R&D Management Co., Ltd. Préparation de lessivage maîtrisé et procédé de fabrication de ladite préparation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07188057A (ja) * 1993-12-27 1995-07-25 Ss Pharmaceut Co Ltd 粒状製剤の製造法
JPH09208458A (ja) * 1996-02-02 1997-08-12 Ss Pharmaceut Co Ltd 不快な味がマスキングされた製剤
JP2000128779A (ja) * 1998-10-20 2000-05-09 Mitsui Chemicals Inc 薬物放出制御型製剤
WO2002066004A1 (fr) * 2001-02-23 2002-08-29 Mitsubishi Pharma Corporation Compositions a liberation controlee de medicament
WO2005092336A1 (fr) * 2004-03-26 2005-10-06 Eisai R&D Management Co., Ltd. Préparation de lessivage maîtrisé et procédé de fabrication de ladite préparation

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