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WO2009101658A1 - Préparation pharmaceutique à libération programmée - Google Patents

Préparation pharmaceutique à libération programmée Download PDF

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Publication number
WO2009101658A1
WO2009101658A1 PCT/JP2008/001707 JP2008001707W WO2009101658A1 WO 2009101658 A1 WO2009101658 A1 WO 2009101658A1 JP 2008001707 W JP2008001707 W JP 2008001707W WO 2009101658 A1 WO2009101658 A1 WO 2009101658A1
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Prior art keywords
manufactured
water
produced
mesh
coating liquid
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English (en)
Japanese (ja)
Inventor
Hideyoshi Kanbe
Ichiro Kawase
Koichi Kuramoto
Yoko Mori
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SSP Co Ltd
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SSP Co Ltd
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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials

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. For this reason, 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.
  • the present invention provides a timed release preparation characterized in that a central core containing a drug and a water-swellable substance is coated with a film containing a water-insoluble polymer and a water-insoluble excipient.
  • the central core containing a drug and a water-swellable substance is coated only with a film containing a water-insoluble polymer and a water-insoluble excipient, so that the time when the drug starts to be released from the preparation and the drug It is possible to provide a time-release preparation capable of freely adjusting the drug release rate after the start of release.
  • the composition of the film, the coating amount, and the mixing ratio of the water-swellable substance in the central core regardless of the pH change in the gastrointestinal tract, it is a pH-independent type that can release the drug quickly after a set lag time Timed release formulation, and within lag time within 5 minutes, 10 minutes and 15 minutes, and within 12 minutes, 15 minutes and 20 minutes after lag time (preferably within 5 minutes, 10 minutes and 15 minutes, respectively)
  • Masking-type timed release formulation capable of releasing more than 80% of the drug contained in the drug, and further, does not release the drug in the acidic and neutral regions, and releases the drug after a certain lag time only in the alkaline region to It is possible to provide a controlled release site-controlled timed release formulation and the like.
  • 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 elution curves of the preparations obtained in Example 2 and Reference Example 1.
  • FIG. 4 is a diagram showing elution curves of the preparations obtained in Example 3 and Reference Example 2.
  • 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 Example 6.
  • FIG. 8 shows the dissolution curve of the preparation obtained in Example 7.
  • FIG. 9 is a diagram showing an elution curve of the preparation obtained in Reference Example 3.
  • FIG. 10 is a view showing an elution curve of the preparation obtained in Example 8.
  • FIG. 11 is a view showing an elution curve of the preparation obtained in Example 9.
  • FIG. 12 shows the dissolution curve of the preparation obtained in Example 10.
  • FIG. 13 shows the elution curve of the preparation obtained in Example 11.
  • 14 is a diagram showing an elution curve of the preparation obtained in Example 12.
  • FIG. 15 is a view showing an elution curve of the preparation obtained in Example 13.
  • FIG. 25 is a diagram showing elution curves of the preparations obtained in Examples 23 to 26.
  • 26 is a diagram showing an elution curve of the preparation obtained in Example 27.
  • FIG. FIG. 27 shows the dissolution curve of the preparation obtained in Example 28.
  • 28 is a diagram showing an elution curve of the preparation obtained in Example 28.
  • FIG. 29 shows the elution curve of the preparation obtained in Example 29.
  • FIG. 30 is a view showing an elution curve of the preparation obtained in Example 29.
  • FIG. 31 shows the dissolution curve of the preparation obtained in Example 30.
  • 32 is a diagram showing an elution curve of the preparation obtained in Example 30.
  • FIG. FIG. 33 shows the elution curve of the preparation obtained in Example 31.
  • FIG. 34 is a view showing an elution curve of the preparation obtained in Example 32.
  • FIG. FIG. 35 is a view showing an elution curve of the preparation obtained in Example 33.
  • FIG. 36 is a diagram showing an elution curve of the preparation obtained in Example 34.
  • FIG. FIG. 37 shows the dissolution curve of the preparation obtained in Example 35.
  • FIG. 38 shows the elution curve of the preparation obtained in Example 35.
  • FIG. 39 shows the dissolution curve of the preparation obtained in Example 35.
  • 40 is a view showing an elution curve of the preparation obtained in Example 36.
  • FIG. 52 is a view showing an elution curve of the preparation obtained in Example 48.
  • FIG. 53 is a view showing an elution curve of the preparation obtained in Example 49.
  • FIG. 54 is a view showing an elution curve of the preparation obtained in Example 50.
  • FIG. 55 is a view showing an elution curve of the preparation obtained in Example 51.
  • FIG. 56 is a view showing an elution curve of the preparation obtained in Example 52.
  • FIG. FIG. 57 shows the elution curve of the preparation obtained in Example 53.
  • 58 is a view showing an elution curve of the preparation obtained in Example 54.
  • FIG. 59 is a view showing an elution curve of the preparation obtained in Example 55.
  • FIG. 60 is a view showing an elution curve of the preparation obtained in Example 56.
  • FIG. 61 is a view showing an elution curve of the preparation obtained in Example 57.
  • FIG. 62 is a view showing an elution curve of the preparation obtained in Example 58.
  • FIG. 63 is a view showing an elution curve of the preparation obtained in Example 59.
  • FIG. 64 is a diagram showing an elution curve of the preparation obtained in Example 60.
  • FIG. FIG. 65 shows the elution curve of the preparation obtained in Example 61.
  • 66 is a view showing an elution curve of the preparation obtained in Example 62.
  • FIG. 67 is a view showing an elution curve of the preparation obtained in Example 63.
  • FIG. 68 is a view showing an elution curve of the preparation obtained in Example 64.
  • FIG. FIG. 69 is a view showing an elution curve of the preparation obtained in Example 65.
  • 70 is a view showing an elution curve of the preparation obtained in Reference Example 4.
  • FIG. 71 is a view showing an elution curve of the preparation obtained in Example 66.
  • FIG. 72 is a view showing an elution curve of the preparation obtained in Example 67.
  • FIG. FIG. 73 shows the dissolution curve of the preparation obtained in Example 68.
  • 74 is a diagram showing an elution curve of the preparation obtained in Example 69.
  • FIG. 75 is a view showing an elution curve of the preparation obtained in Example 70.
  • FIG. 84 is a view showing an elution curve of the preparation obtained in Example 79.
  • FIG. 85 is a view showing an elution curve of the preparation obtained in Example 80.
  • FIG. 86 is a view showing an elution curve of the preparation obtained in Example 81.
  • FIG. 87 is a view showing an elution curve of the preparation obtained in Example 82.
  • FIG. 88 is a view showing an elution curve of the preparation obtained in Example 83.
  • FIG. 89 is a view showing an elution curve of the preparation obtained in Example 84.
  • FIG. 90 is a view showing an elution curve of the preparation obtained in Example 85.
  • FIG. FIG. 91 is a view showing an elution curve of the preparation obtained in Example 86.
  • FIG. 92 is a view showing an elution curve of the preparation obtained in Example 87.
  • FIG. 93 is a view showing an elution curve of the preparation obtained in Example 88.
  • FIG. 94 is a view showing an elution curve of the preparation obtained in Example 89.
  • FIG. 95 is a view showing an elution curve of the preparation obtained in Example 90.
  • 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 contains molecules and water-insoluble excipients.
  • the drug applied to the present invention is not particularly limited as long as it is a drug that 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, chlorphenir
  • 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. Of these, low-substituted hydroxypropylcellulose is particularly preferable.
  • 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, and has an average particle size of 30 ⁇ m or less, particularly 20 ⁇ m. The following are preferred.
  • the water-swellable substance can be used alone or in combination of two or more, and the content thereof is preferably 30% by mass or more, more preferably 40% by mass or more, particularly 50% by mass or more in the central core.
  • the upper limit of the content 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 sugars such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, calcium sulfate and the like.
  • binder for example, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, glucose, sucrose, lactose, maltose, dextrin, sorbitol, mannitol, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, macrogol,
  • 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.
  • solubilizing agent for the pharmaceutical compound include organic acids such as fumaric acid, succinic acid, malic acid, and adipic acid. The amount of these additives used can be appropriately determined according to the type of the drug.
  • water-insoluble polymer constituting the film examples include ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl terpolymer, ethyl cellulose, enteric polymer and low pH soluble polymer.
  • 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 is 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.
  • the material used include polyvinyl acetal diethylaminoacetate, methyl methacrylate / dimethylaminoethyl methacrylate copolymer, and the like.
  • (meth) acrylic binary such as ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl terpolymer, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, etc.
  • a copolymer and ethyl cellulose 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
  • the ratio of methacrylic acid and methallylic acid alkyl ester constituting the binary copolymer is preferably 1: 1 to 1: 2.
  • Examples of commercially available products include Eudragit L (for example, L100, L100-55, L30D-55) or Eudragit S (for example, S100) (manufactured by Degussa Japan).
  • the water-insoluble polymer can be used alone or in combination of two or more.
  • the ratio of each compounding component (RS: RL) is 1: 0.10 to 3.0 by mass ratio, and further 1: 0.15 to 2. 5, especially 1: 0.25 to 2.3 is preferred.
  • the ratio of each compounding component is 1: 0.05 to 0.2 by mass ratio, Further, 1: 0.08 to 0.2, particularly 1: 0.11 to 0.18 is preferable.
  • the ratio of each compounding component is 1: It is preferably 0.12 to 0.24, more preferably 1: 0.12 to 0.2, and particularly preferably 1: 0.13 to 0.18.
  • the lag time is within 5 minutes, 10 minutes or 15 minutes, and after the lag time It is possible to make a timed 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, respectively, or within 5 minutes, 10 minutes or 15 minutes after the lag time, respectively. is there.
  • a pH-independent time-release preparation capable of releasing a drug quickly after a set lag time can be obtained regardless of the pH change in the digestive tract. .
  • the ratio of each component of (C) is 1: 0.10 to 1.0 by mass ratio, and 1: 0.15 to 1.0, especially 1: 0.20 to 1.0, and the content of the water-insoluble excipient in the film is 5 to 40% by mass, further 10 to 35% by mass, particularly 15 to 30% by mass. % Is preferable.
  • the content (solid content) of the water-insoluble polymer in the film is preferably 30% by mass or more, more preferably 40% by mass or more, and particularly preferably 50% by mass or more.
  • the upper limit of the content is preferably 95% by mass, particularly 90% by mass from the viewpoint of coating operability.
  • water-insoluble excipient examples include talc, magnesium stearate, calcium stearate, kaolin, titanium oxide, magnesium oxide, calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, and dry aluminum hydroxide gel.
  • talc, kaolin and titanium oxide are preferable, talc (average particle size: 1 to 40 ⁇ m) is more preferable, and pulverized talc (average particle size: 1 to 10 ⁇ m) is particularly preferable.
  • Such talc is, for example, Victorialite SK-C (average particle size: 3.45 ⁇ m, manufactured by Katsuyama Kogyo Co., Ltd.), Victorialite SK-BB (average particle size: 4.6 ⁇ m, Katsuyama Kogyo Co., Ltd.) )) and can be obtained commercially.
  • the content of the water-insoluble excipient in the film is preferably 5% by mass or more, more preferably 10% by mass or more, further 15% by mass or more, particularly 25% by mass or more, and particularly preferably 30% by mass or more.
  • the upper limit is preferably 80% by mass, more preferably 70% by mass, and particularly preferably 60% by mass.
  • the drug is not released at all in the low pH region such as in the stomach, and after the lag time is generated in the relatively neutral region such as the small intestine and large intestine, the drug is released and released promptly.
  • the content of the water-insoluble excipient in the film is preferably 5 to 40% by mass, more preferably 10 to 35% by mass, and particularly preferably 15 to 30% by mass.
  • the preparation of the present invention can be suitably produced, for example, as follows. First, additives are added to the drug and water-swellable substance as necessary, and after mixing with a mixer such as a stirring granulator (for example, a vertical granulator (manufactured by POWREC)), purified water or hydrous alcohol is added. Knead to obtain a swollen state.
  • a mixer such as a stirring granulator (for example, a vertical granulator (manufactured by POWREC)
  • 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 alcohols 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.
  • the central core according to the present invention 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 a water-insoluble polymer and a water-insoluble excipient. 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 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 (preferably within 5 minutes, 10 minutes or 15 minutes after the lag time, respectively) Is possible.
  • it can be set as the masking type
  • 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 10% by mass, further 20% by mass, particularly 30% by mass or more, and especially 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 lag time.
  • the upper limit is 300% by mass, particularly 250% by mass.
  • drying is preferably performed by extruding and granulating in a swollen state and using spherical methods with a malmerizer.
  • the water swellable material shrinks to obtain spherical cores of smaller spherical particles than the extruded screen diameter.
  • the core of non-parrel 103 average particle size: 840 to 350 ⁇ m, manufactured by Freund Sangyo Co., Ltd.
  • a conventional centrifugal tumbling granulator such as a CF granulator (manufactured by Freund Sangyo Co., Ltd.).
  • a spherical central core containing a drug and a swelling agent can be produced without requiring a high-level formulation technique as compared with a method of powder coating a drug and a water-swellable substance while spraying an aqueous solution of a binder. .
  • 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 of the film containing the water-insoluble polymer and the water-insoluble excipient, the film thickness, the alcohol concentration in the aqueous alcohol solution when forming the central core, and the like. .
  • a masking type timed release formulation that can mask unpleasant-tasting drugs
  • a pH-independent type timed release formulation that can quickly release a drug after a set lag time, regardless of pH change in the digestive tract
  • the film when the film is composed of an ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer and ethyl cellulose or a methacrylic acid / ethyl acrylate copolymer, or from Eudragit RS and Eudragit RL
  • Eudragit RS and Eudragit RL When configured, reducing the blending amount of Eudragit RL, ethyl cellulose, methacrylic acid / ethyl acrylate copolymer increases the lag time, while increasing the blending amount of the water-insoluble excipient increases the lag time. And release after lag time can be made faster.
  • the lag time is within 5 minutes, 10 minutes and 15 minutes, and within 12 minutes, 15 minutes and 20 minutes after the lag time (preferably within 5 minutes, 10 minutes and 15 minutes after the lag time, respectively)
  • a time-release preparation capable of releasing 80% or more of the drug in the preparation can be obtained. Further, it can be adjusted by changing the thickness of the film.
  • 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.
  • 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 are shown in Table 2.
  • the lag time can be freely adjusted according to the coating amount, and it was confirmed that when the coating amount is 30% by mass or more, the release property of the drug after the lag time and the lag time is improved. .
  • Example 2 To 500 g of 10% theophylline-containing granules (20 to 30 mesh) produced in Example 1, 3750 g of the coating liquids (1) to (3) shown in Table 3 were sprayed in the same manner as in Example 1 to form a coating liquid (solid A preparation with 75% coating was prepared.
  • Test example 2 A dissolution test was performed on the preparations produced in Example 2 and Reference Example 1 in the same manner as in Test Example 1.
  • FIG. 3 shows an elution curve.
  • Table 4 shows the lag time and T 80% calculated from the elution curve.
  • Example 3 Using theophylline and L-HPC (LH31) shown in Table 5, 20-30 mesh granules (formulations A to G) containing 10 to 70% theophylline were produced in the same manner as in Example 1. The granule (500 g) was sprayed with 4750 g of the coating liquid shown in Table 1 to produce a preparation in which the coating liquid (solid content) was coated at 95%.
  • Reference example 2 Using theophylline and lactose (200 M) shown in Table 5, 20-30 mesh granules containing 10% of theophylline were produced in the same manner as in Example 1. The granule (500 g) was sprayed with 4750 g of the coating liquid shown in Table 1 to produce a preparation in which the coating liquid (solid content) was coated at 95%.
  • Example 17 Spherical granules containing 30% of 20-30 mesh (840-500 ⁇ m) theophylline were produced in the same manner as in Example 16. Next, 500 g of this spherical granule is sprayed with 3500 g and 5000 g of the coating liquid shown in Table 27 using a fluidized bed coating apparatus MP-01 (manufactured by Pauleck Co., Ltd.), and the coating liquid (solid content) is sprayed on the granules. 70% and 100% coated formulations were produced.
  • a fluidized bed coating apparatus MP-01 manufactured by Pauleck Co., Ltd.
  • Example 23 100 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 900 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, 2800 g of 10% ethanol aqueous solution was added and kneaded, and spherical granules containing 10% of 20-30 mesh (840-500 ⁇ m) diphenhydramine hydrochloride were produced in the same manner as in Example 12.
  • Example 25 500 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, 1400 g of a 10% ethanol aqueous solution was added and kneaded, and spherical granules containing 50% of 20-30 mesh (840-500 ⁇ m) diphenhydramine hydrochloride were produced in the same manner as in Example 12.
  • Example 26 700 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 300 g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) were used with a vertical granulator FM-VG-25 (manufactured by Paulec Co., Ltd.). After mixing, 2000 g of a 10% ethanol aqueous solution was added and kneaded, and spherical granules containing 70% 20-30 mesh (840-500 ⁇ m) diphenhydramine hydrochloride were produced in the same manner as in Example 12.
  • L-HPC LH31 low-substituted hydroxypropyl cellulose
  • FM-VG-25 manufactured by Shin-Etsu Chemical Co., Ltd.
  • Test Example 10 The preparation manufactured in Example 27 was subjected to a dissolution test (test solution: pH 1.2, water, pH 6.8, UV wavelength: 267 nm) in the same manner as in Test Example 1.
  • FIG. 26 shows an elution curve.
  • Table 41 shows the lag time and T 80% calculated from the elution curve.
  • the preparations of Examples 12 to 14 and 16 to 27 were prepared from an ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium copolymer, ethyl cellulose and a water-insoluble excipient in a core containing a drug and a water-swellable substance. It was confirmed that by forming a coating layer with the coating base, a time-release preparation in which the drug elution is constant without depending on the pH of the eluate can be obtained. Therefore, the time-release preparations of Examples 12 to 14 and 16 to 27 have a feature of rapidly releasing the drug after a set lag time regardless of the pH change in the digestive tract.
  • This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.8 mm screen, and spherical particles with Malmerizer Q400 (Fuji Paudal Co., Ltd.). did. Thereafter, it is dried with a fluidized bed dryer WSG-55 (Okawara Seisakusho Co., Ltd.), sized with a 20 and 30 mesh sieve, and spherical granules containing 10% of 20-30 mesh (840-500 ⁇ m) theophylline. Manufactured.
  • Example 29 To 500 g of 10% theophylline-containing granules (20 to 30 mesh) prepared in Example 28, 3750 g and 5000 g of the coating liquid shown in Table 43 were sprayed in the same manner as in Example 28, and 75% of the coating liquid (solid content) was sprayed. A 100% coated formulation was produced.
  • Example 30 To 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 28, 3750 g and 5000 g of the coating liquid shown in Table 44 were sprayed in the same manner as in Example 28, and 75% of the coating liquid (solid content) was sprayed. A 100% coated formulation was produced.
  • Example 31 Formulation prepared by spraying 5000 g of the coating liquid shown in Table 45 on 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 28 in the same manner as in Example 28 and coating the coating liquid (solid content) with 100%. Manufactured.
  • Example 32 To 500 g of 10% theophylline-containing granules (20 to 30 mesh) produced in Example 28, 3750 g and 5000 g of the coating liquid shown in Table 46 were sprayed in the same manner as in Example 28 to coat the coating liquid (solid content) with 100%. The prepared formulation was manufactured.
  • Example 34 Formulation prepared by spraying 5000 g of the coating liquid shown in Table 48 on 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 28 in the same manner as in Example 28 and coating the coating liquid (solid content) with 100% Manufactured.
  • Example 28 By adding 0.22 parts by mass (Example 28), 0.18 (Example 29) or 0.15 parts by mass (Example 30) of Eudragit L100-55 to 1 part by mass of Eudragit RSPO, a pH of 1. 2, water and pH 6.8 test solution showed the same lag time, and the release property after the lag time showed the same tendency.
  • the lag time in the test solution of pH 6.8 was pH 1.2 and the test solution of water.
  • Example 32 When 0.11 part by mass (Example 32) is added, the lag time in the pH 6.8 test solution is longer than the pH 1.2, water test solution, and is pH-dependent. showed that. Further, the addition of Eudragit L100-55 (Example 33) and the addition of Eudragit RLPO (Example 34) also showed pH dependence as in Examples 31 and 32. This indicates that the time-release preparations of Examples 28 to 30 release the pharmaceutical compound rapidly after a certain lag time regardless of the pH change of the digestive tract.
  • Example 35 300 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.). Thereafter, 2100 g of 10% ethanol aqueous solution was added and kneaded, and spherical granules containing 30% of 20-30 mesh (840-500 ⁇ m) theophylline were produced in the same manner as in Example 28.
  • L-HPC LH31 low-substituted hydroxypropylcellulose
  • FM-VG-25 manufactured by Shin-Etsu Chemical Co., Ltd.
  • Test Example 12 The preparation prepared in Example 35 was subjected to a dissolution test (test solution: pH 1.2, water, pH 6.8, UV wavelength: 267 nm) in the same manner as in Test Example 1.
  • Figures 37 to 39 show elution curves.
  • Table 55 shows the lag time and T 80% calculated from the elution curve.
  • Example 35 any coating amount of 15 to 55% showed the same lag time in the test solution of pH 1.2, water and pH 6.8, and the release property after the lag time showed the same tendency. That is, it shows that the lag time independent of pH can be freely adjusted by increasing the coating amount.
  • Example 36 200 g of theophylline (manufactured by Shiratori Pharmaceutical Co., Ltd.) and 800 g of low-substituted hydroxypropyl cellulose (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, 2400 g of 10% ethanol aqueous solution was added and kneaded.
  • L-HPC LH31 low-substituted hydroxypropyl cellulose
  • FM-VG-25 manufactured by Shin-Etsu Chemical Co., Ltd.
  • 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 adjusted with 20 mesh and 24 mesh sieves in the same manner as in Example 28.
  • Spherical granules containing 20% of 20-24 mesh (840-710 ⁇ m) theophylline were produced.
  • 500 g of this spherical granule is sprayed on a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 4500 g of the coating liquid shown in Table 43, and the coating liquid (solid content) is sprayed on the granules.
  • a 90% coated formulation was produced.
  • This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.70 mm screen, and adjusted with a 24 mesh and 30 mesh sieve in the same manner as in Example 28.
  • Spherical granules containing 20% of 24-30 mesh (710-500 ⁇ m) theophylline were produced.
  • 500 g of this spherical granule is sprayed on a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 5000 g of the coating liquid shown in Table 43, and the coating liquid (solid content) is sprayed on the granules.
  • a 100% coated formulation was produced.
  • This kneaded product was extruded and granulated with Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.6 mm screen, and adjusted with 30 mesh and 42 mesh sieves in the same manner as in Example 28.
  • Spherical granules containing 20% granulated 30-42 mesh (500-355 ⁇ m) theophylline were produced.
  • 500 g of this spherical granule is sprayed on a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 5000 g of the coating liquid shown in Table 43, and the coating liquid (solid content) is sprayed on the granules.
  • a 100% coated formulation was produced.
  • Example 39 200 g of theophylline (manufactured by Shiratori Pharmaceutical Co., Ltd.) and 800 g of low-substituted hydroxypropyl cellulose (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, 2400 g of 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 0.50 mm screen, and sized with a 42 and 60 mesh sieve in the same manner as in Example 28.
  • Spherical granules containing 20% of 42 to 60 mesh (355 to 250 ⁇ m) theophylline were produced.
  • 500 g of this spherical granule is sprayed with 7500 g of the coating liquid shown in Table 43 using a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and the coating liquid (solid content) is sprayed on the granules.
  • a 150% coated formulation was produced.
  • any particle size in which the particle size of the granules to be coated was changed to 840 to 710 ⁇ m (Example 36), 710 to 500 ⁇ m (Example 37), 500 to 355 ⁇ m (Example 38), and 355 to 250 ⁇ m (Example 39).
  • the preparation having the central core Even in the preparation having the central core, the same lag time was exhibited in the test solutions of pH 1.2, water and pH 6.8, and the release properties after the lag time showed the same tendency. That is, it was confirmed that the time-release preparation of the present invention can provide a preparation having a fine granule particle size, which was difficult by the conventional production method using nonparrel.
  • Example 40 Vertical granulator FM-VG-25 (manufactured by POWREC) 100 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 900 g of low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) After mixing, 2800 g of 10% aqueous ethanol solution was added and kneaded, and spherical granules containing 10% of 20-30 mesh (840-500 ⁇ m) diphenhydramine hydrochloride were produced in the same manner as in Example 28.
  • L-HPC LH31 low-substituted hydroxypropylcellulose
  • Example 42 500 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 500 g of low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) are used as vertical granulator FM-VG-25 (manufactured by POWREC) After mixing, 1400 g of a 10% ethanol aqueous solution was added and kneaded, and spherical granules containing 50% of 20-30 mesh (840-500 ⁇ m) of diphenhydramine hydrochloride were produced in the same manner as in Example 28.
  • L-HPC LH31 low-substituted hydroxypropylcellulose
  • Example 43 700 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 300 g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) are used as vertical granulator FM-VG-25 (manufactured by POWREC) After mixing, 2000 g of a 10% aqueous ethanol solution was added and kneaded, and spherical granules containing 70% 20-30 mesh (840-500 ⁇ m) diphenhydramine hydrochloride were produced in the same manner as in Example 28.
  • L-HPC LH31 low-substituted hydroxypropyl cellulose
  • FM-VG-25 manufactured by Shin-Etsu Chemical Co., Ltd.
  • Test Example 14 The preparations produced in Examples 40 to 43 were subjected to a dissolution test (test solution: purified water, UV wavelength: 210 nm) in the same manner as in Test Example 1.
  • FIG. 44 shows an elution curve.
  • Table 60 shows the lag time and T 80% calculated from the elution curve.
  • Example 44 200 g of anhydrous caffeine (manufactured by Kongo Chemical Co., Ltd.) and 800 g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.), vertical granulator FM-VG-25 (manufactured by Paulec Co., Ltd.) 2400 g of 10% aqueous ethanol solution was added and kneaded. This kneaded product was extruded and granulated with Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.6 mm screen, and adjusted with 30 mesh and 42 mesh sieves in the same manner as in Example 28.
  • L-HPC LH31 low-substituted hydroxypropyl cellulose
  • FM-VG-25 manufactured by Paulec Co., Ltd.
  • Spherical granules containing 20% anhydrous caffeine of 30-42 mesh (500-355 ⁇ m) were produced.
  • 500 g of this spherical granule was sprayed with 5000 g of the coating liquid shown in Table 43 using a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC), and the coating liquid (solid content) was 100% of the granules.
  • a coated formulation was produced.
  • Example 45 In the same manner as in Example 44, spherical granules containing 20% of anhydrous caffeine of 30 to 42 mesh (500 to 355 ⁇ m) were produced. Next, 500 g of this spherical granule was sprayed with 7500 g of the coating liquid shown in Table 43 using a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and the coating liquid (solid content) was 150% of the granules. A coated formulation was produced.
  • Example 46 In the same manner as in Example 44, spherical granules containing 20% of anhydrous caffeine of 30 to 42 mesh (500 to 355 ⁇ m) were produced. Next, 500 g of this spherical granule was sprayed with 10,000 g of the coating liquid shown in Table 43 using a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.), and the coating liquid (solid content) was 200% of the granules. A coated formulation was produced.
  • Test Example 15 The preparations produced in Examples 44 to 46 were subjected to a dissolution test (test solution: pH 1.2, water, pH 6.8, wavelength: 271 nm) in the same manner as in Test Example 1. 45 to 47 show elution curves. Table 61 shows the lag time and T 80% calculated from the elution curve.
  • Example 47 500 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, 1800 g of 10% ethanol aqueous solution was added and kneaded.
  • L-HPC LH31 low-substituted hydroxypropyl cellulose
  • 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 a sieve of 30 (500 ⁇ m) mesh and 40 (420 ⁇ m) mesh, and 30-40 mesh (500-420 ⁇ m) hydrochloric acid. Spherical granules containing 50% diphenhydramine were produced.
  • Example 48 The coating liquid 2000 g, 2500 g, 3000 g, 3500 g, 4000 g, 4500 g, 5000 g shown in Table 64 was added to 500 g of 50% diphenhydramine-containing granules (30-40 mesh) produced in Example 47 in the same manner as in Example 1. The preparations were sprayed and coated with 40%, 50%, 60%, 70%, 80%, 90%, 100% coating liquid (solid content).
  • Example 49 In the same manner as in Example 1, spray the coating liquid 2000 g, 3000 g, 3500 g, 4000 g, 4500 g, 5000 g, and 5500 g shown in Table 65 onto 500 g of the 50% diphenhydramine hydrochloride-containing granules (30 to 40 mesh) produced in Example 47. Then, the preparations coated with 40%, 60%, 70%, 80%, 90%, 100% and 110% of the coating liquid (solid content) were produced.
  • Example 50 In the same manner as in Example 1, spraying 2500 g, 3000 g, 3500 g, 4000 g, 4500 g, 5000 g, and 5500 g of the coating liquid shown in Table 66 onto 500 g of 50% diphenhydramine-containing granules (30 to 40 mesh) produced in Example 47. Then, preparations coated with 50%, 60%, 70%, 80%, 90%, 100%, and 110% of the coating liquid (solid content) were produced.
  • Example 51 To 500 g of 50% diphenhydramine-containing granules (30 to 40 mesh) prepared in Example 47, the coating liquids 2500 g, 3000 g, 4000 g, and 5000 g shown in Table 67 were sprayed in the same manner as in Example 1 to form a coating liquid (solid content) ) Were coated with 50%, 60%, 80% and 100%.
  • Example 52 To 500 g of 50% diphenhydramine-containing granules (30 to 40 mesh) produced in Example 47, 3000 g, 4000 g and 5000 g of the coating liquid shown in Table 68 were sprayed in the same manner as in Example 1 to spray 60%, 80% of the coating agent. %, 100% coated formulations were produced.
  • Example 51 in which Eudragit RLPO was not added, and in Example 52 in which 0.11 part by mass of Eudragit RLPO was added to Eudragit RSPO 1, a timed release formulation capable of releasing the drug after the lag time and lag time was obtained. However, the release after lag time tended to be delayed.
  • Example 49 Preparation by adding 2.33 parts by weight (Example 50) within 5 minutes, 10 minutes and 15 minutes after lag time and within 5 minutes, 10 minutes and 15 minutes respectively after lag time It was confirmed that a preparation capable of releasing 80% or more of diphenhydramine hydrochloride contained therein was obtained.
  • Example 53 300 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 700 g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) were used with a vertical granulator FM-VG-25 (manufactured by Paulec Co., Ltd.). After mixing, 2100 g of 10% ethanol aqueous solution was added and kneaded.
  • L-HPC LH31 low-substituted hydroxypropyl cellulose
  • Example 73 500 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 0.8 mm screen, and spherical particles with Malmerizer Q400 (Fuji Paudal Co., Ltd.). did. Thereafter, it is dried with a fluidized bed dryer WSG-55 (Okawara Seisakusho Co., Ltd.), sized with a sieve of 20 mesh and 30 mesh, and a spherical shape containing 10% of 20-30 mesh (840-500 ⁇ m) theophylline. Granules were produced.
  • Test Example 24 The preparations produced in Examples 74 to 77 were subjected to a dissolution test (test solution: purified water, UV wavelength: 267 nm) in the same manner as in Test Example 1. 79 to 82 show elution curves. Tables 112 to 115 show the lag time calculated from the elution curve and T 80% .
  • Test Example 25 A dissolution test (test solution: pH 1.2, purified water, pH 6.8, UV wavelength: 267 nm) was carried out in the same manner as in Test Example 1 on the preparations produced in Examples 78-82. 83 to 87 show elution curves. Tables 121 to 126 show the lag time and T 80% calculated from the elution curve.
  • Example 84 700 g of theophylline (manufactured by Shiratori Pharmaceutical Co., Ltd.) and 300 g of low-substituted hydroxypropyl cellulose (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 a 10% ethanol aqueous solution was added and kneaded, and spherical granules containing 70% of 20-30 mesh (840-500 ⁇ m) theophylline were produced in the same manner as in Example 1.
  • Example 86 Vertical granulator FM-VG-25 (Paurec Co., Ltd.) 100 g of anhydrous caffeine (Ningbo Chemical Co., Ltd.) and low substituted hydroxypropylcellulose (L-HPC LH31, Shin-Etsu Chemical Co., Ltd.) 900 g 2800 g of 10% ethanol aqueous solution was added and kneaded, and spherical granules containing 10% of 20-30 mesh (840-500 ⁇ m) anhydrous caffeine were produced in the same manner as in Example 1.
  • Examples 83 to 85 are cases in which the drug content was changed to 85 to 30%, but at any drug content, the test solution was pH 1.2, water did not release the drug, and pH 6.8 had a constant lag. It was confirmed that a timed release formulation that released 80% of the drug in 1 to 1.5 hours after the time was obtained.
  • Examples 86 to 87 are cases where anhydrous caffeine is used as a drug, and Example 87 is a case where the particle size of the central core is 30 to 42 mesh (500 to 355 ⁇ m), but also in the case of anhydrous caffeine, It was confirmed that a time-release preparation that releases 80% of the drug in 1 to 1.5 hours after a certain lag time was confirmed at pH 6.8, where the drug was not released with test solution pH 1.2 and water.
  • Examples 88 to 89 are cases where Eudragit S100 and Eudragit L100 were used in place of the methacrylic acid / ethyl acrylate copolymer with respect to the ethyl acrylate / methyl methacrylate / trimethylammonium methacrylate copolymer.
  • the test solutions pH 1.2, water and pH 6.8 release 80% of the drug in 1 to 1.5 hours after a certain lag time. It was confirmed that a timed release formulation was obtained.
  • Example 90 The coating liquid shown in Table 136, 500 g, 1000 g, 1500 g, 2000 g, 2500, 3000, 3500 g is sprayed on 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 74, and the coating liquid is applied to the granules. (Solid content) Preparations coated with 10%, 20%, 30%, 40%, 50%, 60% and 70% were produced.
  • Example 90 From Example 90, it was confirmed that the lag time can be freely adjusted to 0.3 to 3.3 hours by changing the coating amount.

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Abstract

L'invention concerne une préparation pharmaceutique à libération programmée, caractérisée en ce qu'elle présente une structure selon laquelle un noyau qui comprend un médicament et une substance gonflant à l'eau est revêtu avec un film qui comprend un polymère insoluble dans l'eau et une charge insoluble dans l'eau. La préparation rend possible de contrôler librement la durée nécessaire avant l'initiation de la libération du médicament de la préparation et la vitesse de libération du médicament après l'initiation de la libération du médicament.
PCT/JP2008/001707 2008-02-15 2008-06-30 Préparation pharmaceutique à libération programmée Ceased WO2009101658A1 (fr)

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CN103006569A (zh) * 2011-09-23 2013-04-03 北京天衡药物研究院 改善采用水分散体包衣的膜控缓释微丸抗老化性能的方法
CN103211791A (zh) * 2012-01-18 2013-07-24 北京天衡药物研究院 盐酸文拉法辛膜控缓释微丸胶囊
CN103211794A (zh) * 2012-01-18 2013-07-24 北京天衡药物研究院 富马酸喹硫平膜控缓释微丸胶囊
CN103211798A (zh) * 2012-01-18 2013-07-24 北京天衡药物研究院 氯沙坦钾膜控缓释微丸胶囊
JP2020506918A (ja) * 2017-01-26 2020-03-05 トリアステック インコーポレイテッド 特定の胃腸部位での制御放出の剤形
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US12102721B2 (en) 2017-01-26 2024-10-01 Triastek, Inc. Dosage forms of controlled release at specific gastrointestinal sites

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