WO2009101658A1

WO2009101658A1 - Timed-release pharmaceutical preparation

Info

Publication number: WO2009101658A1
Application number: PCT/JP2008/001707
Authority: WO
Inventors: Hideyoshi Kanbe; Ichiro Kawase; Koichi Kuramoto; Yoko Mori
Original assignee: Ssp Co., Ltd.
Priority date: 2008-02-15
Filing date: 2008-06-30
Publication date: 2009-08-20
Also published as: JP2009191036A

Abstract

A timed-release pharmaceutical preparation characterized by having a structure wherein a core comprising a drug and a water-swellable substance is covered with a film comprising a water-insoluble polymer and a water-insoluble filler. The preparation makes it possible to control freely the time required until the initiation of drug release from the preparation and the drug release rate after the initiation of drug release.

Description

Timed release formulation

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.

In recent years, it has become clear that the pharmacokinetics and pharmacological effects of drugs are time-dependent, and in order to maximize pharmacological effects and minimize side effects, the release rate must be controlled like sustained-release preparations. Instead, a timed release control technology that can precisely control the starting time of the main drug release after taking is required. As for timed release control technology, 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.

For example, 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. As described above, the time-release preparation can be administered in advance while avoiding a time zone in which it is difficult to take.
In addition to bronchial asthma, it is known that myocardial infarction, depression, and seizures are also time-dependent. Furthermore, by setting the release start time to 5 to 6 hours, 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.

An example of such 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). In addition, 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.

Japanese Patent Publication No. 7-72130 JP-A-7-196477 Japanese Patent No. 2558396 Japanese Patent Publication No. 6-74206

However, 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.

Therefore, 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.

As a result of intensive research aimed at developing a time-release preparation that does not require advanced formulation technology and is easy to manufacture, the present inventors have found that water-insoluble in the central core containing a drug and a water-swellable substance. It has been found that the above object can be achieved only by coating one layer of a film containing a polymer and a water-insoluble excipient.

That is, 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.

According to the present invention, 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. In addition, by changing 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. 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. FIG. 15 is a view showing an elution curve of the preparation obtained in Example 13. FIG. 16 is a diagram showing an elution curve of the preparation obtained in Example 14. FIG. 17 is a diagram showing an elution curve of the preparation obtained in Example 15. 18 is a view showing an elution curve of the preparation obtained in Example 16. FIG. FIG. 19 is a view showing an elution curve of the preparation obtained in Example 17. 20 is a view showing an elution curve of the preparation obtained in Example 18. FIG. FIG. 21 shows the elution curve of the preparation obtained in Example 19. 22 is a view showing an elution curve of the preparation obtained in Example 20. FIG. FIG. 23 shows the elution curve of the preparation obtained in Example 21. 24 is a diagram showing an elution curve of the preparation obtained in Example 22. FIG. 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. 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. 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. FIG. 41 is a view showing an elution curve of the preparation obtained in Example 37. 42 is a view showing an elution curve of the preparation obtained in Example 38. FIG. 43 is a view showing an elution curve of the preparation obtained in Example 39. FIG. FIG. 44 shows the elution curves of the preparations obtained in Examples 40-43. 45 is a diagram showing an elution curve of the preparation obtained in Example 44. FIG. FIG. 46 is a view showing an elution curve of the preparation obtained in Example 45. 47 is a view showing an elution curve of the preparation obtained in Example 46. FIG. FIG. 48 is a graph showing changes in plasma concentration of the preparation obtained in Example 44. FIG. 49 is a view showing changes in plasma concentration of the preparation obtained in Example 45. FIG. 50 is a graph showing changes in plasma concentration of the preparation obtained in Example 46. FIG. 51 shows the elution curve of the preparation obtained in Example 47. 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. 76 is a view showing an elution curve of the preparation obtained in Example 71. FIG. 77 is a view showing an elution curve of the preparation obtained in Example 72. FIG. 78 is a view showing an elution curve of the preparation obtained in Example 73. FIG. FIG. 79 shows the elution curve of the preparation obtained in Example 74. 80 is a view showing an elution curve of the preparation obtained in Example 75. FIG. 81 is a view showing an elution curve of the preparation obtained in Example 76. FIG. 82 is a view showing an elution curve of the preparation obtained in Example 77. FIG. 83 is a view showing an elution curve of the preparation obtained in Example 78. 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. 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. FIG.

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, chlorpheniramine maleate, diphenhydramine hydrochloride, promethazine hydrochloride), antipyretic analgesic / anti-inflammatory agents (for example, Buprofen, diclofenac sodium, flufenamic acid, sulpyrine, aspirin, ketoprofen), cardiotonic agents (eg, ethylephrine hydrochloride, digitoxin), antiarrhythmic agents (eg, propranolol hydrochloride, alprenolol hydrochloride), diuretics (eg, caffeine), Vasodilator, antilipidemic agent, nourishing tonic, anticoagulant, liver drug, hypoglycemic agent, antihypertensive agent, anticolitis agent, bronchodilator (eg, theophylline), antiulcer agent (eg, , Cimetidine, pirenzepine hydrochloride), sympathomimetic agents (eg, dihydrocodeine phosphate, dl-methylephedrine hydrochloride), circulatory organ agents (eg, delapril hydrochloride, meclofenoxate hydrochloride, diltiazem hydrochloride), cerebral circulation improver ( For example, vinpocetine), anxiolytics (eg chlordiaze (Oxides, diazepam), vitamins (eg, fursultiamine, thiamine hydrochloride, calcium pantothenate, ascorbic acid, tranexamic acid), antimalarials (eg, quinine hydrochloride), diastatic agents (eg, loperamide hydrochloride), psychotropic Agents (for example, chlorpromazine) and the like.

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.

Examples of the water-swellable substance constituting the central core 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 μm or less, particularly 20 μm. 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. Examples of the excipient include sugars such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, calcium sulfate and the like. As the binder, for example, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, glucose, sucrose, lactose, maltose, dextrin, sorbitol, mannitol, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, macrogol, Examples include gum arabic, gelatin, agar, and starch. In addition, 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. Furthermore, examples of the 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.

Examples of the water-insoluble polymer constituting the film include ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl terpolymer, 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 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. For example, as a gastric soluble polymer in this field, Examples of the material used include polyvinyl acetal diethylaminoacetate, methyl methacrylate / dimethylaminoethyl methacrylate copolymer, and the like.

Among them, (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. As a commercial item, Eudragit RS (for example, RSPO, RS100, RS30D) and Eudragit RL (for example, RLPO, RL100, RL30D) (above, Degussa Japan company make) are illustrated. Eudragit RS has a trimethylammonium chloride group content of 4.48 to 6.77% by mass, and Eudragit RL has a trimethylammonium chloride group content of 8.85 to 11.96% by mass. 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. For example, when two or more types are used in combination, (a) two ternary copolymers having different trimethylammonium chloride group contents are combined, or (b) a ternary copolymer and ethyl cellulose are combined. Or (C) It is preferable to combine a terpolymer and a binary copolymer. In the above (a), when Eudragit RS and Eudragit RL are used in combination, 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. Further, in the above (b), when the ternary copolymer and ethyl cellulose are used in combination, the ratio of each compounding component (ternary copolymer: ethyl cellulose) 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. Furthermore, in the above (C), when a ternary copolymer and a binary copolymer are used in combination, the ratio of each compounding component (ternary copolymer: binary copolymer) 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.
In the case of the combination of (a), for example, masking an unpleasant taste at the time of taking a drug exhibiting an unpleasant bitter taste, 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. In the case of the combination of (b) and (C), for example, 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. . In particular, it does not release the drug at all in a low pH region such as the stomach, and can release and release the drug quickly after a lag time occurs in a region close to neutral pH such as the small intestine and large intestine. In order to obtain a pH-dependent time-release preparation, the ratio of each component of (C) (ternary copolymer: binary copolymer) 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.

Examples of the water-insoluble excipient include talc, magnesium stearate, calcium stearate, kaolin, titanium oxide, magnesium oxide, calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, and dry aluminum hydroxide gel. Among them, talc, kaolin and titanium oxide are preferable, talc (average particle size: 1 to 40 μm) is more preferable, and pulverized talc (average particle size: 1 to 10 μm) is particularly preferable. Such talc is, for example, Victorialite SK-C (average particle size: 3.45 μm, manufactured by Katsuyama Kogyo Co., Ltd.), Victorialite SK-BB (average particle size: 4.6 μm, 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. However, 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. In order to obtain a pH-dependent time-release preparation, 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.

In the film, for example, 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, 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.
Examples of 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. 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 purified 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 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. . Among them, extrusion granulation is preferable, and it is particularly preferable to perform spheronization with a Malmerizer after extrusion granulation. Specifically, 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. Extrusion granulation is performed, and then spheronization is performed with a Malmerizer (manufactured by Fuji Paudal Co., Ltd.), followed by drying with a box dryer or a fluidized bed dryer. Next, 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 | blend the said various additives etc. as needed. Examples of 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. Among these, water, alcohols, or a mixture thereof is preferable, and ethanol or a mixture of ethanol and water is particularly preferable. 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. Moreover, it can be set as the masking type | mold time-release preparation which can mask the unpleasant taste at the time of taking with respect to the medicine which exhibits unpleasant bitterness.

As a coating method of the film, a method commonly used in pharmaceutical technology such as a fluidized bed coating method, a pan coating method, and a rolling fluidized bed coating method can be adopted. The coating base dispersion can be spray coated onto the core material at an appropriate speed from the nozzle of a spray gun while flowing in the apparatus by air pressure.

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. Preferably, the upper limit is 300% by mass, particularly 250% by mass.

As described above, in the present invention, when a central core containing a drug and a water-swellable substance is produced, drying is preferably performed by extruding and granulating in a swollen state and using spherical methods with a malmerizer. Sometimes the water swellable material shrinks to obtain spherical cores of smaller spherical particles than the extruded screen diameter. According to this method, the core of non-parrel 103 (average particle size: 840 to 350 μm, manufactured by Freund Sangyo Co., Ltd.) using a conventional centrifugal tumbling granulator such as a CF granulator (manufactured by Freund Sangyo Co., Ltd.). In addition, 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. . Moreover, in the method using non-parrel, it is the limit to produce a granule having an average particle size of about 1020 to 500 μm at the minimum. However, in the method suitably used in the present invention, the water-swellable substance is extruded in a swollen state. Since granulation is performed, the extrusion pressure at the time of granulation is small, and granulation with 0.3 and 0.4 mm diameter screens, which is difficult to use with ordinary extrusion granulation, becomes possible. As a result, it is possible to produce spherical cores having a particle size of powders or fine granules, for example, microspherical particles having a particle size of 500 to 355 μm, 355 to 250 μm, or 250 to 180 μm. By using such a nucleus, it becomes possible to easily produce a time-release preparation of a powder or fine granule, which has been difficult to produce conventionally.

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. . As a result, 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, Is a controlled-release controlled-release formulation that can release the drug instantaneously at a predetermined lower gastrointestinal tract by adjusting the arrival time from the gastric emptying of the drug to the drug action site or absorption site (ie, adjusting the lag time). It becomes possible to provide. For example, 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 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. As a result, 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.

EXAMPLES Next, although an Example and a reference example are given and this invention is demonstrated concretely, this invention is not limited to these at all. In the following, “%” represents “% by mass”, and the units of lag time and T _{80% in} the tables are Examples 1 to 7, 12 to 30, 35 to 46, 74 to 90, and Reference Examples 1 to 3. Is “hour (hour)”, and in Examples 8 to 11, 31 to 34, 47 to 73 and Reference Example 4, it is “minute”.

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. 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 μm) and 30 (500 μm) mesh sieves, and 20-30 mesh (840-500 μm) theophylline. Spherical granules containing 10% were produced.
Next, 500 g of this spherical granule is sprayed with a fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with the coating liquid shown in Table 1, 1500 g, 3000 g, 4000 g, and 4500 g. Preparations with 30%, 60%, 80%, and 90% coating were manufactured.

Test example 1
The preparation produced in Example 1 was 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 | blended with the formulation was evaluated in percentage. The elution curve is shown in FIG.

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.

2 and Table 2, it can be seen that the lag time tends to be longer by increasing the coating amount, but it has a great effect on the release property after the lag time (straight line, release property = T _80% -lag time). Was confirmed not to give. That is, 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.

Reference example 1
To 500 g of 10% theophylline-containing granules (20 to 30 mesh) produced in Example 1, 3750 g of the coating liquid of Reference Example 1 shown in Table 3 was sprayed in the same manner as in Example 1 to obtain 75 coating liquid (solid content). % Coated preparation was produced.

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.

It was confirmed that when 30% or more of talc was added, the lag time was shortened and theophylline release (T _80% ) after the lag time was faster than when talc was not added (Reference Example 1). This is thought to be due to a decrease in the water permeability of the membrane without the addition of talc. On the other hand, when talc is added in an amount of 30% or more, it is considered that the strength of the film is lowered to promote the destruction of the film.

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%.

Test example 3
The preparations prepared in Example 3 and Reference Example 2 were subjected to a dissolution test in the same manner as in Test Example 1.
FIG. 4 shows an elution curve. Table 6 shows the lag time and T _80% calculated from the elution curve.

It was confirmed that the release time after the lag time and the lag time became slower as the drug content increased. From these results, it was confirmed that the drug content is preferably 70% or less (water swellable substance is 30% or more) in order to sufficiently generate lag time. On the other hand, in Reference Example 2 (no water-swellable substance), it was confirmed that no lag time was generated.

Example 4
Using 100 g of ibuprofen and 900 g of low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.), spherical granules containing 10% of 30 to 42 mesh ibuprofen were obtained in the same manner as in Example 1. Manufactured.
Next, 500 g of this spherical granule was sprayed with 3750 g, 4250 g, and 4750 g of the coating liquid shown in Table 1 with a fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.). ) Were coated with 75%, 85%, and 95%.

Example 5
Using 100 g of acetaminophen and 900 g of low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.), containing 10% 30-42 mesh acetaminophen as in Example 1. Spherical granules were produced.
Next, 500 g of this spherical granule was sprayed with 3750 g, 4250 g, and 4750 g of the coating liquid shown in Table 7 using a fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.). ) Were coated with 75%, 85%, and 95%.

Example 6
30-42 mesh chlorpheniramine maleate using 100 g of chlorpheniramine maleate and 900 g of low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) in the same manner as in Example 1. Spherical granules containing 10% were produced.
Next, 500 g of this spherical granule was sprayed with 3750 g, 4250 g, and 4750 g of the coating liquid shown in Table 8 using a fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and the coating liquid (solid content) ) Were coated with 75%, 85%, and 95%.

Example 7
100 g of anhydrous caffeine and 900 g of low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed with a vertical granulator FM-VG-25 (manufactured by Pauleck Co., Ltd.) and then 10% aqueous ethanol solution 2900 g was added and kneaded. Spherical granules containing 30% to 42 mesh anhydrous caffeine 10% were produced from this kneaded product in the same manner as in Example 1.
Next, 500 g of this spherical granule was sprayed with 3750 g, 4250 g, and 4750 g of the coating liquid shown in Table 8 using a fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and the coating liquid (solid content) ) Were coated with 75%, 85%, and 95%.

Reference example 3
Nonpareil 103 (42 to 60 mesh) 1000 g was placed in a centrifugal fluid granulator (CF-360) and rolled, and 20 g of hydroxypropylcellulose (HPC-L made by Nippon Tanka Co., Ltd.) was added to water-ethanol (1: 1). ) A mixture of 250 g of anhydrous caffeine and 1230 g of lactose is gradually added while spraying a solution dissolved in 500 g of the mixed solution to coat the periphery of non-parrel to produce spherical granules containing 10% 30-42 mesh anhydrous caffeine. did.
Next, 500 g of this spherical granule was sprayed with 3750 g, 4250 g, and 4750 g of the coating liquid shown in Table 1 with a fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.). ) Were coated with 75%, 85%, and 95%.

Test example 4
The preparations prepared in Examples 4 to 7 and Reference Example 3 were subjected to a dissolution test in the same manner as in Test Example 1. As test solutions, those having a pH of 1.2 were used in Examples 4 and 5, pH 6.8 was used in Examples 6 and 7, and purified water was used in Reference Example 3.
The elution curves are shown in FIGS. Tables 9 to 12 show the lag time and T _80% calculated from the elution curve.

Even if the drug is ibuprofen (Example 4), acetaminophen (Example 5), chlorpheniramine maleate (Example 6), or anhydrous caffeine (Example 7), a controlled release start time type preparation is available. It was confirmed that it was obtained. In addition, in the granule of Reference Example 3 (no water-swellable substance) powder-coated with anhydrous caffeine using a centrifugal flow granulator (CF-360), a controlled release start time type preparation was not obtained.

Example 8
To 500 g of 10% theophylline-containing granules (20 to 30 mesh) produced in Example 1, 3500 g and 5000 g of the coating liquid shown in Table 13 were sprayed in the same manner as in Example 1, and the coating liquid (solid content) was 70%. A 100% coated formulation was produced.

Example 9
To 500 g of 10% theophylline-containing granules (20 to 30 mesh) produced in Example 1, 3500 g and 5000 g of the coating liquid shown in Table 14 were sprayed in the same manner as in Example 1, and the coating liquid (solid content) was 70%. A 100% coated formulation was produced.

Example 10
In the same manner as in Example 1, using 100 g of theophylline, 450 g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) and 450 g of carmellose calcium (manufactured by Gotoku Pharmaceutical Co., Ltd.) Spherical granules containing 10% 20-30 mesh theophylline were produced.
Next, the coating liquid 3500g, 4000g, 4500g, 5000g, 5500g, and 6000g shown in Table 1 was sprayed on 500g of 10% theophylline-containing granules (20-30 mesh) in the same manner as in Example 1 to form a coating liquid (solid content). 70%, 80%, 90%, 100%, 110%, 120% coated formulations were prepared.

Example 11
In the same manner as in Example 1, using 100 g of theophylline, 450 g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) and 450 g of croscarmellose sodium (manufactured by Asahi Kasei Kogyo Co., Ltd.) Spherical granules containing 10% 20-30 mesh theophylline were produced.
Next, the coating liquids 3500 g, 4000 g, 4500 g, 5000 g, 5500 g, and 6000 g shown in Table 1 were sprayed on 500 g of 10% theophylline-containing granules (20 to 30 mesh) in the same manner as in Example 1, and the coating agent was 70%. 80%, 90%, 100%, 110%, 120% coated formulations were prepared.

Test Example 5
The preparations produced in Examples 8 to 11 were subjected to a dissolution test (test solution: purified water, UV wavelength: 267 nm) in the same manner as in Test Example 1. 10 to 13 show elution curves. Tables 15 to 18 show the lag time and T _80% calculated from the elution curve.

It was confirmed that even when calcium carbonate (Example 8) or magnesium stearate (Example 9) was added to the water-insoluble excipient instead of talc, a controlled release start time-type preparation was obtained (FIG. 10). 11). Further, it was confirmed that a release-start-time controlled preparation can be obtained even when carmellose calcium (Example 10) and croscarmellose sodium (Example 11) are used as the water-swellable substances (FIG. 12, 13).

Example 12
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. 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 μm) theophylline. Granules were produced.
Next, 500 g of this spherical granule was sprayed with a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 5000 g of the coating liquid shown in Table 19, and 100% of the coating liquid (solid content) was applied to the granules. A coated formulation was produced.

Example 13
Formulation prepared by spraying 5000 g of the coating liquid shown in Table 20 on 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 12 in the same manner as in Example 12 and coating the coating liquid (solid content) with 100% Manufactured.

Example 14
Formulation prepared by spraying 5000 g of the coating liquid shown in Table 21 onto 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 12 in the same manner as in Example 12 and coating the coating liquid (solid content) with 100% Manufactured.

Example 15
Formulation prepared by spraying 5000 g of the coating liquid shown in Table 22 onto 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 12 in the same manner as in Example 12 and coating the coating liquid (solid content) with 100% Manufactured.

Test Example 6
The preparations produced in Examples 12 to 15 were 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. 14 to 17 show elution curves. Tables 23 to 26 show the lag time calculated from the elution curve and T _80% .

When Eudragit RSPO added 0.05 parts by mass of ethyl cellulose (Example 15) to 1, it was confirmed that drug release was exhibited after lag time and ram time, but test solution pH 1.2, water, pH 6. In the order of 8, the lag time became longer and showed no pH independence. Based on this result, when Eudragit RSPO was added to 0.11 (Example 12), 0.14 (Example 13), and 0.18 parts by mass (Example 14), the amount of ethyl cellulose added to 1, respectively. , PH 1.2, water, and pH 6.8 test solutions showed similar release properties after lag time and after lag time, and thus were confirmed to be pH-independent preparations. This indicates that the timed release formulations of Examples 12-14 release the pharmaceutical compound rapidly after a certain lag time, regardless of pH changes in the gastrointestinal tract.

Example 16
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 μm) theophylline were produced in the same manner as in Example 12.
Next, 500 g of this spherical granule is sprayed with 3500 g and 5000 g of the coating liquid shown in Table 19 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.

Example 17
Spherical granules containing 30% of 20-30 mesh (840-500 μm) 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.

Example 18
Spherical granules containing 30% of 20-30 mesh (840-500 μm) 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 28 using a fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.), and the coating liquid (solid content) is sprayed on the granules. 70% and 100% coated formulations were produced.

Test Example 7
The preparations produced in Examples 16 to 18 were 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. 18 to 20 show elution curves. Tables 29 to 31 show the lag time and T _80% calculated from the elution curve.

In Examples 16 to 18, the theophylline 30% by mass granules were coated by changing the type of talc, and it was confirmed that the release properties after lag time showed the same tendency regardless of the type of talc. It was.

Example 19
200 g of anhydrous caffeine (Ningbo Chemical Co., Ltd.) and 800 g of low-substituted hydroxypropyl cellulose (L-HPC LH31, Shin-Etsu Chemical Co., Ltd.) vertical granulator FM-VG-25 (Paurec Co., Ltd.) 2400 g of 10% ethanol aqueous solution was added and kneaded, and spherical granules containing 20% of 20-30 mesh (840-500 μm) anhydrous caffeine were produced in the same manner as in Example 12.
Next, 500 g of this spherical granule was sprayed with 3500 g and 5000 g of the coating liquid shown in Table 32 with a fluidized bed coating apparatus MP-01 (manufactured by Paulek Co., Ltd.), and the coating liquid (solid content) was applied to the granules. 70% and 100% coated formulations were produced.

Example 20
In the same manner as in Example 19, spherical granules containing 20 to 30 mesh (840 to 500 μm) of anhydrous caffeine were produced.
Next, 500 g of this spherical granule was sprayed with 3500 g and 5000 g of the coating liquid shown in Table 33 using a fluidized bed coating apparatus MP-01 (manufactured by Pauleck Co., Ltd.), and the coating liquid (solid content) was sprayed on the granules. 70% and 100% coated formulations were produced.

Example 21
In the same manner as in Example 19, spherical granules containing 20 to 30 mesh (840 to 500 μm) of anhydrous caffeine were produced.
Next, 500 g of this spherical granule is sprayed with 3500 and 5000 g of the coating liquid shown in Table 34 using a fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.), and the coating liquid (solid content) is sprayed on the granules. 70% and 100% coated formulations were produced.

Example 22
In the same manner as in Example 19, spherical granules containing 20 to 30 mesh (840 to 500 μm) of anhydrous caffeine were produced.
Next, 500 g of this spherical granule is sprayed with 3500 g and 5000 g of the coating liquid shown in Table 35 using a fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.), and the coating liquid (solid content) is sprayed on the granules. 70% and 100% coated formulations were produced.

Test Example 8
The preparations produced in Examples 19 to 22 were 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. 21 to 24 show elution curves. Tables 36 to 39 show the lag time and T _80% calculated from the elution curve.

In Examples 19 to 22, coating was carried out on granules of 20% anhydrous caffeine while changing the concentration of pharmacopeia ethanol as a coating solvent. When the concentration of pharmacopeia increased to 80%, 85%, and 90%, the release time after lag time and lag time also increased, but at 95%, it decreased. When the coating amount was the same, it was speculated that an ethanol concentration of 85 to 90% would provide the longest lag time.

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 μm) diphenhydramine hydrochloride were produced in the same manner as in Example 12.
Next, 500 g of this spherical granule is sprayed on a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 3500 g of the coating liquid shown in Table 19, and the coating liquid (solid content) is sprayed on the granules. A 70% coated formulation was produced.

Example 24
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, 2000 g of a 10% ethanol aqueous solution was added and kneaded to produce spherical granules containing 30% of 20-30 mesh (840-500 μm) diphenhydramine hydrochloride in the same manner as in Example 12.
Next, 500 g of this spherical granule is sprayed on a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 3500 g of the coating liquid shown in Table 19, and the coating liquid (solid content) is sprayed on the granules. A 70% coated formulation was produced.

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 μm) diphenhydramine hydrochloride were produced in the same manner as in Example 12.
Next, 500 g of this spherical granule is sprayed on a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 3500 g of the coating liquid shown in Table 19, and the coating liquid (solid content) is sprayed on the granules. A 70% coated formulation was produced.

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 μm) diphenhydramine hydrochloride were produced in the same manner as in Example 12.
Next, 500 g of this spherical granule is sprayed on a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 3500 g of the coating liquid shown in Table 19, and the coating liquid (solid content) is sprayed on the granules. A 70% coated formulation was produced.

Test Example 9
The preparations produced in Examples 23 to 26 were subjected to a dissolution test (test solution: water, UV wavelength: 267 nm) in the same manner as in Test Example 1. FIG. 25 shows an elution curve. Table 40 shows the lag time and T _80% calculated from the elution curve.

Example 27
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 μm) theophylline were produced in the same manner as in Example 12.
Next, 500 g of this spherical granule is sprayed with a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.) with coating liquids 750 g, 1750 g, and 2750 g shown in Table 19, and the coating liquid (solid) Preparations with 15%, 35% and 55% coating were prepared.

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.

From Example 27, it was confirmed that 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. It was done. That is, it shows that the lag time independent of pH can be freely adjusted by increasing the coating amount.

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.

Example 28
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. 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 μm) theophylline. Manufactured.
Next, 500 g of this spherical granule was sprayed with a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.) with 3750 g and 5000 g of the coating liquid shown in Table 42, and the coating liquid (solid content) was sprayed on the granules. A formulation with 75% and 100% coating was produced.

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 33
Formulation prepared by spraying 5000 g of the coating liquid shown in Table 47 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 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.

Test Example 11
The preparations produced in Examples 28 to 34 were 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. 27 to 36 show elution curves. Tables 49 to 54 show the lag time and T _80% calculated from the elution curve.

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. In addition, when Eudragit L100-55 (0.25 part by mass) was added to 1 part by mass of Eudragit RSPO (Example 31), the lag time in the test solution of pH 6.8 was pH 1.2 and the test solution of water. 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 μm) theophylline were produced in the same manner as in Example 28.
Next, 750 g, 1750 g, and 2750 g of the coating liquid shown in Table 43 were sprayed on 500 g of this spherical granule with a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.), and the coating liquid ( Preparations with 15%, 35%, and 55% solid content) were produced.

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.

In 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. 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 μm) theophylline were produced.
Next, 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.

Example 37
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. 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 μm) theophylline were produced.
Next, 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 38
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. 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 μm) theophylline were produced.
Next, 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. 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 μm) theophylline were produced.
Next, 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.

Test Example 13
The preparations produced in Examples 36 to 39 were 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. 40 to 43 show elution curves. Tables 56 to 59 show the lag time and T _80% calculated from the elution curve.

Any particle size in which the particle size of the granules to be coated was changed to 840 to 710 μm (Example 36), 710 to 500 μm (Example 37), 500 to 355 μm (Example 38), and 355 to 250 μm (Example 39). 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 μm) diphenhydramine hydrochloride were produced in the same manner as in Example 28.
Next, 500 g of this spherical granule is sprayed on a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 3500 g of the coating liquid shown in Table 43, and the coating liquid (solid content) is sprayed on the granules. A 70% coated formulation was produced.

Example 41
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.) are used as vertical granulator FM-VG-25 (manufactured by Paulec Co., Ltd.) After mixing, 2000 g of a 10% aqueous ethanol solution was added and kneaded, and spherical granules containing 30% of 20-30 mesh (840-500 μm) of diphenhydramine hydrochloride were produced in the same manner as in Example 28.
Next, 500 g of this spherical granule was sprayed with 3500 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 70% of the granules. A coated formulation was produced.

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 μm) of diphenhydramine hydrochloride were produced in the same manner as in Example 28.
Next, 500 g of this spherical granule was sprayed with 3500 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 70% of the granules. A coated formulation was produced.

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 μm) diphenhydramine hydrochloride were produced in the same manner as in Example 28.
Next, 500 g of this spherical granule was sprayed with 3500 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 70% of the granules. A coated formulation was produced.

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.

By reducing the content of the water-swellable substance in the central core to 90% (Example 40), 70% (Example 41), 50% (Example 42), and 30% (Example 43), Although the release rate after the lag time was slow, it was confirmed that a pH-independent time-release formulation could be obtained with any water-swellable substance content.

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. Spherical granules containing 20% anhydrous caffeine of 30-42 mesh (500-355 μm) were produced.
Next, 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 μm) 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 μm) 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.

Nine beagle dogs (male) fasted overnight were divided into 3 groups, and the preparations produced in Examples 44 to 46 were each administered in an amount of 50 mg anhydrous caffeine. After administration, blood was collected at 1, 2, 3, 4, 6, 8, 10, and 24 hours. In addition, 50 mg of anhydrous caffeine drug substance was administered to 3 beagle dogs (male) fasted overnight, and blood was collected after 0.25, 0.5, 1, 1.5, 2, 4, 8 and 12 hours. Collected. The plasma concentration of anhydrous caffeine was measured by high performance liquid chromatography. Table 62 shows the pharmacokinetic parameters. 48 to 50 show changes in drug concentration in plasma. In FIG. 49, one of the three beagle dogs to which the preparation of Example 45 was administered had data obtained because the drug was discharged after the drug administration, and data was not obtained.

A good correlation was observed between the in vitro lag time from the dissolution test and the in vivo lag time of the plasma concentration, and it was confirmed that a time-release preparation was obtained.

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. 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 μm) mesh and 40 (420 μm) mesh, and 30-40 mesh (500-420 μm) hydrochloric acid. Spherical granules containing 50% diphenhydramine were produced.
Next, 500 g of this spherical granule was subjected to a fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.), and the coating liquid shown in Table 63, 2500 g, 3000 g, 3500 g, 4000 g, 4500 g, 5000 g, 5500 g, In the same manner, preparations were prepared by spraying and coating the coating liquid (solid content) by 50%, 60%, 70%, 80%, 90%, 100%, 110%.

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.

Test Example 16
The preparations produced in Examples 47 to 52 were subjected to a dissolution test (test solution: purified water, UV wavelength: 220 nm) in the same manner as in Test Example 1. 51 to 56 show elution curves. Tables 69 to 74 show the lag time and T _80% calculated from the elution curve.

In 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. In contrast, Eudragit RSPO with low water permeability, Eudragit RLPO with high water permeability 0.66 parts by mass (Example 47), 1.0 part by mass (Example 48), 1.5 parts by mass (implementation) 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. This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.5 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 30 (500 μm) mesh and 40 (420 μm) mesh, and 30-40 mesh (500-420 μm) hydrochloric acid. Spherical granules containing 30% diphenhydramine were produced.
Next, 2500 g, 3000 g, 3500 g, 4000 g, 4500 g, 5000 g, 5500 g, and 6000 g of the coating liquid shown in Table 75 were sprayed on 500 g of this spherical granule (30 to 40 mesh) in the same manner as in Example 1, and the coating liquid ( The solid content was coated with 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%.

Example 54
In the same manner as in Example 1, the coating solutions 2500 g, 3000 g, 3500 g, 4000 g, 4500 g, 5000 g, 5500 g, and 6000 g shown in Table 76 were added to 500 g of 30% diphenhydramine-containing granules (30 to 40 mesh) produced in Example 53. Sprayed to produce a preparation coated with 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120% coating liquid (solid content).

Example 55
500 g of 30% diphenhydramine-containing granules (30 to 40 mesh) produced in Example 53 were mixed with a tumbling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and the coating liquids 1000 g, 1500 g and 1750 g shown in Table 64 were used. 2000 g, 2250 g, and 2750 g were sprayed in the same manner as in Example 1 to prepare preparations in which the coating liquid (solid content) was coated by 20%, 30%, 35%, 40%, 45%, and 55%.

Test Example 17
The preparations produced in Examples 53 to 55 were subjected to a dissolution test (test solution: purified water, UV wavelength: 220 nm) in the same manner as in Test Example 1. Figures 57 to 59 show elution curves. Tables 77 to 79 show the lag time and T _80% calculated from the elution curve.

Example 53 (talc, average particle size: 30 to 40 μm, manufactured by Kihara Kasei Co., Ltd.), Example 54 (talc SK-BB, average particle size: 4.6 μm, manufactured by Katsuyama Kogyo Co., Ltd.), and implementation In Example 55 (talc SK-C, average particle size: 3.45 μm, manufactured by Katsuyama Kogyo Co., Ltd.), a time-release preparation is obtained, and the lag time tends to increase as the particle size of talc increases. confirmed.

Example 56
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, 900 g of a 10% ethanol aqueous solution was added and kneaded. This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) fitted with a 0.3 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 60 (250 μm) mesh and 80 (180 μm) mesh, and 60-80 mesh (250-180 μm) hydrochloric acid. Spherical granules containing 70% diphenhydramine were produced.
Next, 500 g of this spherical granule was sprayed on a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 3250 g and 4250 g of the coating liquid shown in Table 80 in the same manner as in Example 1. A preparation coated with 65% and 85% (solid content) was produced.

Example 57
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, 900 g of a 10% ethanol aqueous solution was added and kneaded.
This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.4 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 42 (355 μm) and 60 (250 μm) mesh, and 42-60 mesh (355-250 μm) of diphenhydramine hydrochloride. A spherical granule containing 70% was produced.
Next, 500 g of this spherical granule was sprayed in a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 2500 g and 3250 g of the coating liquid shown in Table 80 in the same manner as in Example 1. A preparation coated with 50% and 65% (solid content) was produced.

Example 58
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, 900 g of a 10% ethanol aqueous solution was added and kneaded. This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.5 mm screen, and with a melmerizer Q400 (Fuji Paudal Co., Ltd.) did. Thereafter, it is dried with a fluidized bed dryer WSG-5 type (Okawara Seisakusho Co., Ltd.), sized with a sieve of 30 (500 μm) mesh and 42 (355 μm) mesh, and 30 to 42 mesh (500 to 355 μm) hydrochloric acid. Spherical granules containing 70% diphenhydramine were produced.
Next, 500 g of this spherical granule was sprayed in the same manner as in Example 1 using the rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) in the same manner as in Example 1 with 1750 g, 2250 g, and 2750 g of the coating solution shown in Table 80. Preparations with 35%, 45% and 55% coating solution (solid content) were produced.

Example 59
850 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 150 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, 900 g of a 10% ethanol aqueous solution was added and kneaded. This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.7 mm screen, and with a melmerizer Q400 (Fuji Paudal Co., Ltd.) did. Thereafter, it is dried with a fluidized bed dryer WSG-5 (manufactured by Okawara Seisakusho Co., Ltd.), sized with a sieve of 24 (710 μm) mesh and 30 (500 μm) mesh, and 24-30 mesh (710-500 μm) hydrochloric acid. Spherical granules containing 85% diphenhydramine were produced.
Next, 500 g of this spherical granule was sprayed with the rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) in the same manner as in Example 1 with 1000 g, 1250 g and 1500 g of the coating solution shown in Table 80. Preparations with coating solutions (solid content) of 20%, 25% and 30% were produced.

Example 60
850 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 150 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, 4500 g of 10% ethanol aqueous 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 0.8 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 20 (840 μm) mesh and 24 (710 μm) mesh, and 20-24 mesh (840-710 μm) hydrochloric acid. Spherical granules containing 85% diphenhydramine were produced.
Next, 500 g, 750 g, 1000 g, and 1250 g of the coating liquid shown in Table 80 were used in the same manner as in Example 1 by using 500 g of the spherical granules with a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.). The preparations which were sprayed and coated with 10%, 15%, 20% and 25% coating solution (solid content) were produced.

Test Example 18
The preparations produced in Examples 56 to 60 were subjected to a dissolution test (test solution: purified water, UV wavelength: 220 nm) in the same manner as in Test Example 1. 60 to 64 show elution curves. Tables 81 to 85 show the lag time and T _80% calculated from the elution curve.

As shown in FIGS. 60 to 64, the particle diameter containing 70% diphenhydramine hydrochloride is 60 to 80 mesh (250 to 180 μm) central core (Example 56), 42 to 60 mesh (355 to 250 μm) central core. (Example 57), a preparation having a central core (Example 58) of 30 to 40 mesh (500 to 355 μm), a central core having a particle size containing 85% diphenhydramine hydrochloride and having a particle size of 24 to 30 mesh (710 to 500 μm) (Example 59), all of the preparations having a central core (Example 60) of 20 to 24 mesh (840 to 710 μm) had a lag time of 5 minutes, 10 minutes or less, 15 minutes, and 5 lag time after each. It was confirmed that 80% or more of diphenhydramine hydrochloride contained in the preparation was released within minutes, 10 minutes, and 15 minutes.

Example 61
To 500 g of 50% diphenhydramine-containing granules (30-40 mesh) produced in Example 47, 1500 g, 2000 g, and 2750 g of the coating liquid shown in Table 86 were sprayed in the same manner as in Example 1 to spray the coating liquid (solid content). 30%, 40% and 55% coated formulations were prepared.

Example 62
A coating liquid (solid content) was sprayed in the same manner as in Example 1 by spraying 1750 g, 2500 g, and 3500 g of the coating liquid shown in Table 87 onto 500 g of 50% diphenhydramine-containing granules (30 to 40 mesh) prepared in Example 47. 35%, 50% and 70% coated formulations were prepared.

Test Example 19
The preparations produced in Examples 61 to 62 were subjected to a dissolution test (test solution: purified water, UV wavelength: 220 nm) in the same manner as in Test Example 1. 65 to 66 show elution curves. Tables 88 to 89 show the lag time calculated from the elution curve and T _80% .

As shown in FIGS. 65 to 66, when 50% of diphenhydramine hydrochloride is contained (particle size: 840 to 500 μm), the lag times are 5 minutes, 10 minutes, and 15 minutes or less, and 5 minutes after the lag time, It was confirmed that a preparation releasing 80% or more of diphenhydramine hydrochloride contained in the preparation was obtained within 15 minutes.

Example 63
After mixing 100 g of ibuprofen (manufactured by BASF) and 900 g of low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) with a vertical granulator FM-VG-25 (manufactured by Paulec), 10 A 2% ethanol aqueous solution was added and kneaded. 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 30 (500 μm) and 40 (420 μm) mesh sieves, and 30-40 mesh (500-420 μm) ibuprofen. Spherical granules containing 10% were produced.
Next, 500 g of this spherical granule was subjected to the coating solutions 1000 g, 1500 g, 2000 g, 2500 g, 3000 g, 3500 g, 4000 g, 4500 g, and 5000 g shown in Table 90 using a fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.). In the same manner as in Example 1, sprayed coating solutions (solid content) were coated with 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%.

Example 64
The coating liquid of 750 g, 1000 g, 1250 g, 1500 g, 1750 g, and 2000 g shown in Table 91 was sprayed on 500 g of the 10% ibuprofen-containing granules (30 to 40 mesh) produced in Example 63 in the same manner as in Example 1. Preparations with 15%, 20%, 25%, 30%, 35%, 40% coating (solid content) were produced.

Example 65
To 500 g of 10% ibuprofen-containing granules (30 to 40 mesh) produced in Example 63, 1000 g, 1250 g, 1750 g, 2000 g and 2250 g of the coating liquid shown in Table 92 were sprayed in the same manner as in Example 1 to form a coating liquid (solid Min) were coated with 20%, 25%, 35%, 40%, 45%.

Reference example 4
To 500 g of 10% ibuprofen-containing granules (30 to 40 mesh) produced in Example 63, 1750 g, 2000 g and 2250 g of the coating liquid shown in Table 93 were sprayed in the same manner as in Example 1 to obtain 35 coating liquid (solid content). %, 40%, 45% coated formulations were produced.

Test Example 20
The preparations produced in Examples 63 to 65 and Reference Example 4 were subjected to a dissolution test (test solution: pH 6.8, UV wavelength: 220 nm) in the same manner as in Test Example 1. 67 to 70 show elution curves. Tables 94 to 97 show the lag time and T _80% calculated from the elution curve.

Example 65, in which an equivalent coating composition of Eudragit RSPO and talc was dispersed in an 80% aqueous ethanol solution, provides a timed release formulation that can release the drug after lag time and lag time, but release of ibuprofen in the formulation Tended to be delayed. On the other hand, in Examples 63 and 64 in which an equivalent coating composition of Eudragit RSPO and talc was dispersed in a 30% or 50% aqueous ethanol solution, the lag time was within 5 minutes, 10 minutes, 15 minutes, and after the lag time. It was confirmed that a timed release preparation suitable for drug masking was obtained by releasing 80% or more of ibuprofen in the preparation within 12 minutes, 15 minutes and 20 minutes, respectively. This is considered to be due to the formation of a coating layer with high water permeability when the ethanol concentration decreases. In Reference Example 4 where talc was not used for film formation, the lag time was not measurable.

Example 66
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, 900 g of a 10% ethanol aqueous solution was added and kneaded. This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) fitted with a 0.3 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 60 (250 μm) mesh and 80 (180 μm) mesh, and 60-80 mesh (250-180 μm) hydrochloric acid. Spherical granules containing 70% diphenhydramine were produced.
Next, 500 g of this spherical granule was mixed with a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.), and the coating solutions shown in Table 98 were applied in the same manner as in Example 1, 3000 g, 3500 g, 4000 g, 4500 g, and 5000 g. In this way, preparations were prepared by spraying and coating the coating liquid (solid content) 60%, 70%, 80%, 90%, 100%.

Example 67
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, 900 g of a 10% ethanol aqueous solution was added and kneaded. This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.4 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 42 (355 μm) mesh and 60 (250 μm) mesh, and 42-60 mesh (355-250 μm) hydrochloric acid. Spherical granules containing 70% diphenhydramine were produced.
Next, 500 g of this spherical granule was subjected to 2500 g, 2750 g, 3000 g, 3750 g, 4000 g, 4250 g, and 4500 g of the coating liquid shown in Table 98 using a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.). In the same manner as in Example 1, preparations were prepared by spraying and coating the coating liquid (solid content) by 50%, 55%, 60%, 75%, 80%, 85%, 90%.

Example 68
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, 900 g of a 10% ethanol aqueous solution was added and kneaded. This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.5 mm screen, and with a melmerizer Q400 (Fuji Paudal Co., Ltd.) did. Thereafter, it is dried with a fluidized bed dryer WSG-5 type (Okawara Seisakusho Co., Ltd.), sized with a sieve of 30 (500 μm) mesh and 42 (355 μm) mesh, and 30 to 42 mesh (500 to 355 μm) hydrochloric acid. Spherical granules containing 70% diphenhydramine were produced.
Next, 500 g of this spherical granule was mixed with a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.), and 1500 g, 1750 g, 2000 g, 2250 g, 2500 g, and 2750 g of the coating liquid shown in Table 98 were used in Example 1. In the same manner as above, preparations were prepared by spraying and coating the coating liquid (solid content) 30%, 35%, 40%, 45%, 50%, 55%.

Example 69
850 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 150 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, 900 g of a 10% ethanol aqueous solution was added and kneaded. This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.7 mm screen, and with a melmerizer Q400 (Fuji Paudal Co., Ltd.) did. Thereafter, it is dried with a fluidized bed dryer WSG-5 (manufactured by Okawara Seisakusho Co., Ltd.), sized with a sieve of 24 (710 μm) mesh and 30 (500 μm) mesh, and 24-30 mesh (710-500 μm) hydrochloric acid. Spherical granules containing 85% diphenhydramine were produced.
Next, 500 g of this spherical granule was sprayed in a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 1000 g, 1250 g, and 1500 g of the coating solution shown in Table 98 in the same manner as in Example 1. Preparations with coating solutions (solid content) of 20%, 25% and 30% were produced.

Test Example 21
The preparations produced in Examples 66 to 69 were subjected to a dissolution test (test solution: pH 6.8, UV wavelength: 210 nm) in the same manner as in Test Example 1. 71 to 74 show elution curves. Tables 99 to 102 show the lag time and T _80% calculated from the elution curve.

Contains 70% diphenhydramine hydrochloride and has a particle size of 250 to 180 μm (Example 66), 355 to 250 μm (Example 67) or 500 to 350 μm (Example 68), and 85% diphenhydramine hydrochloride. When nuclei having a particle size of 710 to 500 μm (Example 69) were coated on the nuclei using a 30% aqueous ethanol solution (Table 98) of a mixture of Eudragit RSPO and talc SK-BB (1: 1), any particle size It has been confirmed that a timed release formulation can be obtained that releases 80% or more of diphenhydramine hydrochloride in the formulation within 5 minutes, 10 minutes, and 15 minutes, and within 12 minutes, 15 minutes, and 20 minutes after the lag time, respectively. It was. Therefore, it is suitable as a time-release preparation suitable for masking fine granules or powders of 500 μm or less.

Example 70
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.). Thereafter, 2700 g of a 10% ethanol aqueous solution was added and kneaded. 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 30 (500 μm) mesh and 42 (355 μm) mesh, and 30 to 42 mesh (500 to 355 μm) theophylline. Spherical granules containing 10% were produced.
Next, 500 g of this spherical granule was tumbled using a fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and the coating liquid shown in Table 98 was applied in the same manner as in Example 1 to 2250 g, 2500 g, 2750 g, 3000 g, 3250 g. In this way, preparations were prepared by spraying and coating the coating liquid (solid content) by 45%, 50%, 55%, 60%, 65%.

Example 71
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. 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 30 (500 μm) mesh and 42 (355 μm) mesh, and 30 to 42 mesh (500 to 355 μm) theophylline. To produce spherical granules containing 30%.
Next, 500 g of this spherical granule was mixed with a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.), and the coating solutions shown in Table 98 were 1000, 1250, 1500, and 1750 g as in Example 1. Formulations sprayed and coated with 20, 25, 30, 35% coating agent were prepared.

Example 72
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. 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 30 (500 μm) mesh and 42 (355 μm) mesh, and 30 to 42 mesh (500 to 355 μm) theophylline. A spherical granule containing 50% was produced.
Next, 500 g of this spherical granule was tumbled using a fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.), and 750 g, 1000 g, 1250 g and 1500 g of the coating solution shown in Table 98 were used in the same manner as in Example 1. Preparations were prepared by spraying and coating with 15%, 20%, 25%, 30% coating solution (solid content).

Test Example 22
The preparations produced in Examples 70 to 72 were subjected to a dissolution test (test solution: purified water, UV wavelength: 267 nm) in the same manner as in Test Example 1. 75 to 77 show elution curves. Tables 103 to 105 show the lag time and T _80% calculated from the elution curve.

As shown in FIGS. 75 to 77, a 30% aqueous ethanol solution (Table 98) of Eudragit RSPO and an equivalent mixture of talc SK-BB is added to the central core containing 10, 30, and 50% theophylline and having a particle size of 500 to 350 μm. When coated with the used coating solution, 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, respectively, a time limit that releases 80% or more of theophylline in the preparation It was confirmed that a release formulation was obtained.

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.
This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.5 mm screen, and with a melmerizer Q400 (Fuji Paudal Co., Ltd.) did. Thereafter, it is dried with a fluidized bed dryer WSG-5 type (Okawara Seisakusho Co., Ltd.), sized with a sieve of 30 (500 μm) mesh and 42 (355 μm) mesh, and 30 to 42 mesh (500 to 355 μm) hydrochloric acid. Spherical granules containing 50% diphenhydramine were produced.
Next, 500 g of this spherical granule was tumbled using a fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and the coating liquid shown in Table 106 was applied in the same manner as in Example 1 to 1000 g, 1250 g, 1500 g, and 1750 g. Preparations were prepared by spraying and coating with 20%, 25%, 30%, 35% coating liquid (solid content).

Test Example 23
The preparation prepared in Example 73 was subjected to a dissolution test (test solution: purified water, UV wavelength: 210 nm) in the same manner as in Test Example 1. FIG. 78 shows an elution curve. Table 107 shows the lag time and T _80% calculated from the elution curve.

As shown in FIG. 78, even when the central core containing 50% diphenhydramine hydrochloride and having a particle diameter of 500 to 355 μm is coated with a coating solution containing 30% talc, the lag time is 5 minutes, 10 minutes, 15 minutes. Within 12 minutes, 15 minutes and 20 minutes after the lag time, it was confirmed that a time-release preparation that releases 80% or more of diphenhydramine hydrochloride in the preparation was obtained.

Example 74
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. 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 μm) theophylline. Granules were produced.
Next, 500 g of this spherical granule is sprayed with a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 5000 g of the coating liquid shown in Table 108, and 100 g of the coating liquid (solid content) is applied to the granules. % Coated preparation was produced.

Example 75
Formulation prepared by spraying 5000 g of the coating liquid shown in Table 109 on 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 74 in the same manner as in Example 1 and coating the coating liquid (solid content) with 100% Manufactured.

Example 76
Formulation prepared by spraying 5000 g of the coating liquid shown in Table 110 on 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 74 in the same manner as in Example 1 and coating the coating liquid (solid content) with 100% Manufactured.

Example 77
Formulation prepared by spraying 5000 g of the coating liquid shown in Table 111 on 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 74 in the same manner as in Example 1 and coating the coating liquid (solid content) with 100% Manufactured.

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% .

In Example 77, in which the blending ratio of Eudragit RSPO and Eudragit L100-5 was 8: 2, and 50% of talc, which is a water-insoluble excipient, was added, there was a lag time and a timed release formulation capable of releasing the drug after the lag time. Obtained. Furthermore, when the amount of talc added is 40% (Example 74), 30% (Example 75), and 10% (Example 76), the test solution has a pH of 1.2 and water does not release the drug, and the pH is 6.8. Thus, it was confirmed that a time-release preparation that releases 80% or more of the drug in 1 to 1.5 hours after a lag time of 4 to 6 hours can be obtained.

Example 78
To 500 g of 10% theophylline-containing granules (20 to 30 mesh) produced in Example 74, 3750 g and 5000 g of the coating liquid shown in Table 116 were sprayed in the same manner as in Example 1, and the coating liquid (solid content) was 75%. A 100% coated formulation was produced.

Example 79
Formulation obtained by spraying 5000 g of the coating liquid shown in Table 117 on 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 74 in the same manner as in Example 1 and coating the coating liquid (solid content) with 100% Manufactured.

Example 80
Formulation obtained by spraying 5000 g of the coating liquid shown in Table 118 on 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 74 in the same manner as in Example 1 and coating the coating liquid (solid content) with 100% Manufactured.

Example 81
To 500 g of 10% theophylline-containing granules (20 to 30 mesh) produced in Example 74, 3750 g and 5000 g of the coating liquid shown in Table 119 were sprayed in the same manner as in Example 1, and 75% of the coating liquid (solid content) was sprayed. A 100% coated formulation was produced.

Example 82
To 500 g of 10% theophylline-containing granules (20 to 30 mesh) produced in Example 74, 3750 g and 5000 g of the coating liquid shown in Table 120 were sprayed in the same manner as in Example 1, and 75% of the coating liquid (solid content) was sprayed. A 100% coated formulation was produced.

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.

From Examples 78 to 82, by changing the mixing ratio of Eudragit L100-55 to Eudragit RSPO, it is possible to freely adjust the lag time at test solution pH 6.8 to 0.3 to 6.6 hours. It was confirmed.

Example 83
850 g of theophylline (manufactured by Shiratori Pharmaceutical Co., Ltd.) and 150 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, 450 g of a 10% ethanol aqueous solution was added and kneaded, and spherical granules containing 85% of 20-30 mesh (840-500 μm) theophylline were produced in the same manner as in Example 1.
Next, 500 g of this spherical granule was sprayed on a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.) with 3500 g and 5000 g of the coating liquid shown in Table 109, and the coating liquid (solid content) was sprayed on the granules. ) Was coated at 70% and 100%.

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 μm) theophylline were produced in the same manner as in Example 1.
Next, 500 g of this spherical granule was sprayed on a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.) with 3500 g and 5000 g of the coating liquid shown in Table 109, and the coating liquid (solid content) was sprayed on the granules. ) Was coated at 70% and 100%.

Example 85
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 a 10% aqueous ethanol solution was added and kneaded to produce spherical granules containing 30% of 20-30 mesh (840-500 μm) theophylline in the same manner as in Example 1.
Next, 500 g of this spherical granule was sprayed on a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.) with 3500 g and 5000 g of the coating liquid shown in Table 109, and the coating liquid (solid content) was sprayed on the granules. ) Was coated at 70% and 100%.

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 μm) anhydrous caffeine were produced in the same manner as in Example 1.
Next, 500 g of this spherical granule was sprayed on a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.) with 3500 g and 5000 g of the coating liquid shown in Table 109, and the coating liquid (solid content) was sprayed on the granules. ) Was coated at 70, 100%.

Example 87
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 a 10% ethanol aqueous solution was added and kneaded.
Next, 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 Malmerizer Q400 (Fuji Paudal Co., Ltd.). Spherical particles were used. Thereafter, it is dried with a fluidized bed dryer WSG-55 (Okawara Seisakusho Co., Ltd.), sized with a 30-mesh and 42-mesh sieve, and containing 10% of 30-42 mesh (500-355 μm) anhydrous caffeine. Spherical granules were produced.
Next, spherical granules containing 10% of 30-42 mesh (500-355 μm) anhydrous caffeine were produced in the same manner as in Example 1.
Then, 500 g of this spherical granule is sprayed with a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 3500 g of the coating liquid shown in Table 109, and the coating liquid (solid content) is 70% of the granules. A coated formulation was produced.

Example 88
To 500 g of 10% theophylline-containing granules (20 to 30 mesh) produced in Example 74, 3750 g and 5000 g of the coating liquid shown in Table 127 were sprayed in the same manner as in Example 1, and the coating liquid (solid content) was 75%. A 100% coated formulation was produced.

Example 89
To 500 g of 10% theophylline-containing granules (20 to 30 mesh) produced in Example 74, 3750 g and 5000 g of the coating liquid shown in Table 128 were sprayed in the same manner as in Example 1, and 75% of the coating liquid (solid content) was sprayed. A 100% coated formulation was produced.

Test Example 26
The preparations produced in Examples 83 to 89 were subjected to a dissolution test (test solution: pH 1.2, purified water, pH 6.8, UV wavelength: wavelength theophylline: 267 nm, anhydrous caffeine: 271 nm) in the same manner as in Test Example 1. did. 88 to 94 show elution curves. Tables 129 to 135 show the lag time and T _80% calculated from the elution curve.

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 μm), 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. However, unlike Eudragit L100-55, 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.

Test Example 27
The preparation produced in Example 90 was subjected to a dissolution test (test solution: pH 6.8, UV wavelength: 267 nm) in the same manner as in Test Example 1. FIG. 95 shows an elution curve. Table 137 shows the lag time and T _80% calculated from the elution curve.

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.

Claims

A time-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 water-swellable substance is one or more selected from low-substituted hydroxypropylcellulose, carmellose or a salt thereof, croscarmellose sodium, sodium carboxymethyl starch, cros polyvinylpyrrolidone, crystalline cellulose, and crystalline cellulose / carmellose sodium The time-release preparation according to claim 1.
The water-insoluble polymer is one or more selected from ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl terpolymer, ethyl cellulose, enteric polymer and low pH soluble polymer. Item 3. A time-release preparation according to item 1 or 2.
2 types of ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl terpolymers having different contents of trimethylammonium chloride groups as water-insoluble polymers,
The mass ratio of the ternary copolymer having a relatively low trimethylammonium chloride content to the ternary copolymer having a relatively high content of the two terpolymers is 1: The time-release preparation according to claim 3, which is 0.10 to 3.0.
As a water-insoluble polymer, ethyl acrylate, methyl methacrylate, methacrylate trimethyl ammonium ethyl terpolymer, and ethyl cellulose,
The time-release preparation according to claim 3, wherein the mass ratio of the terpolymer and ethylcellulose is 1: 0.05 to 0.2.
As a water-insoluble polymer, ethyl acrylate, methyl methacrylate, methacrylate trimethylammonium ethyl terpolymer, and enteric polymer,
The time-release preparation according to claim 3, wherein the mass ratio of the terpolymer to the enteric polymer is 1: 0.12 to 0.24.
The water-insoluble excipient is one or more selected from talc, magnesium stearate, calcium stearate, kaolin, titanium oxide, magnesium oxide, calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, and dry aluminum hydroxide gel. The time-release preparation according to any one of claims 1 to 6.
The time-release preparation according to any one of claims 1 to 7, wherein the content of the water-swellable substance in the central core is 30% by mass or more.
The time-release preparation according to any one of claims 1 to 8, wherein the content of the water-insoluble polymer in the film is 30% by mass or more.
The time-release preparation according to any one of claims 1 to 9, wherein the central core is produced by wet granulation with water or hydrous alcohol.
The time-release preparation according to any one of claims 1 to 10, wherein the coating amount of the film is 10% by mass or more based on the total mass of the central core.