WO2009101656A1

WO2009101656A1 - Delayed release preparation

Info

Publication number: WO2009101656A1
Application number: PCT/JP2008/001705
Authority: WO
Inventors: Hideyoshi Kanbe
Original assignee: Ssp Co., Ltd.
Priority date: 2008-02-15
Filing date: 2008-06-30
Publication date: 2009-08-20
Also published as: JP2009191034A

Abstract

A delayed release preparation characterized by comprising: a core comprising a drug and a water-swelling substance; and a film which comprises one or more water-insoluble polymers and with which the core is coated. This delayed release preparation can be controlled at will with respect to the time when the drug begins to be released from the preparation and to the rate of drug release after the drug release initiation.

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. In addition, it has been extremely difficult to accurately control the lag time (the time during which no drug is released) and the drug release after the lag time. Therefore, there has been a strong demand for a time-release preparation that does not require advanced preparation techniques and is easy to manufacture.

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 one or more polymers.

That is, the present invention provides a time-release preparation characterized in that the central core containing a drug and a water swelling substance is coated with a film containing one or more water-insoluble polymers.

According to the present invention, the time at which the drug starts to be released from the preparation and the drug can be obtained by coating only one layer containing one or more water-insoluble polymers on the central core containing the drug and the water-swellable substance. It is possible to provide a time-release preparation capable of freely adjusting the drug release rate after the start of release. In particular, by changing the composition of the film, the coating amount, and the blending ratio of the water-swellable substance in the central core, it becomes possible to control the drug release start time and the drug release rate more precisely.

Fig. 1 shows the calculation method of lag time (time when drug is not released), T _80% (time when elution amount reaches 80%), T _80% -lag time (release of time-release preparation) from the dissolution curve. It is a figure for demonstrating. 2 is a diagram showing an elution curve of the preparation obtained in Example 1. FIG. FIG. 3 is a diagram showing an elution curve of the preparation obtained in Example 2. FIG. 4 is a view showing an elution curve of the preparation obtained in Example 3. FIG. 5 is a diagram showing an elution curve of the preparation obtained in Example 4. FIG. 6 is a diagram showing an elution curve of the preparation obtained in Example 5. FIG. 7 is a view showing an elution curve of the preparation obtained in Comparative Example 1. FIG. 8 is a view showing an elution curve of the preparation obtained in Comparative Example 2. FIG. 9 is a diagram showing an elution curve of the preparation obtained in Example 6. 10 is a diagram showing an elution curve of the preparation obtained in Example 7. FIG. FIG. 11 is a view showing an elution curve of the preparation obtained in Example 8. FIG. 12 is a view showing an elution curve of the preparation obtained in Example 9. FIG. 13 shows the elution curve of the preparation obtained in Example 10.

The time-release preparation of the present invention adopts a two-layer structure composed of a central core and a film covering the outer surface of the central core, the central core contains a drug and a water-swellable substance, and the film is highly water-insoluble. It is characterized by containing one or more molecules.

The drug applied to the present invention is not particularly limited as long as it can be administered orally. Such drugs include, for example, chemotherapeutic agents, respiratory accelerators, antineoplastic agents, autonomic nerve agents, psychiatric agents, local anesthetics, muscle relaxants, digestive organ agents, addiction treatments, hypnotic sedatives As vasodilators, antilipidemic agents, nourishing tonics, anticoagulants, liver agents, hypoglycemic agents, antihypertensive agents, anticolitis agents, peptides, proteins, as well as bitterness drugs, Antibiotics (eg, tarampicillin hydrochloride, bacampicillin hydrochloride, cefaclor, erythromycin), antitussives (eg, noscapine hydrochloride, carbetapentane citrate, dextromethorphan hydrobromide, isoaminyl citrate, dimemorphan phosphate), antihistamines (For example, chlorpheniramine maleate, 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. Among them, low-substituted hydroxypropyl cellulose is particularly preferable, and the low-substituted hydroxypropyl cellulose has a hydroxypropoxyl group of about 7.0 to 16.0% by mass, preferably about 10 to 12.9% by mass. The average particle size is preferably 30 μm or less, particularly preferably 20 μm or less.

The water-swellable substance can be used alone or in combination of two or more, and the content thereof is preferably 15% by mass or more, more preferably 30% by mass or more, particularly 40% by mass or more in the central core. The upper limit of the content of the water-swellable substance is preferably 97% by mass, particularly 95% by mass from the viewpoint of drug content.

The central core may be blended with various additives usually used in this field, such as excipients, binders, lubricants, anti-aggregation agents, and solubilizing agents for pharmaceutical compounds. Examples of excipients include saccharides such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, calcium sulfate, etc. Examples of binders include, for example, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid. , Polyvinylpyrrolidone, glucose, sucrose, lactose, maltose, dextrin, sorbitol, mannitol, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, macrogol, gum arabic, gelatin, agar, starch and the like. 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 content of these additives can be appropriately determined according to the type of the drug.

The water-insoluble polymer constituting the film is not particularly limited as long as it is a water-insoluble polymer compound. For example, ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl terpolymer, Examples include ethyl cellulose, enteric polymer, and low pH soluble polymer. The enteric polymer refers to a polymer that does not dissolve in the stomach in an acidic environment but dissolves in the neutral to basic small intestine, such as a methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methacrylic acid. (Meth) acrylic binary copolymers such as acid methyl copolymer, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate. The low pH-soluble polymer means a polymer that dissolves in the acidic region of pH 1 to 5 but does not dissolve in the neutral to alkaline region having a higher pH than that. Specific examples include polyvinyl acetal diethylaminoacetate, methyl methacrylate / dimethylaminoethyl methacrylate copolymer, and the like.

Of these, ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl terpolymer, ethyl cellulose, methacrylic acid / methyl methacrylate copolymer, and hydroxypropyl methylcellulose acetate succinate are preferred. The mass ratio of ethyl acrylate, methyl methacrylate and ethyl trimethylammonium methacrylate constituting the terpolymer is preferably 1: 2: 0.1 to 1: 2: 0.2. 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 methacrylic acid alkyl ester constituting the binary copolymer is preferably 1: 1 to 1: 2. As a commercial item, Eudragit L (for example, L100) or S (for example, S100) (above, Degussa Japan company make) is illustrated.

Water-insoluble polymers 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 used, or (b) ternary copolymer and ethyl cellulose, It is preferable to use a combination of a binary copolymer or hydroxypropyl methylcellulose acetate succinate. In the above (a), when Eudragit RS and Eudragit RL are used in combination, the ratio of each compounding component (RS: RL) is preferably 9.8: 0.20 to 5: 5, more preferably 9.8: 0. 20 to 7.0: 3.0, particularly 9.75: 0.25 to 8.5: 1.5 is preferable. In (b) above, when a ternary copolymer and a polymer other than this are used in combination, the proportion of each blending component (ternary copolymer: other polymer) is 2: 8 by mass ratio. Is preferably 9: 1, more preferably 3: 7 to 8.5: 1.5, and particularly preferably 7: 3 to 8.5: 1.5.

The content (solid content) of the water-insoluble polymer in the film is preferably 80% by mass or more, more preferably 90% by mass or more, and particularly preferably 95% by mass or more, and the film may be composed of only the water-insoluble polymer.

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, if necessary, additives are added to the drug and water-swellable substance, and after mixing with a mixer such as a vertical granulator (manufactured by POWREC Co., Ltd.), purified water or hydrous alcohol is added. Knead to obtain a swollen state.
Examples of the alcohol in the hydrous alcohol include pharmaceuticals such as ethyl alcohol, methyl alcohol, and isopropyl alcohol, or those that can be used in the production thereof. The alcohol concentration is preferably 50% by mass or less, particularly preferably 30% by mass or less, and the lower limit thereof is preferably 5% by mass, particularly 10% by mass. Water or hydrous alcohol is used as a kneading solvent for wet granulation to make the water-swellable substance swell. The amount used is preferably 2 to 5 times, more preferably 2 to 3 times the weight of the water-swellable substance. Additives that can be used normally in pharmaceuticals such as sweeteners, sugars such as refined sucrose, sugar alcohols such as D-mannitol, polymers dissolved or dispersed in water, etc., in the kneading solvent of water or hydrous alcohol May be added.

In the present invention, the central core is preferably produced by wet granulation, but the method applied to wet granulation is not particularly limited as long as it is stirred granulation, fluidized bed granulation and extrusion granulation. 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. After extruding and granulating, and then spheronizing with a Malmerizer (manufactured by Fuji Powder Co., Ltd.), it is dried with a box-type 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 one or more water-insoluble polymers. At this time, you may mix | blend the said various additives 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 It is possible to obtain a time-release preparation capable of releasing 80% by mass or more of the drug contained in the preparation within 12 minutes, 15 minutes or 20 minutes after the lag time. Furthermore, it can be set as the masking type | 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 fluidized bed coating method, pan coating method, rolling fluidized bed coating method, etc. can be adopted. It can be carried out by spray coating the core material at a suitable speed from the spray gun nozzle while flowing by air pressure in the apparatus.

The concentration of the coating base in the coating solution is not particularly limited, but is preferably 5 to 30% by mass in consideration of the film forming ability and workability. The thus obtained preparation of the present invention may be administered as it is in the above-mentioned dosage form, filled in capsules or the like, and further may be a tablet. If necessary, a sugar coating layer or the like may be further coated.

The coating amount of the film is preferably 20% by mass or more, more preferably 30% by mass or more, and particularly preferably 50% by mass or more with respect to the total mass of the central core from the viewpoint of lag time and drug release after the lag time. The upper limit of the coating amount is preferably 300% by mass, particularly preferably 250% by mass.

Thus, in the present invention, when producing a central core containing a drug and a water-swellable substance, a method of extruding and granulating in a swollen state and forming spherical granules with a malmerizer is preferably employed. By shrinking the water-swellable substance, a central core of spherical particles smaller than the extrusion screen diameter can be obtained. 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 rolling granulator such as a CF granulator (manufactured by Freund Sangyo Co., Ltd.). In addition, compared to the powder coating method of drug and water-swellable substance while spraying an aqueous solution of the binder, a spherical central core containing the drug and water-swellable substance is produced without requiring advanced pharmaceutical technology. be able to. 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 core, it becomes possible to easily produce a time-release preparation of powders and fine granules, which has been difficult to produce in the past, and a time-release preparation particularly good in taking feeling can be obtained. It is also possible to use an orally disintegrating tablet with a highly bitter drug.

The main drug release mechanism of the preparation according to the present invention is as follows. The preparation of the present invention administered orally absorbs water in the digestive tract through the film, and the water-swellable substance in the central core gradually swells. Then, after a certain time, the film increases in volume due to the swelling of the water-swellable substance in the central core, and the film is destroyed by the swelling force. As a result, the entire amount of drug is instantaneously released. This time becomes the lag time. This lag time can be freely adjusted by changing the composition ratio of the film containing one or more water-insoluble polymers, the coating amount, and the blending ratio of the water-swellable substance in the central core. In particular, a porous film with high water permeability can be formed by adjusting the ethanol concentration in the aqueous alcohol solution used during film formation to 20 to 60% by mass. As a result, the lag time and the release property after the lag time can be accelerated, and the lag time (time when the drug is not released) is within 5 minutes, 10 minutes, or 15 minutes, and 12 minutes after the lag time. , A time-release preparation capable of releasing 80% by mass or more of the drug in the preparation within 15 minutes or 20 minutes can be produced.

Next, although an Example and a comparative example are given and this invention is demonstrated concretely, this invention is not limited to these at all. Hereinafter, “%” indicates “% by mass”, and the units of lag time and T _{80% in} the table are “hour (hour)” in Examples 1 to 7 and Comparative Examples 1 and 2, and Examples 8 to 10 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, 3500 g, 4500 g, and 5000 g of the coating liquid shown in Table 1 are sprayed onto 500 g of the spherical granules using a fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and the coating liquid (solid content) is sprayed on the granules. 75%, 90% and 100% coated formulations were prepared.

Example 2
300 g of theophylline (manufactured by Shiratori Pharmaceutical Co., Ltd.) and 700 g of low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) are mixed with a vertical granulator FM-VG-25 (manufactured by Paulec Co., Ltd.). Then, 2100 g of 10% ethanol aqueous solution was added and kneaded. 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 30% were produced.
Next, 3750 g of the coating liquids (1) to (4) shown in Table 2 is sprayed on 500 g of the spherical granules (20 to 30 mesh) in the same manner as in Example 1 to coat the coating liquid (solid content) with 75%. The prepared formulation was manufactured.

Example 3
500 g of theophylline (manufactured by Shiratori Pharmaceutical Co., Ltd.) and 500 g of low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) are mixed with a vertical granulator FM-VG-25 (manufactured by Paulec Co., Ltd.). Thereafter, 1500 g of 10% ethanol aqueous solution was added and kneaded. This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.6 mm screen, and spherical granules were formed with a Malmerizer Q400 (Fuji Paudal Co., Ltd.). did. Thereafter, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with a sieve of 20 (840 μm) and 30 (500 μm) mesh, and 20-30 mesh (840-500 μm) of theophylline. Spherical granules containing 50% were produced.
Next, 1750 g, 2000 g, 2250 g, 2500 g, 2750 g, and 3000 g of the coating liquid shown in Table 3 were sprayed on 500 g of the spherical granules (20 to 30 mesh) in the same manner as in Example 1 to obtain 35 coating liquid (solid content). %, 40%, 45%, 50%, 55%, 60% coated formulations were prepared.

Test example 1
The preparations produced in Examples 1 to 3 were subjected to a dissolution test according to the following test method.
Dissolution test method: JP 15 Dissolution test method (2) Second method (paddle method)
Test solution: A formulation having a theophylline content of 60 mg was placed in 900 mL of water and stirred at a rotational speed of 100 rpm / min. The elution amount of theophylline at this time was measured by the UV method (wavelength: 267 nm). And the elution amount with respect to the theophylline quantity mix | blended with the formulation was evaluated in percentage. The elution curves are shown in FIG. 2 (Example 1), FIG. 3 (Example 2), and FIG. 4 (Example 3).

An elution curve as shown in FIG. 1 was prepared for each preparation, and each measured value when the elution amount was 20 to 80% was subjected to correlation analysis. That is, the correlation coefficient and the slope of the straight line are obtained, the point where the straight line is in contact with the horizontal axis (time axis) is defined as the lag time (the time during which the drug is not released), and the time until the elution amount reaches 80% is defined as T _80% . T _80% -Lag time was calculated as the release of the controlled release start time formulation, respectively. The analysis results of each preparation are shown in Table 4 (Example 1), Table 5 (Example 2), and Table 6 (Example 3).

From Example 1 (Table 4 and FIG. 2), by changing the coating amount of the water-insoluble polymer (Eudragit RSPO), it is possible to freely adjust the lag time and the drug release after the lag time. Was confirmed.
From Example 2 (Table 5 and FIG. 3), Eudragit RLPO having high water permeability is added to the water-insoluble polymer (Eudragit RSPO) to freely adjust the lag time and the drug release after the lag time. It was confirmed that it was possible.
From Example 3 (Table 6 and FIG. 4), it was confirmed that the lag time and the drug release after the lag time can be freely adjusted by changing the coating amount of the film. It was also confirmed that it was effective to use etosel instead of Eudragit RLPO.

Example 4
500 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 500 g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) are used with a vertical granulator FM-VG-25 (manufactured by Paulec Co., Ltd.). After mixing, 1500 g of a 10% ethanol aqueous solution was added and kneaded. This kneaded product was extruded and granulated with a twin dome gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.6 mm screen, and with a melmerizer Q400 (Fuji Paudal Co., Ltd.) did. Thereafter, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with a sieve of 20 (840 μm) and 30 (500 μm) mesh, and 20-30 mesh (840-500 μm) of diphenhydramine hydrochloride. A spherical granule containing 50% was produced.
Next, 500 g of this granule (20 to 30 mesh) was sprayed with 3750 g of the coating liquids (1) to (5) shown in Table 7 in the same manner as in Example 1 and 75% of the coating liquid (solid content) was coated. Manufactured.

Example 5
500 g of 50% diphenhydramine-containing granules (20 to 30 mesh) produced in Example 4 were sprayed in the same manner as in Example 1 with 3750 g of the coating liquids (1) to (4) shown in Table 8 to form a coating liquid ( A formulation coated with 75% solids) was produced.

Comparative Example 1
Nonparel 103 (30-42 mesh, manufactured by Freund Sangyo Co., Ltd.) 5000 g was placed in a centrifugal fluid granulator (CF-3601) and rolled, and 20 g of hydroxypropylcellulose (HPC-L manufactured by Nippon Tanka Co., Ltd.) was added. While spraying a solution dissolved in 500 g of a water-ethanol (1: 1) mixture, a mixture of 1250 g of diphenhydramine hydrochloride and 730 g of lactose was gradually added to cover the periphery of the non-parrel, and 20-30 mesh diphenhydramine hydrochloride 50% Containing spherical granules were produced.
Next, 500 g of this spherical granule is sprayed with 1500 g, 2000 g, 2500 g, 3000 g, and 3500 g of the coating solution (4) shown in Table 7 using a fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.). On the other hand, preparations with 30%, 40%, 50%, 60% and 70% coating solution (solid content) were prepared.

Comparative Example 2
Similar to Comparative Example 1, spherical granules containing 50% of 20-30 mesh diphenhydramine hydrochloride were produced.
Next, 500 g of this spherical granule was sprayed with 1500 μg, 2000 g, 2500 g, 3000 g and 3500 g of the coating solution of (3) shown in Table 8 using a fluidized bed coating apparatus MP-01 (manufactured by Pauleck Co., Ltd.). On the other hand, preparations with 30%, 40%, 50%, 60% and 70% coating solution (solid content) were prepared.

Test example 2
Dissolution tests were performed on the preparations produced in Examples 4 to 5 and Comparative Examples 1 and 2 in the same manner as in Test Example 1.
The elution curves are shown in FIGS. Tables 9 to 10 show the lag time and T _80% calculated from the elution curve.

From Example 4 and Example 5, by adding an enteric water-insoluble polymer (Eudragit L100, S100) to the water-insoluble polymer (Eudragit RSPO), the release of the lag time and the drug after the lag time can be freely set. It was confirmed that it was possible to adjust.
On the other hand, it was confirmed from Comparative Examples 1 and 2 that even when the same water-insoluble polymer was coated on normal granules, no lag time was generated and a time-release preparation could not be obtained.

Example 6
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, 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 0.6 mm screen, and with a melmerizer Q400 (Fuji Paudal Co., Ltd.) did. Thereafter, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with a sieve of 20 (840 μm) and 30 (500 μm) mesh, and 20-30 mesh (840-500 μm) of diphenhydramine hydrochloride. A spherical granule containing 70% was produced.
Next, 500 g of this granule (20 to 30 mesh) was sprayed with 3750 g of the coating liquid (1) to (4) shown in Table 11 in the same manner as in Example 1 and 75% of the coating liquid (solid content) was coated. Manufactured.

Example 7
The coating solution (3750 g) of (1) to (3) shown in Table 12 was sprayed in the same manner as in Example 1 to 500 g of 70% diphenhydramine-containing granules (20 to 30 mesh) produced in Example 6, and the coating solution ( A formulation coated with 75% solids) was produced.

Test example 3
Dissolution tests were performed on the preparations produced in Examples 6 to 7 in the same manner as in Test Example 1.
9 to 10 show elution curves. Tables 13 to 14 show the lag time and T _80% calculated from the elution curve.

From Table 13 and FIG. 9 (Example 6), it was confirmed that it is possible to freely adjust the lag time and the drug release property after the lag time by changing the ethanol content in the coating solution.
From Table 14 and FIG. 10 (Example 7), it is possible to freely adjust the lag time and the drug release property after the lag time by blending the water-insoluble polymer (Eudragit RSPO) with the enteric water-insoluble polymer (Acoat). It was confirmed that it was possible to do.

Example 8
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 is sprayed with a fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with the coating liquid shown in Table 15, 1000 g, 1500 g, 2000 g, 2500 g, 30000 g, 3500 g, and 4000 g. On the other hand, preparations with coating solutions (solid content) of 20%, 30%, 40%, 50%, 60%, 70%, 80% were produced.

Example 9
The coating liquid 1000 g, 1250 g, 1500 g, 1750 g, 2000 g, and 2250 g shown in Table 16 were sprayed on 500 g of 10% ibuprofen-containing granules (30 to 40 mesh) produced in Example 8 in the same manner as in Example 8. Preparations with 20%, 25%, 30%, 35%, 40%, 45% coating (solid content) were produced.

Example 10
The coating liquid 1000 g, 1250 g, 1500 g, 1750 g, 2000 g and 2250 g shown in Table 17 were sprayed on 500 g of 10% ibuprofen-containing granules (30 to 40 mesh) produced in Example 8 in the same manner as in Example 8. Formulations coated with 20%, 25%, and 30% (solid content) were produced.

Test example 4
Dissolution tests were conducted on the preparations produced in Examples 8 to 10 in the same manner as in Test Example 1.
The elution curves are shown in FIGS. Tables 18 to 20 show the lag time and T _80% calculated from the elution curve.

In Example 8 in which Eudragit RSPO was coated with a 30% aqueous ethanol solution, the lag time was within 5 minutes, 10 minutes, and 15 minutes, and within 12 minutes, 15 minutes, and 20 minutes after the lag time, respectively, A timed release formulation was obtained that released over 80%. On the other hand, in Example 10 using 80% ethanol aqueous solution, although lag time was generated, the release of ibuprofen in the preparation tended to be delayed as the coating amount increased. Therefore, it was confirmed that if the ethanol concentration in the ethanol aqueous solution is less than 80%, a masking type time-release preparation suitable for drug masking can be obtained. This is presumably because a coating layer with high water permeability was formed when the ethanol concentration decreased.

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 one or more water-insoluble polymers.
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.
The time-release preparation according to any one of claims 1 to 3, wherein the content of the water-swellable substance in the central core is 15% by mass or more.
The time-release preparation according to any one of claims 1 to 4, wherein the coating amount of the film is 20% by mass or more based on the total mass of the central core.
The time-release preparation according to any one of claims 1 to 5, wherein the central core is produced by wet granulation using water or hydrous alcohol.
The time-release preparation according to any one of claims 1 to 6, wherein the film is coated with an aqueous alcohol solution of 20 to 60% by mass.
The lag time is within 5 minutes, 10 minutes, or 15 minutes, and the drug contained in the preparation is eluted at 80% by mass or more within 12 minutes, 15 minutes, or 20 minutes after the lag time, respectively. The timed release formulation as described.
The time-release preparation according to claim 8, which is a masking type.