JP2009191036A - Timed release formulation - Google Patents

Abstract

To provide 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 the drug release.
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.
[Selection figure] None

Description

  The present invention relates to a timed release formulation in which the time at which a drug starts to be released from the formulation and the drug release rate after the start of drug release can be freely adjusted.

  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.

  As such a time-release preparation, for example, a swellable substance and a drug are attached to the periphery of a core particle, and the film is destroyed by the swelling of the water-swellable substance in a preparation coated with a mixed film of ethylcellulose and talc. (Patent Documents 1 and 2), and water-repellent salts such as metal salts of fatty acids such as magnesium stearate and calcium stearate and acrylic acid-based polymers were used as coatings for preparations that obtain a lag time until the start of release. (Patent Document 3), and Eudragit RS (Degussa Japan Co., Ltd.) and an organic acid (Patent Document 4) utilizing the interaction between them.

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

  However, these preparations are achieved by producing granules having a multilayer structure such as a drug layer, a swelling agent layer, a release control layer, etc., on a lactose-like spherical 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 is simple in production and does not require advanced preparation techniques.

  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 formulation that is simple in production and does not require advanced formulation technology, the present inventors have found that water-insoluble in the central core containing a drug and a water-swellable substance. The inventors have found that the above object can be achieved only by coating a single layer of a film containing a polymer and a water-insoluble excipient, thereby completing the present invention.

  That is, the present invention provides a timed release preparation characterized in that a central core containing a drug and a swelling agent 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 5 minutes, 10 minutes, and 15 minutes of lag time, 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 that can release more than 80% of the drug contained in the drug, and also does not release the drug in the acidic and neutral regions, but 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.

  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 can be administered orally. Such drugs include chemotherapeutic agents, respiratory stimulants, anti-neoplastic agents, autonomic nerve agents, neuropsychiatric agents, local anesthetics, muscle relaxants, gastrointestinal agents, addiction treatments, hypnotic sedatives, blood vessels Antibiotics as extenders, antilipidemic agents, nourishing tonics, anticoagulants, liver drugs, hypoglycemic agents, antihypertensive agents, anticolitis agents, peptides, proteins, as well as bitterness drugs (Eg, tarampicillin hydrochloride, bacampicillin hydrochloride, cefaclor, erythromycin), antitussives (eg, noscapine hydrochloride, carbetapentane citrate, dextromethorphan hydrobromide, isoaminyl citrate, dimemorphan phosphate), antihistamines (eg , Chlorpheniramine maleate, diphenhydramine hydrochloride, promethazine hydrochloride), antipyretic analgesics and anti-inflammatory agents (eg, Ibupro , 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 ( For example, cimetidine, pirenzepine hydrochloride), sympathomimetic agents (eg, dihydrocodeine phosphate, dl-methylephedrine hydrochloride), cardiovascular agents (eg, delapril hydrochloride, meclofenoxate hydrochloride, diltiazem hydrochloride), cerebral circulation improving agent (Eg vinpocetine), anxiolytics (eg chlordiazepoxide) Diazepam), vitamins (eg, fursultiamine, thiamine hydrochloride, calcium pantothenate, ascorbic acid, tranexamic acid), antimalarial agents (eg, quinine hydrochloride), antistatic agents (eg, loperamide hydrochloride), psychotropic agents ( For example, chlorpromazine) and the like can be mentioned.

  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, and particularly preferably 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 that can be commonly 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, and binders include polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, Examples include glucose, sucrose, lactose, maltose, dextrin, sorbitol, mannitol, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, macrogol, gum arabic, gelatin, agar, starch, and the like. Further, 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 solubilizing agents for pharmaceutical compounds 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 an acidic region of pH 1 to 5, but does not dissolve in a neutral to alkaline region having a higher pH than this, 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 trimethylammonium ethyl methacrylate constituting the terpolymer is preferably 1: 2: 0.1 to 1: 2: 0.2, and is commercially available. Examples include Eudragit RS (for example, RSPO, RS100, RS30D) and Eudragit RL (for example, RLPO, RL100, RL30D) (manufactured by Degussa Japan Co., Ltd.). 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 in terms of mass ratio. Eudragit L (for example, L100, L100-55, L30D-55) or S (for example, S100) (manufactured by Degussa Japan Co., Ltd.).

The water-insoluble polymer can be used alone or in combination of two or more. For example, when two or more kinds of water-insoluble polymers are used in combination, (a) two ternary compounds having different contents of trimethylammonium chloride groups. A combination of a copolymer, (b) a terpolymer and ethyl cellulose, or (C) a terpolymer and a binary copolymer is preferred. In that case, the ratio (RS: RL) of each compounding component of (a) is 1: 0.10 to 3.0, further 1: 0.15 to 2.5, particularly 1: 0.25 to 2 in mass ratio. .3 is preferred. In addition, the ratio of each compounding component (b) (ternary copolymer: ethylcellulose) in the mass ratio is 1: 0.05 to 0.2, more preferably 1: 0.08 to 0.2, and particularly 1: 0. .11 to 0.18 is preferred. Furthermore, the ratio (ternary copolymer: binary copolymer) of each compounding component of (C) is 1: 0.12-0.24 by mass ratio, further 1: 0.12-0.2, Particularly preferred is 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 also possible to make 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, or within 5 minutes, 10 minutes or 15 minutes, respectively. 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 timed-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. In addition, the upper limit of the content is preferably 90% by mass, particularly 95% 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 these, 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. For example, Victoria Lite SK-C (average particle size: 3.45 μm, manufactured by Katsuyama Industrial Co., Ltd.), Victoria Light SK-BB (average particle size: 4.6 μm, manufactured by Katsuyama Industrial Co., Ltd.) is commercially available. Can be obtained.

  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, additives such as wax, stearic acid, masking agent, colorant, fragrance, lubricant, anti-aggregation agent and the like 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, an additive is added to the drug and water-swellable substance as necessary, 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, and 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 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 in a swollen state. It is preferable to be -3 mass times. Additives that can be used normally in pharmaceuticals such as sweeteners, sugars such as refined sucrose, sugar alcohols such as D-mannitol, polymers dissolved or dispersed in water, etc., in the kneading solvent of water or hydrous alcohol May be added.

  The central core 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, the kneaded product in a swollen state is extruded by a granulator, 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 Paudal 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 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, or mixtures thereof, preferably water, Alcohols or a mixture thereof is particularly preferable ethanol or a mixture of ethanol and water. The alcohol concentration of the aqueous alcohol solution can be appropriately determined according to the purpose, but the lag time is within 5 minutes, 10 minutes or 15 minutes by setting it to less than 80% by weight, particularly 20 to 60% by weight, and Within 12 minutes, 15 minutes or 20 minutes after the lag time (preferably within 5 minutes, 10 minutes or 15 minutes, respectively), 80% by mass or more of the drug contained in the preparation can be released, and unpleasant bitterness, etc. 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 drug to exhibit.

  For coating 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. The coating material dispersion can be spray-coated onto the core material at an appropriate speed from the nozzle of a spray gun while flowing by air.

  Although the density | concentration of the coating base in a coating liquid is not specifically limited, If film formation ability, workability | operativity, etc. are considered, 5-30 mass% is preferable. 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, it is dried by suitably adopting a method of extruding and granulating in a swollen state and forming a spherical granule with a malmerizer. Sometimes the water-swellable material shrinks and a central core of spherical particles smaller than the extruded screen diameter can be obtained. Spherical nuclei obtained by this method are obtained by using non-parrel 103 (average particle size: 840 to 350 μm, Freund Sangyo Co., Ltd.) using a conventional centrifugal rolling granulator such as a CF granulator (manufactured by Freund Sangyo Co., Ltd.). Compared to the powder coating method of drug and water-swellable substance while spraying aqueous solution of binder on the core of the product (manufactured), a spherical central core containing the drug and swelling agent is produced without requiring advanced formulation technology can do. Moreover, in the method using non-parrel, it is the limit to produce a granule having an average particle diameter of about 1020 to 500 μm at the minimum, but in the method suitably used in the present invention, the water-swellable substance is brought into a swollen state. Because of extrusion granulation, the extrusion pressure during granulation is small, and granulation with 0.3 and 0.4 mm diameter screens, which is usually difficult to use with extrusion granulation, is possible. Spherical nuclei, for example microspherical particles of 500-355 μm, 355-250 μm, 250-180 μm can be produced. By using this core, it becomes possible to easily produce time-release preparations of powders and fine granules that have been difficult to produce.

  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 period of time, the film is destroyed by the swelling force of the volume increase due to the swelling of the water-swellable substance in the central core, and the entire amount of the 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 coating is composed of ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer and ethyl cellulose or 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 (preferably within 5 minutes, 10 minutes, and 15 minutes, respectively) after the lag time. A time-release preparation capable of releasing 80% or more of the drug 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, “%” indicates “mass%”, and the units of lag time and T _{80% in} the table are Examples 1 to 7, 12 to 30, 35 to 46, 74 to 90, and Reference Examples 1 to 3. It is “hour (hour)”, and Examples 8 to 11, 31 to 34, 47 to 73 and Reference Example 4 are “minutes”.

Example 1
100 g of theophylline (manufactured by Shiratori Pharmaceutical Co., Ltd.) and 900 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, 2900 g of a 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 0.8mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, 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) theophylline. Spherical granules containing 10% were produced.
Next, 500 g of this spherical granule is sprayed with the fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with the coating liquids shown in Table 1, 1500 g, 3000 g, 4000 g and 4500 g. Min), 30%, 60%, 80%, 90% coated preparations were produced.

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 When a 60 mg content preparation of theophylline is placed in 900 mL of water and stirred at 100 rpm, the dissolution amount of theophylline Was measured by the UV method (wavelength: 267 nm). And it evaluated by the percentage of the elution amount with respect to the theophylline quantity mix | blended with the formulation. The elution curve is shown in FIG.

As shown in FIG. 1, each analysis value of 20-80% of the elution amount is analyzed from the elution curve. The time T _80% when the elution amount reaches _80% was calculated, and T _80% -lag time was defined as the release property of the controlled release start time. The results are shown in Table 2.

Figure 2 and Table 2 show that the lag time tends to increase as the coating amount increases, but it has a significant effect on the release property after the lag time (straight line, release property = _T80% -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
3750 g of the coating liquids (i) to (iii) shown in Table 3 was sprayed in the same manner as in Example 1 on 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 1, and the coating liquid (solid A preparation with 75% coating was prepared.

Reference example 1
3750 g of the coating liquid of Reference Example 1 shown in Table 3 was sprayed on 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 1 in the same manner as in Example 1 to obtain 75 coating liquid (solid content). A% coated formulation 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, it is considered that the addition of 30% or more of talc promotes the destruction of the film by reducing the film strength.

Example 3
Theophylline and L-HPC (LH31) shown in Table 5 were produced in the same manner as in Example 1 to produce 20-30 mesh granules (formulations A to G) containing 10 to 70% theophylline.
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
Theophylline and lactose (200M) shown in Table 5 were produced in the same manner as in Example 1 to produce 20-30 mesh granules containing 10% theophylline.
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 lag time and the release after the lag time become slower as the drug content increases. 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
In the same manner as in Example 1, 100 g of ibuprofen and 900 g of low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) were used to produce spherical granules containing 10% of 30-42 mesh ibuprofen.
Next, 500 g of this spherical granule is 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.). ) With 75%, 85% and 95% coating.

Example 5
In the same manner as in Example 1, 100 g of acetaminophen and 900 g of low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) were used to produce spherical granules containing 10% 30-42 mesh acetaminophen. Manufactured.
Next, 500 g of this spherical granule is 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 POWREC Co., Ltd.). ) With 75%, 85% and 95% coating.

Example 6
In the same manner as in Example 1, 100 g of chlorpheniramine maleate and 900 g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) are contained in a 30-42 mesh chlorpheniramine maleate 10%. Spherical granules were produced.
Next, 500 g of this spherical granule is 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 POWREC Co., Ltd.). ) With 75%, 85% and 95% coating.

Example 7
After mixing 100 g of anhydrous caffeine and 900 g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) with a vertical granulator FM-VG-25 (manufactured by Paulek), 10% ethanol aqueous solution 2900 g was added and kneaded. Spherical granules containing 30% to 42 mesh anhydrous caffeine 10% were produced in the same manner as in Example 1.
Next, 500 g of this spherical granule is 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 POWREC Co., Ltd.). ) With 75%, 85% and 95% coating.

Reference example 3
Nonpareil 103 (42-60 mesh) 1000g was placed in a centrifugal fluid granulator (CF-360) and rolled, and 20g of hydroxypropylcellulose (HPC-L made by Nippon Tanks 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 the solution dissolved in 500 g of the mixed solution to coat the periphery of non-parrel to produce spherical granules containing 10% of 30-42 mesh anhydrous caffeine. did.
Next, 500 g of this spherical granule is 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.). ) With 75%, 85% and 95% coating.

Test example 4
The preparations produced 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 when 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 release start time control type preparation was not obtained.

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

Example 9
The coating liquid 3500 g and 5000 g shown in Table 14 were sprayed in the same manner as in Example 1 to 10% theophylline-containing granules (20 to 30 mesh) 500 g produced 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, 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% 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 are sprayed on 500 g 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 produced.

Example 11
In the same manner as in Example 1, 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% 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 produced.

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. The elution curves are shown in FIGS. 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 when carmellose calcium (Example 10) and croscarmellose sodium (Example 11) are used as water-swellable substances (FIG. 12, 13).

Example 12
100 g of theophylline (manufactured by Shiratori Pharmaceutical Co., Ltd.) and 900 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, 2900 g of a 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 0.8mm screen, and made into spherical particles with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, it is dried with a fluid bed dryer WSG-55 type (Okawara Seisakusho Co., Ltd.), sized with a 20 and 30 mesh sieve, and spherical granules containing 10-30% (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 POWREC Co., Ltd.) with 5000 g of the coating liquid shown in Table 19, and the coating liquid (solid content) was 100% of the granules. A coated formulation was produced.

Example 13
Formulation prepared by spraying 5000 g of the coating solution 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 solution (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 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.

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 and T _80% calculated from the elution curve.

  When 0.05 parts by weight of ethylcellulose (Example 15) was added to Eudragit RSPO of 1, it was confirmed that drug release was exhibited after the lag time and ram time, but the lag in the test solution of pH 6.8 The time was shorter than the lag time of the pH 1.2 and water test solutions and showed no pH independence. Based on this result, when Eudragit RSPO increased the addition amount of ethyl cellulose to 1 to 0.11 (Example 12), 0.14 (Example 13) and 0.18 parts by mass (Example 14), respectively. , PH 1.2, water and pH 6.8 test solution showed similar release properties after lag time and after lag time, confirming that it was a pH-independent preparation. 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 a 10% ethanol aqueous 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 12.
Next, 500 g of this spherical granule is sprayed with 3500 g and 5000 g of the coating liquid shown in Table 19 with 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 17
In the same manner as in Example 16, spherical granules containing 30% of 20-30 mesh (840-500 μm) theophylline were produced.
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 Paulec Co., Ltd.), and the coating liquid (solid content) is sprayed on the granules. 70% and 100% coated formulations were produced.

Example 18
In the same manner as in Example 16, spherical granules containing 30% of 20-30 mesh (840-500 μm) theophylline were produced.
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 applied to 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 16-18, theophylline 30% by mass granules were coated by changing the type of talc, but it was confirmed that the release properties after lag time showed the same tendency regardless of the type of talc. .

Example 19
Vertical granulator FM-VG-25 (Paurec Co., Ltd.) 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.) 2400 g of 10% ethanol aqueous solution was added and kneaded, and spherical granules containing 20% of 30-30 mesh (840-500 μm) anhydrous caffeine 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 32 with a fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and the coating liquid (solid content) is sprayed on the granules. 70% and 100% coated formulations were produced.

Example 20
Spherical granules containing 20% of 20-30 mesh (840-500 μm) anhydrous caffeine were produced in the same manner as in Example 19.
Next, 500 g of this spherical granule is 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 POWREC Co., Ltd.), and the coating liquid (solid content) is sprayed on the granules. 70% and 100% coated formulations were produced.

Example 21
Spherical granules containing 20% of 20-30 mesh (840-500 μm) anhydrous caffeine were produced in the same manner as in Example 19.
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 applied to the granules. 70% and 100% coated formulations were produced.

Example 22
Spherical granules containing 20% of 20-30 mesh (840-500 μm) anhydrous caffeine were produced in the same manner as in Example 19.
Next, 500 g of this spherical granule is sprayed with 3500 g and 5000 g of the coating liquid shown in Table 35 with a fluidized bed coating apparatus MP-01 (manufactured by Paulec 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. The elution curves are shown in FIGS. 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 the local ethanol of the coating solvent. When the concentration of pharmacopoeia ethanol was increased to 80%, 85%, and 90%, the release time after lag time and lag time also became longer, but at 95% it became shorter. When the coating amount was the same, it was speculated that an ethanol concentration of 85 to 90% would give the longest lag time.

Example 23
100g diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 900g low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) 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 the spherical granule is sprayed with 3500 g of the coating liquid shown in Table 19 using a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and the coating liquid (solid content) is sprayed on the granule. A 70% coated formulation was produced.

Example 24
300g diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 700g low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) with a vertical granulator FM-VG-25 (manufactured by Paulec Co., Ltd.) After mixing, 2000 g of 10% ethanol aqueous solution was added and kneaded, and spherical granules containing 30-30% (840-500 μm) of diphenhydramine hydrochloride were produced in the same manner as in Example 12.
Next, 500 g of the spherical granule is sprayed with 3500 g of the coating liquid shown in Table 19 using a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and the coating liquid (solid content) is sprayed on the granule. A 70% coated formulation was produced.

Example 25
500g diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 500g low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) with a vertical granulator FM-VG-25 (manufactured by Paulec Co., Ltd.) After mixing, 1400 g of a 10% aqueous ethanol 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 the spherical granule is sprayed with 3500 g of the coating liquid shown in Table 19 using a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and the coating liquid (solid content) is sprayed on the granule. A 70% coated formulation was produced.

Example 26
700g diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 300g low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) 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 the spherical granule is sprayed with 3500 g of the coating liquid shown in Table 19 using a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and the coating liquid (solid content) is sprayed on the granule. 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 a 10% ethanol aqueous 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 12.
Next, 500 g of this spherical granule is sprayed with the rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with the coating liquids shown in Table 19, 750 g, 1750 g, and 2750 g. Preparations with 15%, 35% and 55% coating were prepared.

Test Example 10
The preparation prepared 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 the same lag time was exhibited in the test solution of pH 1.2, water and pH 6.8 at any coating amount of 15 to 55%, and the release property after the lag time also 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 consist of 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 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, 2900 g of a 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 0.8mm screen, and made into spherical particles with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, it is dried with a fluid bed dryer WSG-55 type (Okawara Seisakusho Co., Ltd.), sized with a 20 and 30 mesh sieve, and spherical granules containing 10-30% (840-500 μm) theophylline. Manufactured.
Next, 500 g of this spherical granule is sprayed with a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with the coating liquids shown in Table 42, 3750 g and 5000 g, and the coating liquid (solid content) is sprayed on the granules. A formulation with 75% and 100% coating was produced.

Example 29
The coating liquid 3750 g and 5000 g shown in Table 43 was sprayed on 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 28 in the same manner as in Example 28, and the coating liquid (solid content) was 75%. A 100% coated formulation was produced.

Example 30
The coating liquid 3750 g and 5000 g shown in Table 44 were sprayed on 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 28 in the same manner as in Example 28, and the coating liquid (solid content) was 75%. 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
The coating liquid (solid content) is sprayed in the same manner as in Example 28 by spraying 3750 g and 5000 g of the coating liquid shown in Table 46 on 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 28. 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) and 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 0.25 parts by mass (Example 31) of Eudragit L100-55 is added to 1 part by mass of Eudragit RSPO, the lag time in the test solution of pH 6.8 is 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 timed release formulations of Examples 28-32 release the pharmaceutical compound rapidly after a certain lag time, regardless of pH changes in the gastrointestinal 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, 500 g of this spherical granule is sprayed with 750 g, 1750 g, and 2750 g of the coating liquid shown in Table 43 with a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.). 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. The elution curves are shown in FIGS. 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 pH 1.2, water and pH 6.8 test solutions, and the release properties 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 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, 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 Powdal Co., Ltd.) equipped with a 0.8 mm screen, and sized with 20 and 24 mesh sieves 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 with 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 applied to 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 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, 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 0.70 mm screen, and sized with a 24 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 with 5000 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) 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 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, 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 0.6 mm screen, and sized with a 30 and 42 mesh sieve in the same manner as in Example 28. Spherical granules containing 20% of 30-42 mesh (500-355 μm) theophylline were produced.
Next, 500 g of this spherical granule is sprayed with 5000 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) 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 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, 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 0.50 mm screen, and sized with 42 and 60 mesh sieves as in Example 28. Spherical granules containing 20% of 42-60 mesh (355-250 μm) theophylline 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 POWREC Co., Ltd.), and the coating liquid (solid content) was 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. The elution curves are shown in FIGS. 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 840-710 μm (Example 36), 710-500 μm (Example 37), 500-355 μm (Example 38), 355-250 μm (Example 39) In the preparation having the central core, the same lag time was exhibited 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 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 Paulec) 100 g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 900 g of low-substituted hydroxypropylcellulose (L-HPC LH31, Shin-Etsu Chemical 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 28.
Next, 500 g of this spherical granule is sprayed with 3500 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) is sprayed on the granules. A 70% coated formulation was produced.

Example 41
Vertical granulator FM-VG-25 (manufactured by POWREC Co., Ltd.) 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.) After mixing in 2000, 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 is sprayed with 3500 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) is sprayed on the granules. A 70% coated formulation was produced.

Example 42
Vertical granulator FM-VG-25 (manufactured by POWREC) 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.) Then, 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 28.
Next, 500 g of this spherical granule is sprayed with 3500 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) is sprayed on the granules. A 70% coated formulation was produced.

Example 43
700g diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 300g low-substituted hydroxypropylcellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) vertical granulator FM-VG-25 (manufactured by Paulec Co., Ltd.) After mixing in 2000, 2000 g of 10% ethanol aqueous solution was added and kneaded, and in the same manner as in Example 28, spherical granules containing 70% of 20-30 mesh (840-500 μm) diphenhydramine hydrochloride were produced.
Next, 500 g of this spherical granule is sprayed with 3500 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) is sprayed on the granules. A 70% 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), 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
200g of anhydrous caffeine (manufactured by Kongo Chemical Co., Ltd.) and 800g 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.) ), And 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 0.6 mm screen, and sized with a 30 and 42 mesh sieve in the same manner as in Example 28. Spherical granules containing 20% 30-42 mesh (500-355 μm) anhydrous caffeine were produced.
Next, 500 g of this spherical granule is sprayed with 5000 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) is sprayed on the granules. A 100% coated formulation was produced.

Example 45
In the same manner as in Example 44, spherical granules containing 20% of 30-42 mesh (500-355 μm) anhydrous caffeine 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 POWREC Co., Ltd.), and the coating liquid (solid content) was sprayed on the granules. A 150% coated formulation was produced.

Example 46
In the same manner as in Example 44, spherical granules containing 20% of 30-42 mesh (500-355 μm) anhydrous caffeine were produced.
Next, 10000 g of the coating liquid shown in Table 43 is sprayed on a rolling fluidized bed coating apparatus MP-01 (Paulec Co., Ltd.) with 500 g of this spherical granule, and the coating liquid (solid content) is applied to the granules. A 200% 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.

  The preparations produced in Examples 44 to 46 were administered to 9 beagle dogs (male) fasted overnight to 50 mg anhydrous caffeine. 1, 2, 3, 4, 6, 8, 10 and 24 hours after administration, and anhydrous caffeine drug substance at 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 plasma drug concentration.

  A good correlation was observed between the in vitro lag time from the dissolution test and the in vivo lag time of plasma concentrations, confirming that a timed release formulation was obtained.

Example 47
500g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 500g 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 0.8mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, 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) diphenhydramine hydrochloride. A spherical granule containing 50% was produced.
Next, 500 g of this spherical granule was added to Example 1 using a fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 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 sprayed and coated with 50%, 60%, 70%, 80%, 90%, 100%, 110% coating solution (solid content) were produced.

Example 48
In the same manner as in Example 1, the coating liquid 2000 g, 2500 g, 3000 g, 3500 g, 4000 g, 4500 g, and 5000 g shown in Table 64 were added to 500 g of 50% diphenhydramine-containing granules (30 to 40 mesh) produced in Example 47. Sprayed coating liquid (solid content) was manufactured with 40%, 50%, 60%, 70%, 80%, 90%, 100% coated preparation

Example 49
In the same manner as in Example 1, the coating solutions 2000 g, 3000 g, 3500 g, 4000 g, 4500 g, 5000 g, and 5500 g shown in Table 65 were added to 500 g of 50% diphenhydramine-containing granules (30 to 40 mesh) produced in Example 47. The preparations were sprayed and coated with 40%, 60%, 70%, 80%, 90%, 100%, 110% coating liquid (solid content).

Example 50
In the same manner as in Example 1, 500 g of 50% diphenhydramine-containing granules (30 to 40 mesh) produced in Example 47 were coated with 2500 g, 3000 g, 3500 g, 4000 g, 4500 g, 5000 g, and 5500 g of the coating liquid shown in Table 66. Sprayed coating liquid (solid content) was manufactured with 50%, 60%, 70%, 80%, 90%, 100%, 110% coated preparation

Example 51
To 500 g of 50% diphenhydramine-containing granules (30 to 40 mesh) produced in Example 47, 2500 g, 3000 g, 4000 g and 5000 g of the coating liquid shown in Table 67 were sprayed in the same manner as in Example 1 to form a coating liquid (solid Min) were prepared with 50%, 60%, 80% and 100% coated preparations.

Example 52
The coating liquid 3000 g, 4000 g, and 5000 g shown in Table 68 were sprayed in the same manner as in Example 1 to 500 g of 50% diphenhydramine-containing granules (30 to 40 mesh) produced in Example 47, and the coating agent was 60%. 80% and 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. The elution curves are shown in FIGS. 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 lag time and lag time was obtained. 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 (Example 49), 2.33 parts by mass 80 parts of diphenhydramine hydrochloride contained in the preparation within 5 minutes, 10 minutes, and 15 minutes, and within 5 minutes, 10 minutes, and 15 minutes after the lag time, respectively. It was confirmed that a preparation with a release of more than% was obtained.

Example 53
300g diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 700g low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) 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 Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.5mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, 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) diphenhydramine hydrochloride. Spherical granules containing 30% 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 are sprayed on 500 g of the spherical granules (30 to 40 mesh) in the same manner as in Example 1 to form a coating liquid ( Solid formulations were coated with 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%.

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

Example 55
500 g of 30% diphenhydramine-containing granules (30 to 40 mesh) produced in Example 53 were mixed with a rolling fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.) with coating solutions of 1000 g, 1500 g and 1750 g shown in Table 64. , 2000 g, 2250 g, and 2750 g were sprayed in the same manner as in Example 1 to prepare formulations 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. 57 to 59 show elution curves. Tables 77 to 79 show the lag time calculated from the elution curve and T _80% .

  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 Examples 55 (talc SK-C, average particle size: 3.45 μm, manufactured by Katsuyama Kogyo Co., Ltd.), a time-released preparation was obtained, and it was confirmed that the lag time tends to increase as the particle size of talc increases. It was.

Example 56
700g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 300g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) 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 Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.3mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with a sieve of 60 (250 μm) and 80 (180 μm) mesh, and 60-80 mesh (250-180 μm) diphenhydramine hydrochloride. A spherical granule containing 70% was 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
700g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 300g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) 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 Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.4mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, 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 to 60 mesh (355 to 250 μm) of diphenhydramine hydrochloride. A spherical granule containing 70% was produced.
Next, 500 g of this spherical granule was sprayed with 2500 g and 3250 g of the coating liquid shown in Table 80 in the same manner as in Example 1 using a tumbling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.). A preparation coated with 50% and 65% (solid content) was produced.

Example 58
700g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 300g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) 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 Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.5mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with 30 (500 μm) and 42 (355 μm) mesh sieves, and 30 to 42 mesh (500 to 355 μm) diphenhydramine hydrochloride. A spherical granule containing 70% was 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 liquid 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.) at 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 Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.7mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, it is dried with a fluid bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with a sieve of 24 (710 μm) and 30 (500 μm) mesh, and 24-30 mesh (710-500 μm) diphenhydramine hydrochloride. Spherical granules containing 85% 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 20%, 25% and 30% coating solution (solid content) 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.) at 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 0.8mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with a sieve of 20 (840 μm) and 24 (710 μm) mesh, and 20-24 mesh (840-710 μm) diphenhydramine hydrochloride. Spherical granules containing 85% 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 POWREC Co., Ltd.). The preparations were sprayed and coated with 10%, 15%, 20%, 25% coating liquid (solid content).

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 size containing 70% of 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), 30 to 40 mesh (500 to 355 μm) central core (Example 58), 85% diphenhydramine hydrochloride particle diameter of 24 to 30 mesh (710 to 500 μm) central core (Example 59), 20-24 mesh (840-710μm) central core (Example 60), all within 5 minutes, 10 minutes, 15 minutes, and within 5 minutes, 10 minutes, 15 minutes after the lag time, respectively It was confirmed that a preparation capable of releasing 80% or more of diphenhydramine hydrochloride contained in the preparation was obtained.

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 form a coating liquid (solid content) 30%, 40%, 55% coated preparations were manufactured

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

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. The elution curves are shown in FIGS. Tables 88 to 89 show the lag time and T _80% calculated from the elution curve.

  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, 10 minutes, respectively. It was confirmed that within 80 minutes, 80% or more of diphenhydramine hydrochloride contained in the preparation was released.

Example 63
After mixing 100 g of ibuprofen (BASF) and 900 g of low-substituted hydroxypropylcellulose (L-HPC LH31, Shin-Etsu Chemical Co., Ltd.) with a vertical granulator FM-VG-25 (Paulec Co., Ltd.), 10 A 2% 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 0.6mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, 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 to 40 mesh (500 to 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 by using a fluidized bed coating apparatus MP-01 (manufactured by Paulec 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 750 g, 1000 g, 1250 g, 1500 g, 1750 g, and 2000 g shown in Table 91 was sprayed and coated in the same manner as in Example 1 on 500 g of 10% ibuprofen-containing granules (30 to 40 mesh) produced in Example 63. Formulations with 15%, 20%, 25%, 30%, 35%, 40% coating of the liquid (solid content) were produced.

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

Reference example 4
To 500 g of 10% ibuprofen-containing granules (30-40 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 spray the coating liquid (solid content). 35%, 40% and 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.

  In Example 65, in which an equivalent coating composition of Eudragit RSPO and talc was dispersed in an 80% aqueous ethanol solution, a lag time and a timed release formulation capable of releasing the drug after the lag time were obtained, but the release of ibuprofen in the formulation was Tended to be delayed. On the other hand, in Examples 63 and 64 in which the equivalent coating composition of Eudragit RSPO and talc was dispersed in a 30% or 50% ethanol aqueous solution, the lag time was within 5 minutes, 10 minutes, 15 minutes, and after the lag time. It was confirmed that 80% or more of ibuprofen in the preparation was released within 12 minutes, 15 minutes and 20 minutes, respectively, and a timed release preparation suitable for drug masking was obtained. 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
700g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 300g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) 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 Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.3mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with a sieve of 60 (250 μm) and 80 (180 μm) mesh, and 60-80 mesh (250-180 μm) diphenhydramine hydrochloride. A spherical granule containing 70% 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 3000 g, 3500 g, 4000 g, 4500 g, and 5000 g of the coating liquid shown in Table 98 were used in the same manner as in Example 1. In this way, preparations were prepared by spraying and coating the coating liquid (solid content) 60%, 70%, 80%, 90%, 100%.

Example 67
700g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 300g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) 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 Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.4mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, 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 to 60 mesh (355 to 250 μm) of diphenhydramine hydrochloride. A spherical granule containing 70% was 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
700g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 300g of low-substituted hydroxypropyl cellulose (L-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) 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 Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.5mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with 30 (500 μm) and 42 (355 μm) mesh sieves, and 30 to 42 mesh (500 to 355 μm) diphenhydramine hydrochloride. A spherical granule containing 70% was produced.
Next, 500 g of this spherical granule was tumbled using a fluidized bed coating apparatus MP-01 (manufactured by Paulec Co., Ltd.), and 1500 g, 1750 g, 2000 g, 2250 g, 2500 g, 2750 g of the coating solution 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) with 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.) at 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 Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.7mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, it is dried with a fluid bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with a sieve of 24 (710 μm) and 30 (500 μm) mesh, and 24-30 mesh (710-500 μm) diphenhydramine hydrochloride. Spherical granules containing 85% 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 98. Preparations with 20%, 25% and 30% coating solution (solid content) 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. The elution curves are shown in FIGS. Tables 99 to 102 show the lag time and T _80% calculated from the elution curve.

  70% diphenhydramine hydrochloride and a particle size of 250-180 μm (Example 66), 355-250 μm (Example 67), 500-350 μm (Example 68) and 85% diphenhydramine hydrochloride and a particle size of 710 When nuclei of ~ 500 μm (Example 69) are coated on nuclei using Eudragit RSPO and 30% aqueous solution of ethanol (Table 98) of talc SK-BB (1: 1), lag time is obtained at any particle size. It was confirmed that a time-release preparation that releases 80% or more of diphenhydramine hydrochloride in the preparation within 5 minutes, 10 minutes, and 15 minutes and within 12 minutes, 15 minutes, and 20 minutes after the lag time, respectively, was obtained. 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 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, 2700 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 0.6mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . After that, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with 30 (500 μm) and 42 (355 μm) mesh sieves, 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 POWREC Co., Ltd.), and 2250 g, 2500 g, 2750 g, 3000 g and 3250 g of the coating liquid shown in Table 98 were used in the same manner as in Example 1. 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 Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) equipped with a 0.6mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . After that, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with 30 (500 μm) and 42 (355 μm) mesh sieves, and 30 to 42 mesh (500 to 355 μm) theophylline. Spherical granules containing 30% were produced.
Next, 500 g of this spherical granule was tumbled using a fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.), and 1000, 1250, 1500, and 1750 g of the coating liquid shown in Table 98 were used in the same manner 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.). Then, 1500 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 0.6mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . After that, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with 30 (500 μm) and 42 (355 μm) mesh sieves, and 30 to 42 mesh (500 to 355 μm) theophylline. Spherical granules containing 50% 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 750 g, 1000 g, 1250 g and 1500 g of the coating liquid shown in Table 98 were used in the same manner as in Example 1. The preparations were sprayed and coated 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% ethanol aqueous solution (Table 98) of Eudragit RSPO and talc SK-BB equivalent mixture 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 coating solution used, 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 formulation. It was confirmed that a release formulation was obtained.

Example 73
500g of diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) and 500g 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 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 0.5mm screen, and made into spherical granules with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, it is dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), sized with 30 (500 μm) and 42 (355 μm) mesh sieves, and 30 to 42 mesh (500 to 355 μm) diphenhydramine hydrochloride. 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 1000 g, 1250 g, 1500 g, and 1750 g of the coating liquid shown in Table 106 were used in the same manner as in Example 1. The preparations were sprayed and coated with 20%, 25%, 30%, 35% coating solution (solid content).

Test Example 23
The preparation produced 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, the lag time is 5 minutes, 10 minutes, and 15 minutes 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. 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 can be obtained.

Example 74
100 g of theophylline (manufactured by Shiratori Pharmaceutical Co., Ltd.) and 900 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, 2900 g of a 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 0.8mm screen, and made into spherical particles with Malmerizer Q400 (Fuji Paudal Co., Ltd.). . Then, it is dried with a fluid bed dryer WSG-55 type (Okawara Seisakusho Co., Ltd.), sized with a 20 and 30 mesh sieve, and spherical granules containing 10-30% (840-500 μm) theophylline. Manufactured.
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 coating liquid (solid content) is sprayed on 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 onto 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 and T _80% calculated from the elution curve.

  In Example 77 in which the blending ratio of Eudragit RSPO and Eudragit L100-5 was 8 to 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, water does not release the drug, and the pH is 6.8. Thus, it was confirmed that a timed release formulation that releases 80% of the drug in 1 to 1.5 hours after a lag time of 4 to 6 hours was obtained.

Example 78
The coating liquid (3750 g, 5000 g) shown in Table 116 was sprayed onto 500 g of 10% theophylline-containing granules (20 to 30 mesh) produced in Example 74 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 prepared 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 prepared 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
The coating liquid 3750 g and 5000 g shown in Table 119 were sprayed in the same manner as in Example 1 to 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 74, and 75% of the coating liquid (solid content) was sprayed. A 100% coated formulation was produced.

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

Test Example 25
The preparations produced in Examples 78 to 82 were subjected to a dissolution test (test solution: pH 1.2, purified water, pH 6.8, UV wavelength: 267 nm) in the same manner as in Test Example 1. 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, it was confirmed that the lag time in the test solution pH 6.8 can be freely adjusted to 0.3 to 6.6 hours by changing the mixing ratio of Eudragit L100-55 to Eudragit RSPO. It was.

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% aqueous ethanol solution was added and kneaded to produce spherical granules containing 85% of 20-30 mesh (840-500 μm) theophylline in the same manner as in Example 1.
Next, 500 g of this spherical granule is 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 prepared with 70% and 100% coating.

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 is 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 prepared with 70% and 100% coating.

Example 85
300 g of theophylline (manufactured by Shiratori Pharmaceutical Co., Ltd.) and 700 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, 2100 g of a 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 1.
Next, 500 g of this spherical granule was sprayed on a rolling fluidized bed coating apparatus MP-01 (manufactured by POWREC Co., Ltd.) with 3500 g and 5000 g of the coating liquid shown in Table 109, and the coating liquid (solid content) ) Was prepared by coating with 70% and 100%.

Example 86
Vertical granulator FM-VG-25 (Paurec Co., Ltd.) 100 g of anhydrous caffeine (Ningya Chemical Co., Ltd.) and 900 g of low-substituted hydroxypropylcellulose (L-HPC LH31, Shin-Etsu Chemical Co., Ltd.) After mixing, 2800 g of 10% ethanol aqueous solution was added and kneaded to produce spherical granules containing 10% 20-30 mesh (840-500 μm) anhydrous caffeine in the same manner as in Example 1.
Next, 500 g of this spherical granule is 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 prepared by coating with 70, 100%.

Example 87
Vertical granulator FM-VG-25 (Paurec Co., Ltd.) 100 g of anhydrous caffeine (Ningya Chemical Co., Ltd.) and 900 g of low-substituted hydroxypropylcellulose (L-HPC LH31, Shin-Etsu Chemical Co., Ltd.) After mixing, 2800 g of 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 spherical with a Malmerizer Q400 (Fuji Paudal Co., Ltd.). Particles were used. Then, it is dried with a fluidized bed dryer WSG-55 (Okawara Seisakusho Co., Ltd.), sized with a 30 and 42 mesh sieve, and contains 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 70% of the coating liquid (solid content) is applied to the granule. A coated formulation was produced.

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

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

Test Example 26
Elution tests (test solution: pH 1.2, purified water, pH 6.8, UV wavelength: wavelength theophylline: 267 nm, anhydrous caffeine: 271 nm) were carried out for the preparations produced in Examples 83 to 89 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.

In Examples 83-85, the results when the drug content was changed to 85-30% were shown. At any drug content, the test solution pH 1.2, water did not release the drug, and at pH 6.8, a timed release formulation was obtained that released 80% of the drug in 1 to 1.5 hours after a certain lag time. .
Examples 86 to 87 show the results when anhydrous caffeine was used as a drug. Example 87 shows a case where the particle size of the central core is 30 to 42 mesh (500 to 355 μm). Even in the case of anhydrous caffeine, the test solution pH 1.2, water does not release the drug, and pH 6.8 provides a timed release formulation that releases 80% of the drug in 1 to 1.5 hours after a certain lag time. It was.
In Examples 88 to 89, when Eudragit S100 and Eudragit L100 were used in place of the methacrylic acid / ethyl acrylate copolymer for the ethyl acrylate / methyl methacrylate / trimethylammonium methacrylate copolymer showed that. Unlike Eudragit L100-55, a time-release formulation that releases 80% of the drug in 1 to 1.5 hours after a certain lag time is obtained with any of the test liquids at pH 1.2, water, and pH 6.8. It was.

Example 90
The coating liquid shown in Table 136, 500 g, 1000 g, 1500 g, 2000 g, 2500, 3000, 3500 g, was sprayed onto 500 g of 10% theophylline-containing granules (20-30 mesh) produced in Example 74, and the coating liquid was applied to the granules. Formulations coated with 10%, 20%, 30%, 40%, 50%, 60% and 70% (solid content) were produced.

Test Example 27
The preparation prepared 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 could be freely adjusted to 0.3 to 3.3 hours by changing the coating amount.

To explain 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 timed release formulation) from dissolution curve FIG. 1 is a diagram showing an elution curve of a preparation obtained in Example 1. FIG. It is a figure which shows the elution curve of the formulation obtained in Example 2 and Reference Example 1. It is a figure which shows the elution curve of the formulation obtained in Example 3 and Reference Example 2. FIG. 4 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. 6 is a diagram showing an elution curve of the preparation obtained in Example 6. FIG. 6 shows an elution curve of the preparation obtained in Example 7. It is a figure which shows the elution curve of the formulation obtained in Reference Example 3. 10 is a diagram showing an elution curve of the preparation obtained in Example 8. FIG. FIG. 10 is a diagram showing an elution curve of the preparation obtained in Example 9. FIG. 3 is a diagram showing an elution curve of the preparation obtained in Example 10. 2 is a diagram showing an elution curve of the preparation obtained in Example 11. FIG. FIG. 4 shows an elution curve of the preparation obtained in Example 12. It is a figure which shows the elution curve of the formulation obtained in Example 13. It is a figure which shows the elution curve of the formulation obtained in Example 14. It is a figure which shows the elution curve of the formulation obtained in Example 15. FIG. 10 shows an elution curve of the preparation obtained in Example 16. FIG. 4 shows an elution curve of the preparation obtained in Example 17. FIG. 10 shows an elution curve of the preparation obtained in Example 18. FIG. 10 shows an elution curve of the preparation obtained in Example 19. 2 is a diagram showing an elution curve of the preparation obtained in Example 20. FIG. 2 is a diagram showing an elution curve of the preparation obtained in Example 21. FIG. 2 is a diagram showing an elution curve of the preparation obtained in Example 22. FIG. It is a figure which shows the elution curve of the formulation obtained in Examples 23-26. FIG. 10 shows an elution curve of the preparation obtained in Example 27. It is a figure which shows the elution curve of the formulation obtained in Example 28. It is a figure which shows the elution curve of the formulation obtained in Example 28. FIG. 4 shows an elution curve of the preparation obtained in Example 29. FIG. 4 shows an elution curve of the preparation obtained in Example 29. FIG. 3 is a diagram showing an elution curve of the preparation obtained in Example 30. FIG. 3 is a diagram showing an elution curve of the preparation obtained in Example 30. FIG. 4 shows an elution curve of the preparation obtained in Example 31. FIG. 4 shows an elution curve of the preparation obtained in Example 32. 4 is a diagram showing an elution curve of a preparation obtained in Example 33. FIG. FIG. 10 shows an elution curve of the preparation obtained in Example 34. FIG. 10 shows an elution curve of the preparation obtained in Example 35. FIG. 10 shows an elution curve of the preparation obtained in Example 35. FIG. 10 shows an elution curve of the preparation obtained in Example 35. FIG. 10 shows an elution curve of the preparation obtained in Example 36. FIG. 10 shows an elution curve of the preparation obtained in Example 37. FIG. 10 shows an elution curve of the preparation obtained in Example 38. FIG. 10 shows an elution curve of the preparation obtained in Example 39. It is a figure which shows the elution curve of the formulation obtained in Examples 40-43. FIG. 10 shows an elution curve of the preparation obtained in Example 44. FIG. 4 shows an elution curve of the preparation obtained in Example 45. FIG. 4 shows an elution curve of the preparation obtained in Example 46. FIG. 6 is a graph showing changes in plasma concentration of the preparation obtained in Example 44. It is a figure which shows the plasma concentration transition of the formulation obtained in Example 45. It is a figure which shows plasma concentration transition of the formulation obtained in Example 46. FIG. 10 shows an elution curve of the preparation obtained in Example 47. FIG. 10 shows an elution curve of the preparation obtained in Example 48. FIG. 10 shows an elution curve of the preparation obtained in Example 49. FIG. 10 shows an elution curve of the preparation obtained in Example 50. FIG. 4 shows an elution curve of the preparation obtained in Example 51. FIG. 10 shows an elution curve of the preparation obtained in Example 52. FIG. 10 shows an elution curve of the preparation obtained in Example 53. FIG. 10 shows an elution curve of the preparation obtained in Example 54. FIG. 10 shows an elution curve of the preparation obtained in Example 55. FIG. 10 shows an elution curve of the preparation obtained in Example 56. FIG. 10 shows an elution curve of the preparation obtained in Example 57. FIG. 10 shows an elution curve of the preparation obtained in Example 58. FIG. 10 shows an elution curve of the preparation obtained in Example 59. 2 is a diagram showing an elution curve of the preparation obtained in Example 60. FIG. 2 is a diagram showing an elution curve of a preparation obtained in Example 61. FIG. 2 is a diagram showing an elution curve of a preparation obtained in Example 62. FIG. FIG. 6 shows an elution curve of the preparation obtained in Example 63. FIG. 10 shows an elution curve of the preparation obtained in Example 64. FIG. 10 shows an elution curve of the preparation obtained in Example 65. It is a figure which shows the elution curve of the formulation obtained in Reference Example 4. FIG. 10 shows an elution curve of the preparation obtained in Example 66. FIG. 10 shows an elution curve of the preparation obtained in Example 67. FIG. 10 shows an elution curve of the preparation obtained in Example 68. FIG. 10 shows an elution curve of the preparation obtained in Example 69. 2 is a diagram showing an elution curve of a preparation obtained in Example 70. FIG. FIG. 10 shows an elution curve of the preparation obtained in Example 71. FIG. 4 shows an elution curve of the preparation obtained in Example 72. FIG. 10 shows an elution curve of the preparation obtained in Example 73. FIG. 4 shows an elution curve of the preparation obtained in Example 74. FIG. 10 shows an elution curve of the preparation obtained in Example 75. FIG. 10 shows an elution curve of the preparation obtained in Example 76. FIG. 10 shows an elution curve of the preparation obtained in Example 77. FIG. 10 shows an elution curve of the preparation obtained in Example 78. FIG. 10 shows an elution curve of the preparation obtained in Example 79. 2 is a diagram showing an elution curve of a preparation obtained in Example 80. FIG. FIG. 10 shows an elution curve of the preparation obtained in Example 81. 2 is a diagram showing an elution curve of the preparation obtained in Example 82. FIG. FIG. 10 shows an elution curve of the preparation obtained in Example 83. FIG. 10 shows an elution curve of the preparation obtained in Example 84. FIG. 10 shows an elution curve of the preparation obtained in Example 85. FIG. 10 shows an elution curve of the preparation obtained in Example 86. FIG. 10 shows an elution curve of the preparation obtained in Example 87. FIG. 10 shows an elution curve of the preparation obtained in Example 88. FIG. 10 shows an elution curve of the preparation obtained in Example 89. 2 is a diagram showing an elution curve of a preparation obtained in Example 90. FIG.

Claims (11)

  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 content ratio by mass of the ternary copolymer having a relatively low trimethylammonium chloride content and 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 and 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 as described in any one of Claims 1-6.   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.

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