JPH09194347A - Production of film-coated particle - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare granules causing no deterioration in their functions during its storage through treatments at low humidity and low temperature for a shortened time with no occurrence of agglomeration during the treatments, by atomizing an aqueous dispersion of specific spherical solid particles and a plasticizer to effect coating of particles. SOLUTION: Coarse grains containing medicines are rolled and fluidized in a rolling and fluidization type coater and a dispersion of spherical solid particles mainly comprising ethyl cellulose substantially <=1μm particle size and a plasticizer in water is atomized preferably tangentially to the direction of the coater rotation and coated particles are heat treated at 40-80 deg.C under an atmosphere of 8.5-60% relative humidity.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing granules having a film for controlling the dissolution rate of a drug or a moisture-proof film, and more specifically, the performance is changed immediately after production and after storage for a long period of time. The present invention relates to a method for producing a film-coated granule having a stable film.

[0002]

2. Description of the Related Art Pharmaceutical preparations are provided with a film in order to control the dissolution rate of a drug (medicinal drug active ingredient) or to prevent a decrease in titer due to moisture. Conventionally, a polymer material, which is a film base, is dissolved in an organic solvent and used for film coating. However, from the viewpoint of environmental pollution problems and improvement of working environment of workers in recent years, an aqueous film coating base has been used in order to avoid the use of an organic solvent.

An aqueous dispersion of ethyl cellulose is commercially available as one of water-based film coating bases which can control the dissolution rate of a drug or can strongly prevent moisture. Examples of using an aqueous dispersion of ethyl cellulose as a film coating agent for producing a sustained-release preparation include an annealing agent (water-soluble polymer) compound (JP-A-55-500709) and pore formation. There are known compounding agents (JP-A-3-3275618) and Eudragit compounding (JP-A-57-109716), which change the function (sustained release) of the film by long-term storage. , And its stabilization are not described. Regarding the stabilization of the film, it is preferable to perform heat treatment in an atmosphere of suitable temperature and humidity.
No. 89 and Japanese Patent Application Laid-Open No. 7-165609. However, since these do not take into consideration the coating conditions, for example, at 60 ° C., 9% RH (relative humidity), and 24 hours, the humidity is too low to sufficiently stabilize the film. It says that a high humidity atmosphere is required. An example of preferable conditions is a treatment at 60 ° C., humidity of about 60% or more, and time of 48 hours.
~ 72 hours. From these descriptions,
It is estimated that the effect is not sufficient in a low humidity atmosphere of 0 to about 50% RH.

However, the humidity atmosphere is about 60% RH
If the above is the case, it must be dried before proceeding to the next operation, and in the case of granules, it will consolidate significantly, so a loosening operation is necessary. In particular, the solidification of the granules damages the film when it is loosened, so it is necessary to avoid it. Furthermore, the heat treatment time is too long (4
Since it is 8 hours or more), it is necessary to shorten it from the viewpoint of improving productivity.

[0005]

DISCLOSURE OF THE INVENTION The present invention solves the above problems and provides a film-coated granule having a stable film in which the performance such as sustained release does not deteriorate even during long-term storage, in the production process. It is an object of the present invention to provide a method for efficiently producing an agent without causing solidification of the agent and reduction of the drug titer.

[0006]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that the heat treatment conditions under a humid atmosphere can be significantly relaxed by using a specific film coating method. The present invention was found out and the present invention was completed. That is, according to the present invention, an elementary granule containing a drug is tumbled and fluidized by using a tumbling fluid type coating device, and a spherical solid particle containing ethyl cellulose having a diameter of 1 μm or less as a main component and a plasticizer are substantially used. Coating is carried out by spraying with an aqueous dispersion of
As described above, the present invention relates to a method for producing film-coated granules, which comprises performing heat treatment at a temperature of 80 ° C. or lower.

The present invention will be described below. In the present invention, the drug-containing granules used for film coating include one or more drugs and excipients (eg, lactose, corn starch, crystalline cellulose, mannitol, low-substituted hydroxy). Propyl cellulose, croscarmellose sodium, partially pregelatinized starch, hydroxypropyl cellulose, polyoxyethylene polyoxypropylene glycol, polyethylene glycol, magnesium stearate, light anhydrous silicic acid, etc.). The size is 10 μm or more, 5 m
m or less, and its shape is spherical, elliptical granular, rod-shaped,
Polyhedral shape, etc. Preferably, the ratio of the minor axis to the major axis (minor axis / major axis), which is dense and has a smooth surface, is 0.8.
The above spherical shape has a size of 75 to 1410 μm. More preferably, the particle size distribution is such that the maximum particle size is about 1.7 times or less than the minimum particle size. As the manufacturing method, high speed stirring granulation, extrusion granulation, extrusion granulation + malm, rolling granulation, fluidized bed granulation, rolling fluidized bed granulation, coating granulation using core particles, etc. are used. , Particularly preferably,
Extrusion granulation + Malmo method and coating granulation method using core particles (modified granulation method). When the modified granulation method is used, the commercially available spherical granules Celfia <registered trademark> (Asahi Kasei Co., Ltd.) are used in terms of shape and particle size distribution.
It is preferable to use non-pareil (trade name of Freund Industrial Co., Ltd.) or the like.

In the present invention, the drug is used for treatment, prevention and diagnosis of human and animal diseases,
It is not an instrument machine, and examples thereof include the following. That is, an antiepileptic agent (eg, phenytoin, acetylphenetride, trimetadione, phenobarbital, primidone, nitrazepam, sodium valproate, sultiam, etc.), antipyretic analgesic and antiinflammatory agent (eg, acetaminophen, phenylacetylglycine methylamide, mefenum) Acid, diclofenac sodium, floctafenin, aspirin, aspirin aluminum, etenzamid, oxyphenbutazone, sulpirine, phenylbutazone, ibuprofen,
Alclofenac, naproxen, ketoprofen, tinoridine hydrochloride, benzydamine hydrochloride, tiaramid hydrochloride, indomethacin, piroxicam, salicylamide, etc.),
Antiphlogistics (eg, dimenhydrinate, meclizine hydrochloride, diphenidol hydrochloride, etc.), narcotics (eg, opium alkaloid hydrochloride, ethylmorphine hydrochloride, codeine phosphate, dihydrocodeine phosphate, oxymethebanol, etc.), psychotropic agents ( Examples, chlorpromazine hydrochloride, levomepromazine maleate, perazine maleate, propericiadine,
Perphenazine, chlorprothixene, haloperidol, diazepam, oxazepam, oxazolam, mexazolam, alprazolam, zotepine, etc., skeletal muscle relaxants (eg, chlorzoxazone carbamic acid, chlormezanone, prizinol mesylate, eperisone hydrochloride, etc.) ), Agents for autonomic nerves (eg, bethanechol chloride, neostigmine bromide, pyridostigmine bromide,
Etc.), antispasmodic agents (eg, atropine sulfate, butropium bromide, butylspocholamine bromide, propantheline bromide, papaverine hydrochloride, etc.), anti-Parkinson's agents (eg, biperidene hydrochloride, trihexyphenidyl hydrochloride, amantadine hydrochloride, levodopa) , Etc.), ophthalmic agents (eg, dichlorphenamide, metazolamide, etc.), antihistamines (diphenhydramine hydrochloride, dl-chlorpheniramine maleate,
d-chlorpheniramine maleate, promethazine, mequitazine, clemastine fumarate, etc.), cardiotonic agent (eg,
Aminophylline, caffeine, dl-isoisoproterenol hydrochloride, etilefrine hydrochloride, norphenerine hydrochloride,
Ubidecarenone, etc.), arrhythmic agents (eg, procainamide hydrochloride, pindolol, metoprolol tartrate, disoviramide, etc.), diuretics (eg, potassium chloride, cyclopentiazide, hydrochlorothiazide, triamterene, etc.)
Acetazolamide, furosemide, etc.).

Furthermore, antihypertensive agents (eg, hexamethonium bromide, hydralazine hydrochloride, syrosingopine, reserpine, propranolol hydrochloride, captopril, methyldopa, etc.), vasoconstrictors (eg, dihydroergotamine mesylate, etc.), blood vessels Dilators (eg etafenone hydrochloride, diltiazem hydrochloride, carbochromene hydrochloride, pentaerythritol tetranitrate, dipyridamole, isosorbide dinitrate, nifedipine, nicametate citrate, cyclanderate,
Cinnarizine, etc.), agents for arteriosclerosis (eg, ethyl linoleate, lecithin, clofibrate, etc.), agents for circulatory organs (eg, nicardipine hydrochloride, meclofenoxate hydrochloride, cytochrome C, pyridinol carbamate, pinbocetin, Calcium hopantenate, pentoxifylline, idebenone, etc.), respiratory stimulants (eg, dimephrine hydrochloride, etc.), antitussive expectorants (eg, codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide,
Noscapine, L-methylcysteine hydrochloride, bromhexine hydrochloride, theophylline, ephedrine hydrochloride, amlexanox, etc.), choleretic agent (eg, osalmid, phenylpropanol, hymecromon, etc.), intestinal regulator (eg, berberine chloride, loperamide hydrochloride, etc.), Digestive agent (eg, metoclopramide, phenpentol, domperidone,
Etc.), vitamin agents (eg, retinol acetate, dihydrotaxosterol, etretinate, thiamine hydrochloride, thiamine nitrate, fursultiamine, octothiamine, shicothiamine, riboflavin, pyridoxine hydrochloride, pyridoxal phosphate, nicotinic acid, pantethine, cyanocobalamin,
Biotin, ascorbic acid, phytonadione, menatetrenone, etc.), antibiotics (eg, benzylpenicillin benzathine, amoxicillin, ampicillin, cyclacillin, cefaclor, cephalexin, erythromycin, kitasamycin, josamycin, chloramphenicol, tetracycline, griseofulvin, cefuzorubin, cefuzoline Sodium, etc.), chemotherapeutic agents (eg, sulfamethoxazole, isoniazid, ethionamide, thiazosulfone, nitrofurantoin, enoxacin, ofloxacin, norfloxacin, etc.) and the like.

In particular, the present invention makes it possible to perform low-temperature treatment, so that the melting point is low, or the potency is lowered by heat, so that a drug that could not be heat-treated at high temperature,
For example, zotepine, ibuprofen, chlorphenesin carbamate, ubidecarenone, disobiramide, isosorbide dinitrate, cyclanderate, idebenone, retinol acetate, ethylmorphine hydrochloride, neostigmine bromide, butylsporamine bromide, propantheline bromide, clemastine fumarate. , Thiamine hydrochloride, fursultiamine, octothiamine, ascorbic acid, benzylpenicillin benzathine, amoxicillin, cyclacillin, cefaclor, cephalexin, erythromycin, josamycin, sulfamethoxazole, etc.
The drug content in the granules depends on the dose of the drug, but if we dare to show an example, a drug that exerts a drug effect in a very small amount is about 0.01% by weight, and a large amount of drug is required for the drug effect to appear. In other cases, it is about 95% by weight.

In the present invention, the film coating agent contains ethyl cellulose as a main component and has a diameter of substantially 1 μm.
An aqueous dispersion containing spherical solid particles of m or less and a plasticizer is used. The particle size distribution of the spherical solid particles containing ethyl cellulose as a main component is substantially 1 μm or less in diameter. The term “substantially” means that spherical solid particles having a diameter of more than 1 μm (however, about 5 μm at the maximum) are present in an amount that does not impair the film-forming property and dispersion stability as a film coating agent. And its amount is 0.5% by volume
It is as follows. It is preferable that the spherical solid particles are small, but the distribution thereof is 95% by volume or more for particles having a diameter of 0.6 μm or less and 75% by volume or more for particles having a diameter of 0.5 μm or less.
Those having a thickness of 4 μm or less are preferably 1% by volume or more. The “spherical shape” of the spherical solid particles means that the sphericity is 0.7 or more, and more preferably 0.8 or more.

As an auxiliary component other than ethyl cellulose,
Encapsulated or complexed with spherical solid particles, necessary for producing an aqueous dispersion of spherical solid particles, or necessary to maintain the dispersion stability of spherical solid particles in water. Auxiliary agents, or auxiliary agents for preventing bacterial contamination. Examples include surfactants (eg, sodium lauryl sulfate), emulsification aids (eg, cetyl alcohol), defoamers, bacteriostats, bactericides, and the like. The blending amount thereof is 30% by weight or less, preferably 20% by weight or less with respect to ethyl cellulose.

Such an ethyl cellulose aqueous dispersion by itself cannot be put to practical use because its minimum film forming temperature is too high. Therefore, it is necessary to add a plasticizer to lower the minimum film formation temperature, but if the size of the spherical solid particles containing ethyl cellulose as the main component as described above is 1 μm or less, the amount of plasticizer used may be small. . The compounding of the plasticizer has a drawback that when the compounding amount is large, separation (bleeding) or the like occurs after film formation, and the drug dissolution rate changes with time. In the case of the film coating agent used in the present invention, since the amount of the plasticizer used may be small, the change with time can be minimized. In the present invention, spherical solid particles of ethyl cellulose are stably dispersed in water, most of the plasticizer is absorbed by the ethyl cellulose particles, and in some cases, a part thereof is dissolved in water. The plasticizer should not separate from water to form oil globules or separate into two layers. In some cases, water-soluble polymers, sugars, drug dissolution rate regulators such as ionic substances, ammonia water, dispersion stabilizers such as ammonium hydroxide, talc, light anhydrous silicic acid, titanium oxide, corn starch, crystals It may also contain auxiliaries commonly used for film coating, such as film coating auxiliaries such as cellulose.

Aqueous dispersions of spherical solid particles of ethyl cellulose are produced by various methods, for example Pharmaceuth.
Optical Technology, Vol. 11,
No. 3, p56-68 (1987), the emulsion-solvent evaporation method or the phase inversion method. As an example, "A manufactured by FMC (US)"
quacoat ”ECD-30 and the like.

The ethyl cellulose used in the present invention means The United States Pharm.
Guide to Gen of acopia23 (USA)
eral Chapters / General Tes
t and Assays / <431> Methoxy
Determination method (however, 0.1N
1 mL of sodium thiosulfate solution has 0.751 ethoxyl groups
Ethoxyl group (-0 corresponding to 0 mg)
C ₂ H ₅₎ content of is of from 41.0 to 51.0 wt%.

The plasticizer used in the present invention is a substance that lowers the glass transition temperature and the minimum film formation temperature of ethyl cellulose. Examples include acetylated monoglyceride, triethyl citrate, triacetin, dibutyl sebacate, dimethyl sebacate, medium chain fatty acid triglyceride, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, dibutyl adipate, oleic acid, oleinol, etc. Can be mentioned. The selection of the plasticizer largely depends on the solubility of the drug and the design of the drug (drug dissolution rate, setting of storage stability). For example, when the solubility of the drug is low, it is preferable to use acetylated monoglyceride because it can reduce the batch variation of the film coating, and when the solubility of the drug is high, the amount of film coating can be reduced to triethyl citrate. Is preferably used. The blending amount is determined in consideration of the minimum film forming temperature, the fusion property due to thermal softening of the film (which affects the film coating operation), the storage stability, etc., but is approximately 10 to 70 parts by weight with respect to 100 parts by weight of ethyl cellulose. , Preferably about 25 to 50 parts by weight.

As the water-soluble polymer used in the present invention, those commonly used in pharmaceutical preparations are used, and examples thereof include methyl cellulose, hydroxyethyl cellulose,
Examples include hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hereinafter sometimes abbreviated as HPMC), carboxymethyl cellulose, dextrin, pullulan, polyvinyl alcohol, polyvinyl pyrrolidone, gum arabic, sodium alginate, propylene glycol alginate, xanthan gum, and the like. it can. In the present invention, one type or two or more types are used.

The rolling fluid type coating apparatus used in the present invention comprises a substantially cylindrical space, a disk for rolling the particles to be coated and a slit or a small hole for supplying hot air to the bottom. It has an air outlet (usually with a bag filter) for discharging warm air in the upper part, and a spray nozzle for spraying the film coating liquid from the upper part to the lower part, or almost It is mounted tangentially to the rotation of the disk at the bottom of the cylindrical space. Various devices depending on the shape of the substantially cylindrical space, the shape of the disk for rolling, the shape and position of the slits or small holes for supplying hot air, and the shape of the spray nozzle (spraying ability, prevention of foreign matter adhesion) Is proposed,
Any device may be used in the present invention. As commercial products, "Multiplex" manufactured by Paulec Co., Ltd., "New Marmelizer" manufactured by Fuji Paudal Co., Ltd., "Spiraflow" manufactured by Freund Sangyo Co., Ltd., "Flow Coater" with the same "rotor container", etc. There is. A particularly preferred device is a "multiplex".

When an ethyl cellulose aqueous dispersion is sprayed and film-coated by using a rolling fluid type coating device, the granules are given a fluidizing action by hot air and a rolling action by a disc. The coating agent adhered to is spread well before it dries. Further, it is preferable to spray the ethyl cellulose aqueous dispersion tangentially for the rolling motion of the disk from the lower part of the substantially cylindrical space. By spraying tangentially in this way, the distance from the tip of the spray nozzle to the spherical elementary granules is shortened. Since it adheres with sufficient water content, the adhesion efficiency will be high and the spreading effect after that will also be high. The resulting film is more dense, and the continuation of ethylcellulose particles is easily achieved even by heat treatment under significantly relaxed conditions as compared with the prior art, and as a result, the dissolution rate of the drug even during long-term storage. It is thought that it will be a stable film that does not change. The reason why "multiplex" is preferable is that the spray nozzle has a mechanism to let air flow in the same direction as the spray on the outside, and this air prevents the adhesion of non-coated particles and the like, and also the adhesion of the film coating agent. This is because it has an action of preventing and adhering the sprayed droplets well to the sphere-shaped granules, and a function of making the sphere-shaped granules roll and flow well.

In the present invention, the film of the film-coated granules preferably has a thickness of 30 μm or more. When the thickness is 30 μm or less, the film strength is low, and it tends to change over time. There is no particular upper limit, but if it is too thick, film coating takes a long time, which is not practical. From such a constraint, the upper limit is about 100 μm. When the film becomes thicker, the elution rate will become too slow, but in such a case, even if a suitable elution rate and a suitable film thickness are secured by, for example, appropriately mixing a water-soluble substance. Good. The coating amount varies greatly depending on the particle size and shape of the granular material, the smoothness of the surface, etc., but is about 5 to 100 parts by weight, preferably about 10 to 25% by weight, relative to 100 parts by weight of the granular material. .

The film-coated granules thus obtained are treated in a relative humidity atmosphere of 8.5% or more and less than 60.0% at a temperature of 40 ° C. or more and 80 ° C. or less for an appropriate time. Humidity is less than 8.5% RH or 40 ℃
When it is less than the above range, the ethylcellulose particles are not sufficiently continuous, and the dissolution rate of the drug is changed by long-term storage. Further, if the humidity is 60.0% RH or more, the granules will not absorb much moisture, drying will be essential, and the granules will solidify, so that they cannot be used unless they are loosened. If the temperature exceeds 80 ° C, the titer of the drug tends to decrease, which is not preferable. Even if the humidity is less than 8.5%, if the temperature is set to 60 ° C. or more, a stable film can be produced, but it takes a longer time than the method of the present invention, which is disadvantageous in terms of productivity. It is preferably 9.0 to 58.0% RH and 40 to 70 ° C, and more preferably 9.5 to 30.0% RH and 40 to 60 ° C. It is necessary to conduct tests by changing the heating time at several levels to find and set the conditions at which the dissolution rate bottoms out. Usually 0.5 to 24 hours, most of them 1 to 6
It is a short period of time.

In this heat treatment, a desiccator is charged with an aqueous solution of sulfuric acid or an aqueous solution of a saturated salt which gives an appropriate humidity, granules for film coating are put therein, and the desiccator is placed in an incubator for humidification / heating, or The coated granules are directly humidified and heated by a thermo-hygrostat, or the film-coated granules are tumbled and fluidized (fluidized) in a tumbling fluidized bed or a fluidized bed, and at the same time, water is sprayed to granulate the granules. It can be humidified and heated. Although the moisture content may increase due to humidification, since the present invention is a process of relatively low humidity and a short time, problems such as solidification of granules hardly occur. However, when it is stored for a long period of time or when an accelerated storage stability test is carried out, light solidification of the granules may occur. In order to avoid this, it is effective to perform a drying process.

Since the present invention can be processed at a lower temperature, it has a great effect when a drug having a low melting point or a drug which is inactivated by heating is used. Conventionally, when a film containing such a drug is coated with an aqueous dispersion of ethyl cellulose, the use of the drug may have to be abandoned due to insufficient stabilization of the film. When heating in a humidity atmosphere, the reason why the continuation of the ethylcellulose particles can be promoted even at a lower temperature is considered to be that the water content of the film acts as a plasticizer to lower the glass transition point.

The drug dissolution rate of granules is required to be stable within the quality assurance period of pharmaceutical products. Usually, the period is 3 years, and the limit of the variation in the dissolution rate is within the range where the manifestation of the pharmacological effect is equivalent. As a guideline, for example, "Guideline for design and evaluation of sustained-release preparations (orally administered drug)" (edited by Japan Official Book Association, Pharmaceutical Manufacturing Guidelines 1992 edition, p107-112 (Yakuji Jikhosha)), the final product In the packaging form of 40 ℃, 75% R
H, storage stability test for 6 months was performed, during which, at appropriate time of dissolution rate of 20-40%, 40-60%, 70% or more, within ± 15%, within ± 15%, ±, respectively.
It is shown to be within 10%. The present invention can achieve this by a low-temperature treatment or a short-time treatment, which was difficult in the prior art.

In the present invention, the film-coated granules are used for the purpose of reducing the batch variation of the coating of the ethyl cellulose aqueous dispersion film or preventing the change in the blending between the drug and the ethyl cellulose aqueous dispersion film.
A water-soluble polymer (eg, hydroxypropylmethylcellulose, etc.) may be film-coated on the outside of the granules, and for the purpose of preventing caking during storage or imparting enteric property, Another film coating agent may be further coated on the outside of the ethyl cellulose aqueous dispersion film.

The particle size distribution of the film-coated granules thus obtained is the particle size distribution of the above-mentioned elementary granules with the film thickness increased. It is 75-1410μ
It is preferably within the range of m. More preferably, it is substantially within the range of 75 to 500 μm. If the particle size distribution is within this range, it is easy to take, and it can be mixed with foods and taken, and it can be referred to as "powder" or "granule" prescribed in the 12th Revised Japanese Pharmacopoeia General Regulations. Since it has a good mixing property, it has advantages that it is easy to prepare a drug, and even if it is mixed with other excipients and tableted, the film is less damaged.
By "substantially" is meant that particles may be included that are less than 75 μm or greater than 500 μm to the extent that they do not impair the aforementioned advantages, i.e., 10% by weight or less of particles less than 75 μm, particles greater than 500 μm. Is 5
It means that the content is not more than weight% (however, the maximum is about 850 μm).

In the present invention, the film-coated granules are used as they are, or they are used by filling them into capsules, or they are mixed with other drugs, or other excipients or It is used by mixing it with a drug, a drug-containing granule, or a film-coated granule, and then tableting into a tablet. It is also possible to administer the drug by mixing it with a food or a tube-fed liquid food. In addition to pharmaceuticals, they can also be used as agricultural chemicals, fertilizers, or industrial applications.

[0028]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in detail with reference to examples. The measuring method, the preparing method and the like are as follows. Measurement method of particle size distribution [wt%] 50 g of each of the elementary granules and the coated granules were accurately weighed using a JIS standard sieve, and expressed by the weight percentage of the weight on the sieve when sieved with a low tap type sieving machine. Coarse specific volume [cm ³ / g] Elementary granules 2 on a medicine packing paper placed on a sieve with an opening of 4000 μm
Place 0 g, slowly remove the medicine packing paper and drop it into a 50 cm ³ graduated cylinder. The volume at that time was divided by the weight of the granules of 20 g. Sphericality of spherical solid particles containing ethyl cellulose as the main component [-] The particle shape was photographed using an electron microscope, and the average value of the ratio of the minor axis to the major axis of 50 particles (minor axis / major axis) was taken. . Particle size distribution of spherical solid particles containing ethyl cellulose as a main component [volume%] A sample water dispersion was diluted with water to a concentration showing an appropriate transmittance, ultrasonically dispersed for 1 minute, and then stirred to obtain a relative refractive index. Laser diffraction type particle size distribution measuring apparatus (LA-9, manufactured by Horiba, Ltd.) under the conditions of 1.2 and the number of loadings of 10 times.
10 type) to determine the volume-based particle size distribution. Method for measuring drug dissolution rate [%] The drug dissolution rate was measured by the paddle method (100 rpm) using an automatic dissolution tester DT-600 manufactured by JASCO Corporation. The test solution used was the second test solution of the 12th Revised Japanese Pharmacopoeia General Test Method Disintegration Test Method. The measurement was performed twice and the average value was taken. Preparation of Elementary Granules 70 parts by weight of ibuprofen and crystalline cellulose (Avicel <registered trademark> PH-101, manufactured by Asahi Kasei Kogyo Co., Ltd.) 30
After mixing parts by weight into powder, the mixture was hydrolyzed while stirring with a planetary mixer (5-DM type, paddle: beater type manufactured by Shinagawa Kogyo Co., Ltd.), and an extruder having a die hole diameter of 0.5 mm (dome gran, DG). -1L type, Fuji Paudal Co., Ltd.
Extruded with a spheronizer, then spheronizer (Marumerizer,
Q-230 type, manufactured by Fuji Paudal Co., Ltd., and spheroidized for 15 minutes was dried in a fluidized bed drier to have an opening of 1410μ.
Coarse particles remaining on the sieve were removed with a sieve of m to obtain an elementary granule. The ratio of the short diameter to the long diameter of the granule was 0.86, and the rough specific volume was 2.20 cm ³ / g. Table 1 shows the particle size distribution of the obtained granules. Preparation of HPMC coated granules Rolling fluid type coating equipment (multiplex, MP
-01 type, manufactured by Paulec Co., Ltd., was charged with the above-mentioned granules and sprayed with a coating liquid consisting of 5 parts of hydroxypropylmethyl cellulose (TC-5E manufactured by Shin-Etsu Chemical Co., Ltd.) and 95 parts of water to form granules. An HPMC-coated granule having 5 parts by weight of HPMC coated on 100 parts by weight was obtained. Table 2 shows the particle size distribution.

[0029]

Example 1 Aqueous dispersion of ethyl cellulose (“Aquac
oat "ECD-30, solid content concentration: 30%, manufactured by FMC, sold by Asahi Kasei Kogyo Co., Ltd., 32 parts, triethyl citrate 2.4 parts, hydroxypropylmethyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd., TC-5E). ) 10% aqueous solution 3
A coating liquid consisting of 0 part and 35.6 parts of water was prepared, and 700 g of HPMC coated granules were coated with the rolling fluid type coating device described above using a rotating plate rotation speed of 45.
0 rpm, using tangential bottom spray,
Spray air pressure: 1.6 kgf / cm ² , spray air flow rate: 40 L / min, air supply temperature: 55 ° C., exhaust temperature: 36 ° C., air volume: 105 m ³ / hr, coating liquid supply rate: 14 g / min Coated.
The ethyl cellulose aqueous dispersion used had no particles of 0.4 μm or more, had an average size of 0.145 μm (median diameter), and had a sphericity of 1.0. Coating is 1 for 100 parts by weight of HPMC coated granules.
5 parts by weight were used. After stopping the supply of the coating liquid, the coating liquid was left as it was, and when the exhaust temperature rose to 40 ° C., the heater was turned off and cooled to room temperature, and the coating granules were taken out. About 30 after turning off the heater
It took a minute. Table 3 shows the particle size distribution of the obtained coated granules. The thickness of the coating film was 36 μm (calculated from the particle size distribution under the 50% cumulative distribution).

Then, about 500 g of the obtained coated granules were placed in a desiccator containing a saturated aqueous solution of ZnCl _2.
And heated at 50 ° C. for 2 hours with a hot air dryer. At this time, the temperature in the desiccator is 50 ° C and the relative humidity is 1
It was 0.0% RH. No solidification of the coated granules was observed. Put this in a glass airtight container and 40
A storage stability test was conducted by leaving it under the conditions of 75 ° C. and 75% RH. The results are shown in Table 4.

The elution rate after standing for 8 weeks showed almost no change compared with the elution rate before storage.
Further, the granules in the glass airtight container after storage for 8 weeks were hardly solidified.

[0032]

Example 2 The coated granules prepared in Example 1 were
A constant temperature and constant humidity machine (manufactured by Tabai Espec Corporation) was used for humidification and heat treatment at 50 ° C. and 57.0% RH for 2 hours. The granules were lightly set so that they could be loosened by shaking. This was placed in a glass airtight container and left under the conditions of 40 ° C. and 75% RH to perform a storage stability test. Table 5 shows the results.

The elution rate after standing for 8 weeks showed almost no change compared with the elution rate before storage.
Further, the granules in the glass airtight container after storage for 8 weeks were solidified, but could be lightly loosened with a spatula.

[0034]

Comparative Example 1 The coated granules prepared in Example 1
Heat treatment was performed at 0 ° C. and 8.0% RH for 2 hours. Put this in a glass airtight container, 40 ℃, 75% RH, and 50
A storage stability test was carried out by leaving it under conditions of 8 ° C. and 8% RH. The results are shown in Tables 6 and 7. In this case, the elution rate after storage for 8 weeks was significantly delayed under both conditions compared to the elution rate before storage.

[0035]

[Table 1]

[0036]

[Table 2]

[0037]

[Table 3]

[0038]

[Table 4]

[0039]

[Table 5]

[0040]

[Table 6]

[0041]

[Table 7]

[0042]

INDUSTRIAL APPLICABILITY According to the present invention, stable film-coated granules whose functions such as sustained release of the film are not changed during long-term storage are treated at low humidity, low temperature and short time. It can be produced without causing the solidification of granules.

Claims (2)

[Claims] 1. A granule containing a drug is tumbled and flowed by using a tumbling flow type coating device, and substantially composed of spherical solid particles having a diameter of 1 μm or less and containing ethyl cellulose as a main component and a plasticizer. A film characterized by being sprayed with an aqueous dispersion for coating, and then heat-treated in an atmosphere of relative humidity of 8.5% or more and less than 60.0% and at a temperature of 40 ° C. or more and 80 ° C. or less. Method for producing coated granules. 2. A water dispersion comprising spherical solid particles containing ethyl cellulose as a main component and a plasticizer is sprayed in a tangential direction for rolling motion of a rolling fluid type coating device. Method for producing film-coated granules.