JPH09165329A - Film-coated granule and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a film-coated granule having a controlled dissolution rate of a medicine, excellent in stability of dissolution rate with time, by coating the outside of a spherical raw granule containing a medicine with a medicine dissolution rate adjusting film having a proper strength. SOLUTION: A spherical raw granule containing a medicine is coated with a film coating agent which is a water dispersion comprising a spherical solid particle consisting essentially of ethyl cellulose and having substantially <=1μm diameter, a plasticizer and a medicine dissolution rate adjusting substance and forms a film having >=0.08kgf strength to give the objective film-coated granule. The spherical granule containing the medicine preferably comprises a medicine and a spherical nuclear particle and the nuclear particle contains preferably >=30wt.% crystalline cellulose. Hydroxypropyl cellulose and hydroxypropyl cellulose are preferable as the medicine dissolution rate adjusting substance. The content of the substance is 15-35wt.% in the film. The thickness of the film is preferably >=30μm.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a granule having a controlled drug dissolution rate and a method for producing the same. More specifically, it relates to a spherical drug-containing granule coated with a drug dissolution control film and a method for producing the same.

[0002]

2. Description of the Related Art In pharmaceutical preparations, the dissolution rate of a drug (medicinal drug active ingredient) is controlled for the purpose of reducing side effects and reducing the number of doses. Such preparations are called sustained-release preparations, sustained-release preparations, sustained-release preparations, and are designed so that the entire amount of the drug is eluted from the preparation in a few hours to a dozen hours.

As an example of using an aqueous dispersion of ethyl cellulose as a film coating agent for producing a sustained-release preparation, an annealing agent (water-soluble polymer) is blended (Japanese Patent Publication No. 55-500709). Mixing of a pore forming agent (JP-A-3-275618), Eudragit (JP-A-57-109716), solid particles (talc, starch) (JP-A-2-3608), and the like. Are known.

However, the conventional method has the disadvantage that the elution rate decreases as the amount of elution increases, and further,
It was inferior in stability over time.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a film-coated granule in which the dissolution rate of a drug is substantially constant regardless of the dissolution time, and the dissolution rate thereof is excellent in stability over time.
And a method for producing the same.

[0006]

In view of the present situation, the present inventors have considered that the drug permeability of a drug dissolution rate adjusting film is
And, as a result of earnestly studying the simultaneous control of mechanical strength, the present invention has been achieved. That is, the present invention is as follows. (1) For forming a drug dissolution rate-adjusting film in a film-coated granule having a drug-containing spheroidal granule and a drug dissolution rate-adjusting film containing ethyl cellulose, a plasticizer, and a drug dissolution rate-adjusting substance on the outside thereof The film coating agent is an aqueous dispersion containing ethyl cellulose as a main component and substantially spherical solid particles having a diameter of 1 μm or less, a plasticizer and a drug dissolution rate adjusting substance, and the film strength formed by this dispersion is 0.08 kg.
A film-coated granule characterized by being f or more. (2) The spheroidal granule containing a drug comprises a drug and a spherical core particle, and the core particle is a spheroidal granule containing 30% by weight or more of crystalline cellulose. Coated granules. (3) The drug dissolution rate adjusting substance is one or more selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone, and 15% by weight or more in the drug dissolution rate adjusting film. The above (1) characterized in that the content is 30% by weight or less.
Alternatively, the film-coated granule according to (2). (4) The film coated granule according to the above (1), (2) or (3), wherein the drug dissolution rate adjusting film has a thickness of 30 μm or more. (5) The above (1), (2), characterized in that the particle size distribution is substantially in the range of 75 to 600 μm.
The film-coated granule according to (3) or (4). (6) In a method for producing a film-coated granule having a drug-containing spheroidal granule and a drug-eluting rate adjusting film containing ethyl cellulose, a plasticizer and a drug-eluting rate adjusting substance on the outside thereof, a drug-eluting rate adjusting film is provided. The film coating agent for forming is an aqueous dispersion containing substantially spherical spherical solid particles mainly containing ethyl cellulose and having a diameter of 1 μm or less, a plasticizer and a drug dissolution rate adjusting substance, and a rolling fluid type coating device. A method for producing film-coated granules, which comprises coating a sphere-shaped granule with a drug dissolution rate adjusting film by using. (7) The strength of the drug dissolution rate adjustment film is 0.08 kg
f or more, The method for producing film-coated granules according to (6) above. (8) The above-mentioned (6) or (7), wherein the spheroidal granule containing the drug comprises a drug and spherical core particles, and the core particle is a spheroidal granule containing 30% by weight or more of crystalline cellulose. ) A method for producing the film-coated granules described above. (9) The drug dissolution rate adjusting substance is one or more selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone, and 15% by weight or more in the drug dissolution rate adjusting film. The method for producing film-coated granules according to (6), (7) or (8) above, wherein the content is 30% by weight or less. (10) The film coating granule according to (6), (7), (8) or (9) above, characterized in that the film coating agent is sprayed in a tangential direction for rolling motion of a rolling fluid type coating device. Production method.

Hereinafter, the present invention will be described in detail. The spheroid granules used in the present invention contain a drug. Preferably, the spheroid granules contain spherical core particles and a drug. The spherical core particles preferably contain 30% by weight or more of crystalline cellulose. If the crystalline cellulose is less than 30% by weight, the mechanical strength is low, and when the drug is supported and the drug dissolution rate adjusting film is coated, breakage occurs,
Also, although depending on the properties of other components, the water absorption is usually low, so that coalescence of particles may occur in the film coating step and the yield may be reduced. The content of crystalline cellulose is more preferably 50% by weight, further 100% by weight
Most preferably (excluding water). The degree of polymerization of the crystalline cellulose contained in the spherical core particles used in the present invention is preferably 60 to 375, and more preferably 110 to 240.

The "spherical shape" of the spherical particles and spherical core particles used in the present invention means that the sphericity is 0.7 or more. If the sphericity of the spheroid granules is less than 0.7,
It will have a large convex portion. Further, if the sphericity of the spherical core particles is less than 0.7, as a result, the sphericity of the drug-loaded elementary granules decreases. The drug dissolution rate adjusting film is difficult to be placed on the large convex portion, and the desired drug dissolution property cannot be obtained unless a large amount of coating is applied. Therefore, the drug dissolution rate adjusting film is used unnecessarily, and the film coating operation takes time. Ideally, the surface should be a perfect sphere, but for practical purposes it is preferable that the sphericity is 0.7 or higher, and if it is 0.8 or higher, the film coating amount and coating time are significantly reduced. It is possible to do so, which is preferable.

The spherical core particles used in the present invention have the above-mentioned properties and have a water absorption capacity of 0.5 to 1.5 g / g,
It is preferable that the tapping apparent density is 0.65 g / cm ³ or more, the friability is 1% or less, and the particle size distribution is in the range of 75 to 600 μm. As an example, "SELFIA" CP-102, CP-203, CP-3 manufactured by Asahi Kasei Kogyo Co., Ltd.
05, Nonpareil-105 manufactured by Freund Industrial Co., Ltd.
And the like. In addition, the measuring method of each property,
Details of the above will be described later.

The drug used in the present invention is a drug used for treatment, prevention and diagnosis of human and animal diseases, not an instrument or machine. Examples thereof are as follows. There are many things. Antiepileptic agents such as phenytoin, acetylphenetride, trimetadione, phenobarbital, primidone, nitrazepam, sodium valproate, sultiam, etc., antipyretic and analgesic agents such as acetaminophen, phenylacetylglycine methylamide, mefenamic acid, diclofenac. Sodium, floctafenin, aspirin, aspirin aluminum, etenzamid, oxyphenbutazone, sulpiline, phenylbutazone, ibuprofen,
Alclofenac, naproxen, ketoprofen, tinoridine hydrochloride, benzydamine hydrochloride, tiaramid hydrochloride, indomethacin, piroxicam, salicylamide, etc., sedatives such as dimenhydrinate, meclizine hydrochloride,
Narcotics, such as diphenidol hydrochloride, etc., such as opium alkaloids, morphine hydrochloride, codeine phosphate, dihydrocodeine phosphate, oxymethebanol, etc., neuroleptic agents, such as chlorpromazine hydrochloride, levomepromazine maleate, perazine maleate, propericia. gin,
Perphenazine, chlorprothixene, haloperidol, diazepam, oxazepam, oxazolam, mexazolam, alprazolam, zotepine, etc., skeletal muscle relaxants such as chlorzoxazone, chlorphenesine carbamate, chlormezanone, prizinol mesylate, eperisone hydrochloride, etc., Agents for autonomic nerve, for example, bethanechol chloride, neostigmine bromide, pyridostigmine bromide,
Antispasmodic agents such as atropine sulfate, butropium bromide, butylspocholamine bromide, propantheline bromide, papaverine hydrochloride, etc., anti-Parkinson's agents such as biperidene hydrochloride, trihexyphenidyl hydrochloride, amantadine hydrochloride, levodopa, etc. , Ophthalmic agents such as dichlorphenamide, metazolamide, etc., antihistamines such as diphenhydramine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, promethazine, mequitazine, clemastine fumarate, etc., cardiotonic agents , For example, aminophylline, caffeine, dl-isoisoproterenol hydrochloride, etilefrine hydrochloride, norphenerine hydrochloride, ubidecarenone, etc., arrhythmia agents, for example, procainamide hydrochloride, pindolol, metoprolol tartrate, disobila. De, etc., diuretics, e.g., potassium chloride, cyclopenthiazide thiazide, hydrochlorothiazide, triamterene, acetazolamide, furosemide,
Etc., blood pressure-lowering agents such as hexamethonium bromide, hydralazine hydrochloride, syrosingopine, reserpine, propranolol hydrochloride, captopril, methyldopa, etc., vasoconstrictors such as dihydroergotamine mesylate, etc., vasodilators such as hydrochloric acid. Etafenone, diltiazem hydrochloride, carbochromene hydrochloride, pentaerythritol tetranitrate, dipyridamole, isosorbide nitrate, nifedipine, nicotinate citrate, cyclanderate, cinnarizine, etc., arteriosclerotic agents such as ethyl linoleate, lecithin, clofibrate, etc. , Cardiovascular agents,
For example, nicardipine hydrochloride, meclofenoxate hydrochloride, cytochrome C, pyridinol carbamate, pinbocetine, calcium fopanthenate, pentoxifylline, idebenone, etc., respiratory stimulants such as dimefrine hydrochloride, etc., antitussive expectorants, eg, Codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, noscapine, L-methylcysteine hydrochloride, bromhexine hydrochloride, theophylline, ephedrine hydrochloride, amlexanox, etc., choleretic agents such as osalmid, phenylpropanol, hymechromone, etc. , Antiflatulents, for example,
Berberine chloride, loperamide hydrochloride, etc., agents for digestive organs,
For example, metoclopramide, phenipentol, domperidone, etc., vitamin agents such as 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, such as benzylpenicillin benzathine, amoxicillin, ampicillin, cyclacillin, cefachlor, cephalexin, erythromycin, kitasamycin, josamycin, chlors. Phenicol, tetracycline, griseofulvin, cefzonam sodium and the like, chemotherapeutic agents such as sulfamethoxazole, isoniazid, ethionamide, thiazosulfone, nitrofurantoin, enoxacin, ofloxacin, norfloxacin and the like.

A known method can be used as a method for producing spherical elementary granules, for example, an extrusion-Malmo method or a method of loading a drug on core particles (modified granulation method). Spheroidal granules having a drug loaded on the outside and / or the inside of the spherical core particle is one of the preferred embodiments of the present invention. A state in which the spherical core particles are coated so that the drug exhibits an outer shell is also one of the preferred embodiments of the present invention.

Stabilization to facilitate the loading of the drug on the spherical core particles, to prevent the drug from peeling in the post-processing step, to adjust the dissolution rate of the drug, or to stabilize the drug. Therefore, for example, the following may be used in combination to support the drug. Binders such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, etc., film coating bases such as hydroxypropyl methyl cellulose phthalate,
Hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, ethylcellulose, ethylcellulose aqueous dispersion, aminoalkylmethacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer S, methacrylic acid copolymer LD, aminoalkylmethacrylate copolymer RS, Etc., surfactants such as sucrose fatty acid ester, polyoxyethylene polyoxypropylene glycol, polysorbate, sodium lauryl sulfate,
Excipients such as sugar, for example, corn starch, rice starch, powdered sugar, lactose, crystalline cellulose, etc., disintegrating agents,
For example, low-substituted hydroxypropyl cellulose, carmellose calcium, croscarmellose sodium,
Inorganic substances such as partially pregelatinized starch, such as talc, magnesium stearate, light anhydrous silicic acid, synthetic aluminum silicate, titanium oxide, etc., and others, such as crystalline cellulose / carmellose sodium, hydrogenated oil, macrogol, Etc.

For the purpose of coating (carrying) a drug and reducing batch variation of coating of a drug rate adjusting film,
A two-layer structure of a drug and a water-soluble polymer (for example, hydroxypropylmethyl cellulose) on the outside of the spherical core particle (when the water-soluble polymer is coated on the outside of the core particle and the drug is coated on the outside of the core particle, and the core particle) Of the drug on the outside of the core and a water-soluble polymer on the outside) and a three-layer structure (when the water-soluble polymer on the outside of the core particle, the drug on the outside, and the water-soluble polymer on the outside) It is also one of the preferable embodiments of the sphere element granules of the present invention.

As a method for supporting the drug on the spherical core particles, a known method can be used. As an example, a method of continuously spraying an aqueous solution of a binder while at the same time rolling a spherical core particle in a centrifugal fluidized type coating device, and simultaneously spraying a drug powder (containing an excipient if necessary), A method of spraying a liquid in which a drug is dissolved or suspended in a binder aqueous solution while flowing spherical core particles in a fluidized bed coating device (or a rolling fluid type coating device),
While rolling the spherical core particles with a high-speed stirring granulator, a method of adding an aqueous solution of the drug and the binding solution in an amount that can be absorbed by the core particles, a method of immersing the spherical core particles in the aqueous solution of the drug and the binding solution, etc. Can be mentioned. In any of the methods, an operation such as drying and removal of coalesced particles is carried out as necessary to provide a drug dissolution rate adjusting film coating.

The drug loading depends on the dose of drug. For example, in the case of a drug that exerts a medicinal effect in a very small amount, the loading amount is about 0.01% by weight with respect to the spherical core particles, and when a large amount of the drug is required to exert a medicinal effect, the loading amount is about 300% by weight. is there. In the present invention, the general carrying amount is 0.5 to
100% by weight. The film-coated granules of the present invention have a drug dissolution rate adjusting film containing ethyl cellulose, a plasticizer, and a water-soluble polymer on the outside of the spheroid granules.

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 (-O measured by 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). As an 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 use of triethyl citrate, which can reduce the film coating amount, is used. Is preferred. 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 drug dissolution rate adjusting substance used in the present invention, those commonly used in pharmaceutical preparations are used, and examples thereof include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and dextrin. , Pullulan, organic aliphatic or aromatic diols such as polyvinyl alcohol and polyvinylpyrrolidone, all containing polyol, urea, dimethyl sulfone, nicotinamide, gum arabic, sodium alginate, propylene glycol alginate, xanthan gum, aminoalkyl methacrylate Copolymer, methacrylic acid copolymer, alkali metal salt, alkaline earth metal salt, transition metal salt, saccharose such as glucose and lactose It can be mentioned id, sorbitol, mannitol, trehalose and the like. In the present invention, one type or two or more types are used. Of these, the water-soluble polymer gradually elutes from the drug elution rate adjusting film when the film-coated granules come into contact with body fluid such as gastric juice, so that small holes are formed in the film.
That is, the diffusion resistance of the film decreases with time (drug elution).

Usually, in the case of film-controlled sustained release granules used in the present invention, while the concentration of the aqueous drug solution in the film is kept saturated, the drug is proportional to the time of the outside of the film ( It has the drawback that it elutes into body fluids, that is, the elution rate is constant, but the elution rate also decreases as the concentration of the aqueous solution decreases. This is contrary to the purpose of the sustained-release preparation of "maintaining the drug concentration in blood at a constant level for a long time", and has been considered as one of the points to be improved. However, in the present invention, as described above, since the diffusion resistance of the film is gradually reduced, the total amount of the drug is eluted while the dissolution rate is not reduced even if the concentration of the aqueous solution of the drug in the film is decreased. It was possible to let them do it.

Further, it is important that the sustained-release preparation has a limited drug dissolution rate, and it is necessary for the sustained-release preparation to have a sufficiently small change over time as well as variation among products. The limit of variation in the dissolution rate is considered to be within the range where the pharmacological effect is equivalently expressed. As a guideline, for example, "Guidelines for design and evaluation of sustained-release preparations (orally-administered drug)" (Japanese Official Protocol) Ed. By Japan Society for Pharmaceutical Manufacturing, 1992 edition, p107-112 (Yakuji Jihosha))
Is shown in Since the incorporation of water-soluble polymer will eventually increase the drug dissolution rate of the film, increase the film coating amount to obtain the desired sustained release (time to elute the total amount of drug), that is, the drug dissolution rate. The adjustment film will be thickened. When the film is thickened, the mechanical strength is increased, and the storage stability can be improved.

The film strength of the film-coated granules of the present invention is 0.08 kgf or more. When the strength of the film is less than 0.08 kgf, not only the strength is insufficient and change over time easily occurs, but also the film is easily broken, so that the elution rate cannot be controlled. The film strength is
A desired value, that is, 0.08 kgf or more can be obtained by balancing the blending amount of the water-soluble polymer and the film thickness (= coating amount) while considering the dissolution rate.

Further, when the film-coated granules are stored for a long period of time, the phenomenon that the film surface is fused and the granules are lightly blocked may be caused by the influence of the kind and blending amount of the plasticizer. This is often disliked for reasons such as impairing aesthetics, but the incorporation of a water-soluble polymer also has the effect of preventing this blocking, and film coating for preventing further blocking is unnecessary.

The selection and blending amount of the water-soluble polymer depend on the drug dissolution (molecular weight, solubility, osmotic pressure, etc.), formulation design (drug content, dissolution rate, granule size, storage stability, etc.). ) And film strength, but preferably hydroxypropyl cellulose,
One or more selected from hydroxypropylmethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol and polyvinylpyrrolidone are used. The compounding amount is 1 in the drug dissolution rate adjusting film.
5% by weight or more and 30% by weight or less, preferably 18% by weight
To 23% by weight. When the blending amount is 15% by weight or more, the dissolution rate of the drug is easily controlled, and the thickness of the film is sufficiently thick, so that the storage stability is improved. In addition, the anti-blocking effect of the film-coated granules becomes remarkable. If the compounding amount exceeds 30% by weight, the drug dissolution rate adjusting film layer may be rapidly disintegrated and the dissolution rate may not be sufficiently controlled.

In the present invention, as a film coating agent for forming a drug dissolution rate adjusting film, it contains spherical solid particles containing ethyl cellulose as a main component and having a diameter of substantially 1 μm or less, a plasticizer, and a drug dissolution rate adjusting substance. A water dispersion 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 the amount is 0.5% by volume or less. Smaller spherical solid particles are preferred, but the distribution is 95 vol% or more for particles with a diameter of 0.6 μm or less, and 75 vol% for particles with a diameter of 0.5 μm or less.
As described above, the content of 0.4 μm or less is preferably 1% by volume or more. “Sphericality” of spherical solid particles means that the sphericity is 0.
It means 7 or more, and more preferably 0.8 or more.

As auxiliary components other than ethyl cellulose,
It is encapsulated in spherical solid particles or presents in a complexed state, and is an auxiliary agent necessary for producing an aqueous dispersion of spherical solid particles, or maintains the dispersion stability of spherical solid particles in water. It is an auxiliary agent required for the purpose, or an auxiliary agent 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 aqueous dispersion of ethyl cellulose has a minimum minimum film forming temperature which is too high for practical use. 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. . When the amount of the plasticizer is large, separation (bleeding) occurs after film formation,
It has a drawback that 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 can be small, the change over time can be minimized.

In the film coating agent for forming the drug dissolution rate controlling film, 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 of the plasticizer is dissolved in water. The substance to be dissolved and used as the drug dissolution rate adjusting substance is in a state of being dissolved or dispersed in water. Optionally an aminoalkyl methacrylate copolymer,
Aqueous dispersion such as methacrylic acid copolymer, or
It may contain auxiliary agents used for ordinary film coating, such as dispersion stabilizers such as aqueous ammonia, talc, light anhydrous silicic acid, titanium oxide, corn starch, additives for film coating such as crystalline cellulose, and the like.

Aqueous dispersions of spherical solid particles of ethyl cellulose are produced by various methods, for example Pharmaceucia.
Optical Technology, Vol. 11,
No. 3, p56-68 (1987), the emulsion-solvent evaporation method or the phase inversion method. For example, "Aq" manufactured by FMC (US)
uacoat ”ECD-30 and the like. In addition, Colo supplied with a plasticizer mixed in advance
"Surelease" from rcon (USA) can also be mentioned as an example of the water dispersion used in the present invention.

The thickness (coating amount) of the drug dissolution rate adjusting film is determined by the drug dissolution property, formulation design and film strength, and as described above, is greatly influenced by the blending of the water-soluble polymer. However, the thickness is preferably 30 μm or more. 30 μm
Below, 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.

A method for forming a drug dissolution rate adjusting film by coating spherical granules with a film coating agent is a fluidized bed type coating device (eg, "Flow Coater" manufactured by Freund Sangyo Co., Ltd.) with a Wurster column. Fluidized bed type coating equipment (eg, Glact GPCG)
Series), centrifugal fluidized coating equipment (eg, "CF-Granulator" manufactured by Freund Sangyo Co., Ltd.), tumbling fluidized coating equipment (eg, "Multiplex" manufactured by Paulec, Fuji Paudal Corporation) A general-purpose method using "New Marmelizer" manufactured by Freund Sangyo Co., Ltd., "Spiraflow" manufactured by Freund Industrial Co., Ltd., "Flow Coater" with the same "rotor container", and the like can be used. Particularly preferably, a rolling fluid type coating device is used, and more preferably a method of spraying a film coating agent in a tangential direction for rolling motion of the device.

The rolling fluid type coating device has a substantially cylindrical space, a disc for rolling the particles to be coated and a slit or a small hole for supplying warm air at the bottom, and the upper part at the top. It has an exhaust port (usually with a bag filter) for discharging hot air, and a spray nozzle for spraying the film coating liquid is from the top to the bottom, or the disk at the bottom of the approximately cylindrical space rotates. Mounted tangentially. 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) However, any device may be used in the present invention. A particularly preferred device is the aforementioned "multiplex".

The reason why the rolling fluid type coating device is preferable is that it is possible to form a dense drug dissolution rate adjusting film with time. The mechanism is probably due to the fact that the spherical particles are given rolling action by the disc in addition to the flow action by the warm air, so that the coating agent attached to the spherical particles is well spread before it is dried, and as a result, it is more dense. It is considered that a film for adjusting drug dissolution rate is formed. Especially when spraying the film coating in the tangential direction for the rolling motion of the disc, the distance from the tip of the spray nozzle to the spherical elementary granules is short, and the particles adhere with sufficient moisture, so the adhesion efficiency is high and the subsequent spreading The spreading effect is also enhanced, which is preferable. The "multiplex" spray nozzle is equipped with a mechanism that allows air to flow to the outside in the same direction as the spray. In addition to preventing non-coating particles from adhering, this air also prevents film coating agents from adhering.
It is particularly preferable because it has a function of well adhering the sprayed droplets to the sphere-shaped granules and a function of well rolling-flowing the sphere-shaped granules.

The particle size distribution of the film-coated granules thus obtained is preferably substantially within the range of 75 to 600 μm. More preferably 75 to 5
It is within the range of 00 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 600 μm to the extent that the aforementioned advantages are not impaired, that is, 10 particles less than 75 μm.
It means that the content of particles is not more than 5% by weight, but not more than 5% by weight (however, about 850 μm at maximum).

Whether the film-coated granules of the present invention are dosed as they are, or filled into capsules, or mixed with other drugs,
Alternatively, it is used by mixing it with granules containing other excipients, drugs or drugs, or film-coated granules, and then tableting them into tablets. As mentioned above, it is also possible to administer the drug by mixing it with a food product, a tube liquid food, or the like.

[0035]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in detail with reference to examples. The methods for measuring the physical properties of spherical core particles and the like are as follows. (1) Spheroidal granules, spherical core particles, sphericity of spherical solid particles containing ethyl cellulose as a main component [-] The particle shape was photographed using an optical microscope, an electron microscope, etc. Ratio of major axis (minor axis / major axis)
The average value of was taken. (2) Average degree of polymerization of crystalline cellulose [-] INDUSTRIAL AND ENGINEERIN
G CHEMISTRY Vol. 42, no. 3 p
Measured by the copper ammonium solution viscosity method described in 502 to 507 (1950). If necessary, the sample was ground in a mortar and then used for measurement. (3) Water absorption capacity of spherical core particles [g / g] 30 g of distilled water was added to 10 g of spherical core particles (converted to dry matter), and the mixture was allowed to stand at room temperature for 1 hour and then collected by filtration. Then, the weight was measured and the water content was divided by 30. The number of repetitions was 5, and the average value was taken. (4) Tapping apparent density of spherical core particles [g / cm ³ ] 30 g of spherical core particles is loosely filled in a 100 cm ³ glass graduated cylinder and placed on a table with a low impact such as a desk laid with a rubber plate. , Tapping by hand. The tapping is performed by dropping it from a height of several cm perpendicularly to the table until the compaction of the particle layer stops. After tapping, the volume of the particle layer is read and divided by 30. The number of repetitions was 3, and the average value was taken. (5) Friability of spherical core particles [%] 10 g of spherical core particles were charged into a Kagaki-type friability measuring device, and 2
Rotate at 5 rpm for 15 minutes, and measure and calculate the weight loss rate due to pulverization. The number of repetitions was 3, and the average value was taken. (6) Particle size distribution of spherical core particles, spherical particles, and film-coated granules [% by weight] JIS standard sieve (Z8801-1987) with a low-tap type sieve shaker (manufactured by Hiraiko Seisakusho: Sieve Shaker A type)
The particle size distribution was measured by sieving 30 g of the sample for 30 minutes using a. (7) Thickness of film for adjusting drug dissolution rate [μm] The 50% cumulative particle size was obtained from the particle size distribution [wt%] of spherical particles and film-coated granules, and the film thickness was calculated from the difference between the two. . (8) Particle size distribution of spherical solid particles containing ethyl cellulose as a main component [volume%] The aqueous dispersion of the sample was diluted with water to a concentration showing an appropriate transmittance, ultrasonically dispersed for 1 minute, and then stirred. A laser diffraction type particle size distribution analyzer (manufactured by Horiba, Ltd., LA-9) under the conditions of a relative refractive index of 1.2 and the number of incorporations of 10 times.
10 type) to determine the volume-based particle size distribution. (9) Film strength A film coating agent for forming a drug dissolution rate-adjusting film is applied on a glass plate and then at 80 ° C. for 1 hour.
A heat film forming process was performed to prepare several kinds of films having different thicknesses of 30 to 100 μm. Width of the resulting film 10
mm, length 50 mm, crosshead speed 50 mm / min, TENSIRON (TOYO BALDWIN
CO ,. The breaking strength was measured with LTD, UTM-4-100 type). The relationship between the breaking strength obtained from the measurement of the film at 10 points or more and the thickness of the provided film is linearly regressed by the least squares method, and the breaking strength corresponding to the obtained drug preparation film thickness is calculated, The film strength was used.

[0036]

Example 1 Spherical core particles (manufactured by Asahi Kasei Kogyo Co., Ltd., “Celphia” CP-30) were added to a rolling fluid coating device (manufactured by Paulec Co., Ltd., “Multiplex” MP-25 type).
5) was charged and sprayed with 10 parts of riboflavin, 2 parts of hydroxypropyl cellulose (L type manufactured by Nippon Soda Co., Ltd.), and 88 parts of water to spray the drug coating solution, and the riboflavin content was 2% by weight.
Spheroidal granules having a sphericity of 0.9 were obtained. Table 1 shows the physical properties of the spherical core particles used, and Table 2 shows the particle size distribution of the obtained spherical elementary granules.

Next, an aqueous dispersion of ethyl cellulose ("Aq
uacoat "ECD-30, solid content concentration: 30%, F
Manufactured by MC, 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 30 parts, water 35.6 parts A film coating solution consisting of a ratio was prepared, and a rotating plate rotation speed: 380 rpm, using a multiplex, for 1.5 kg of the above-mentioned elementary granules.
Using tangential bottom spray, spray air pressure: 1.6 kgf / cm ² , spray air flow rate:
40 L / min, supply air temperature: 75 ° C, exhaust air temperature: 36
° C, air volume: 75 m ³ / hr, coating liquid supply rate:
The solid content of the coating liquid was 30.0, 40.0, 50.3 for the elementary granules under the condition of 21 g / min.
It was coated in an amount of 61.4% by weight. The coated granules thus obtained were dried on a tray at 50 ° C. for 30 minutes,
Further curing at 80 ° C for 60 minutes (heating film forming process)
did.

The solid particles in the "Aquacoat" used were spherical and the particle size distribution is shown in Table 3. Dissolution rate [%] of the drug is from JASCO Corporation, automatic dissolution tester D
It measured by the paddle method (100 rpm) using T-600. The test solution used was the test solution No. 1 of the 12th Revised Japanese Pharmacopoeia General Test Method Disintegration Test Method. The measurement was performed 3 times, and the average value was taken.

The results of coating amount and riboflavin elution amount are shown in FIG. As shown in the figure, the main drug was eluted with almost no change in the dissolution rate. Also, the coating amount is 5
FIG. 2 shows the change in elution after 0.3% (particle size distribution is shown in Table 4. Film thickness: 39 μm) was placed in a reagent glass bottle and stored at 60 ° C. for 2 months. As shown in the figure, there was almost no change in the elution amount before and after storage. In addition, the particles in the glass bottle for reagents after storage were lightly blocked, but they were easily broken by shaking the bottle.

The regression equation for obtaining the film strength is
0.00202 × A + 0.0128 = B (A: film thickness, B: film strength), and the coating amount is 5
The film strength of 0.3% is 0.0916kgf
Met.

[0041]

[Comparative Example 1] The composition of the film coating liquid was as follows: 38 parts of ethyl cellulose aqueous dispersion, triethyl citrate 2.9
Part, hydroxypropylmethylcellulose 10% aqueous solution 7 parts, and water 52.1 parts, except that film-coated granules were prepared in the same manner as in Example 1. The particle size distribution of the obtained coated granules is shown in Table 5, and the results of the coating amount and the riboflavin elution amount are shown in FIG. As shown in the figure, when the elution rate is 50% or more, the elution rate extremely decreases.

The change in elution after a coating amount of 5.0% (particle size distribution is shown in Table 5. Film thickness: 5 μm) was placed in a reagent glass bottle and stored at 60 ° C. for 2 weeks was shown. As shown in FIG. As shown in the figure, elution was accelerated after storage. In addition, the particles in the reagent-use glass bottle after storage were blocked, and the particles were difficult to be loosened.

The regression equation for obtaining the film strength is
0.00913 × A + 0.00877 = B (A: film thickness, B: film strength), and the film strength of a coating amount of 5.0% is 0.0544 kgf
Met.

[0044]

[Table 1]

[0045]

[Table 2]

[0046]

[Table 3]

[0047]

[Table 4]

[0048]

[Table 5]

[0049]

The film-coated granules of the present invention are
The drug elution rate is almost constant regardless of the elution time, the rate does not change even after long-term storage, and there is no blocking of the granules. Therefore, it is very suitable as a sustained release granule.

[Brief description of the drawings]

FIG. 1 is a coating amount of Example 1 ranging from 30.0% to 61.
It is an dissolution diagram of the main drug in the dissolution test of coated granules up to 4%.

FIG. 2 is a dissolution diagram of the main drug in a dissolution test before and after storage of coated granules having a coating amount of 50.3% of Example 1.

FIG. 3 Coating amount of Comparative Example 1 5.0% to 10.0
FIG. 4 is a dissolution diagram of the main drug in a dissolution test of coated granules up to%.

FIG. 4 is an elution diagram of a main drug in a dissolution test before and after storage of coated granules having a coating amount of 5.0% in Comparative Example 1.

Claims (10)

[Claims] 1. A drug-eluting rate adjusting film is formed in a film-coated granule having a drug-containing spheroidal granule and a drug-eluting rate adjusting film containing ethyl cellulose, a plasticizer and a drug-eluting rate adjusting substance on the outside thereof. The film coating agent for use in the present invention is an aqueous dispersion containing spherical solid particles containing ethyl cellulose as a main component and having a diameter of substantially 1 μm or less, a plasticizer, and a drug dissolution rate adjusting substance, and the film strength formed by this dispersion is 0. .0
A film-coated granule having a weight of 8 kgf or more. 2. A spheroidal granule containing a drug comprises a drug and a spherical core particle, and the core particle comprises crystalline cellulose.
The film-coated granule according to claim 1, wherein the film-coated granule is a spheroidal granule containing at least wt%. 3. The drug dissolution rate adjusting substance is one or two or more kinds selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol and polyvinylpyrrolidone, and 1 in the drug dissolution rate adjusting film.
The film-coated granules according to claim 1 or 2, which are contained in an amount of 5% by weight or more and 30% by weight or less. 4. The drug dissolution rate adjusting film has a thickness of 30.
The thickness is at least μm.
The film-coated granules described. 5. The particle size distribution has a size substantially in the range of 75 to 600 μm.
Or the film-coated granule according to item 4. 6. A method for producing a film-coated granule having a drug-containing spheroidal granule and a drug-eluting rate adjusting film containing ethyl cellulose, a plasticizer and a drug-eluting rate adjusting substance on the outside thereof, wherein the drug-eluting rate is adjusted. The film coating agent for forming a film is based on ethyl cellulose and has a diameter of substantially 1 μm.
It is an aqueous dispersion containing the following spherical solid particles, a plasticizer and a drug dissolution rate adjusting substance, and characterized in that the spherical particle granules are coated with a drug dissolution rate adjusting film using a rolling fluid type coating device, A method for producing film-coated granules. 7. The strength of the drug dissolution rate adjusting film is 0.
The method for producing film-coated granules according to claim 6, wherein the weight is 08 kgf or more. 8. A spheroidal granule containing a drug comprises a drug and a spherical core particle, and the core particle comprises crystalline cellulose.
The method for producing film-coated granules according to claim 6 or 7, wherein the spherical granules are contained in an amount of at least wt%. 9. The drug dissolution rate adjusting substance is one or two or more kinds selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol and polyvinylpyrrolidone, and 1 in the drug dissolution rate adjusting film.
The method for producing film-coated granules according to claim 6, 7 or 8, wherein the content is 5% by weight or more and 30% by weight or less. 10. The method for producing film-coated granules according to claim 6, wherein the film coating agent is sprayed in a tangential direction for rolling motion of a rolling fluid type coating device.