JPH0987203A - Medicine-containing granule and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine-containing granule uniform in diameter, high in sphericity, excellent in medicine content uniformity, ability to mask both the taste and odor inherent in the medicine and medicine release-controlling ability, thus useful as e.g. a pharmaceutical preparation for oral administration, by carrying a medicine inside specific porous granule. SOLUTION: This granule is obtained by carrying (B) a medicine inside (A) porous granule made of a cellulose-based material such as (regenerated) cellulose or cellulose derivative (e.g. <=1.2 in sphericity, 50-1,000μm in number- average granular diameter, the respective dismeters of ∞90% of the total granules fall within the range of the number-average granular diameter ±20%, and >=1.5 in swelling degree) followed by, if necessary, coating the surface of the granules with a coating agent such as an enteric coating agent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention is useful for producing a granule preparation or fine granule preparation in which the release of a drug is controlled, the unpleasant taste or odor of the drug is corrected, and the discomfort upon administration is reduced. The present invention relates to a drug-containing particle carrying a drug and a method for producing the same.

[0002]

2. Description of the Related Art Conventionally, various pharmaceutical compositions have been devised for the purpose of controlling the release of a drug or masking a drug when it has an unpleasant taste or odor. These controlled-release pharmaceutical compositions have a reduced number of doses,
There are advantages such as improvement of dose compliance, reduction of side effects by suppressing a sharp increase in drug blood concentration, and maintenance of a therapeutic effect by maintaining a constant blood concentration for a long time.

The formulation forms include capsules, tablets,
Granules have been reported, but especially granules or fine granules
Because of its ease of administration, good dispersibility in the digestive tract, and small difference in gastric emptying rate and drug absorption between individuals, it is used as it is, or in capsules, or in tablets. In adding release control ability to these granules and fine granules, or masking taste and odor,
When coating the granules or fine particles themselves,
The capsules or tablets containing them are roughly classified into those which are subjected to pharmaceutical processing such as coating. In recent years, the granules or fine particles themselves have been coated in order to make better use of the above characteristics of the granules or fine particles. There is an increasing demand for types of formulations. Then, as a method for producing granules or fine granules which are subjected to pharmaceutical processing such as a film, a stirring granulation method, an extrusion granulation method, a fluidized granulation method and the like are known.

Furthermore, in recent years, a method for producing small-diameter particles containing a drug intended to be used as fine granules having excellent ingestion feel and miscibility with other excipients has been developed. . A method for producing these particles is described in JP-A 1-2
No. 72643, No. 1-106817, No. 4-321621, No. 4-327528.
Japanese Patent Laid-Open No. 5-194275 and Japanese Patent Laid-Open No. 5-194275 report that a drug is supported in the pores of porous particles, and the outer surface of the drug is coated or sealed as necessary. There is.

[0005]

However, there is a problem with the conventional one. That is, a porous particle produced by a method such as a stirring granulation method, an extrusion granulation method, and a fluidized granulation method generally has a wide particle size distribution and its sphericity (the ratio of the major axis / minor axis of the granule is It has been pointed out that there is a problem in the use as granules or fine particles whose outer surface is coated with a coating agent, such as a low level (expressed). The particles produced by these granulation methods generally have a large particle size and are not always sufficient when used as fine particles. Further, JP-A-1-272643, JP-A-1-106817, JP-A-4-321621, and JP-A-4-327.
No. 528 and Japanese Patent Laid-Open No. 5-194275, ie, particles in which a drug is supported on porous particles composed of crystalline cellulose, amorphous cellulose, chitin, etc., the particle size distribution is Widely, 90% or more of the porous particles do not fall within ± 20% of the number average particle size,
In addition, it is difficult to say that it has sufficient sphericity, etc., from the viewpoint of use in pharmaceuticals. Therefore, the present invention has a uniform particle diameter and is suitable for forming a film for the purpose of imparting release control ability, masking, etc. due to its high sphericity, or the content of the drug in encapsulation and tableting. An object of the present invention is to provide fine particles containing a drug with less variation and less discomfort during administration.

[0006]

Means for Solving the Problems As a result of intensive studies by the present inventors, the porous particles are made of a cellulosic material such as cellulose, a cellulose derivative or regenerated cellulose having a small particle size distribution and a high sphericity. Due to the drug-containing particles in which the drug is carried in the pores of the porous particles, the particle size is uniform, the sphericity is high, and the drug content varies little.
Furthermore, they have found that it is possible to prepare fine particles useful as granules or fine particles suitable for applying a film for controlling release of a drug or masking taste, odor, etc.
The present invention has been completed.

The object of the present invention can be solved by the following drug-containing particles and a method for producing the same. That is,
It is a drug-containing particle in which a drug is carried inside porous particles made of a cellulosic material such as cellulose, a cellulose derivative or regenerated cellulose. In the drug-containing particles, 90% or more of the porous particles are ± 20% of the number average particle size.
Or the number average particle diameter of the porous particles is 50 to 100
It can be 0 μm, the sphericity of the porous particles is 1.2 or less, and the swelling degree of the porous particles is 1.5 or more. Furthermore, the drug-containing particles can be coated on the outer surface with a coating agent. Then, such drug-containing particles can be used as a granule preparation, a fine granule, a capsule filled in a capsule, or a tablet obtained by compression-molding with an excipient.

[0008] Porous particles made of a cellulosic material such as cellulose, cellulose derivative or regenerated cellulose are immersed in a solution or dispersion containing a drug, and the drug is impregnated inside the particles and dried to carry the drug. This is a method for producing drug-containing particles. Cellulose, a cellulose derivative, or a porous particle made of a cellulosic material such as regenerated cellulose, a solution or a dispersion liquid containing a drug is dropped, the drug is impregnated inside the particle and dried to support the drug. And a method for producing drug-containing particles. By mixing the porous particles made of a cellulosic material such as cellulose, a cellulose derivative or regenerated cellulose with a powdery drug, and filling the powdery drug in the pores of the porous particle, the drug is contained inside the particle. It is a method for producing drug-containing particles, which comprises: Porous particles made of a cellulosic material such as cellulose, a cellulose derivative or regenerated cellulose and a drug having sublimability are mixed and housed in a closed container, and the drug is sublimated and adsorbed on the pore surface of the porous particles. This is a method for producing drug-containing particles in which a drug is supported inside the porous particles. Also,
This is a method for producing drug-containing particles, which comprises supporting a drug inside the porous particles and further coating the outer surface with a coating agent.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Cellulose is one in which a large number of glucose, which is a monosaccharide, is polymerized to form a polymer and exists as a polysaccharide. Therefore, the cellulose in the present invention is a so-called natural type cellulose, and examples thereof include defatted cotton fibers, pulp obtained from hemp and wood, and purified cellulose obtained by purifying the pulp. . The cellulose derivative is derived from cellulose in which some or all of the hydroxyl groups of the cellulose are esterified or etherified. Specific examples where the hydroxyl groups of the cellulose are partially or wholly esterified, for example, cellulose acetate, cellulose propionate, nitrocellulose, cellulose phosphate, cellulose acetate butyrate, cellulose nitrate,
Examples thereof include, but are not limited to, cellulose dithiocarboxylic acid ester (viscose rayon) and the like. Specific examples of the etherified part or all of the cellulose, for example, methyl cellulose,
Examples thereof include, but are not limited to, ethyl cellulose, benzyl cellulose, trityl cellulose, cyanoethyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, aminoethyl cellulose, oxyethyl cellulose and the like.

[0010] Further, regenerated cellulose is a cellulose derivative which can be easily molded once, is molded and then converted into cellulose again. Specifically, it is prepared by hydrolyzing an ester derivative of cellulose such as cellulose acetate or cellulose propionate, but is not limited thereto.

The porous particles used in the present invention are porous particles composed of a cellulose-based material such as the above-mentioned cellulose, cellulose derivative, regenerated cellulose and having a uniform particle size and a high sphericity. For example, a polymer solution in which a cellulosic material such as cellulose or a cellulose derivative is dissolved is disclosed in, for example, JP-A-62-191033.
It is manufactured by applying the apparatus and method (method combining vibration method and dry-wet coagulation method) described in the publication.

Therefore, the method for producing the porous particles made of this cellulosic material will be described in detail below. In this method, a polymer solution having a predetermined viscosity in which a cellulosic material such as cellulose or a cellulose derivative is dissolved is extruded from a nozzle having a small diameter while directly applying a vibration having a predetermined frequency to a liquid having a uniform particle size. It forms droplets and solidifies them. FIG. 1 is a sectional view of a part of an apparatus used for producing porous particles made of this cellulosic material. This method uses a highly viscous polymer solution and a small pore size nozzle (5),
A relatively large jet pressure is required for the polymer solution.
Therefore, a method of inserting a vibrating rod (6) into the cylinder (2) is adopted in order to apply a cyclically changing pressure to the polymer solution. The vibrating rod (6) is connected to an appropriate vibration generating source, for example, a magnetostrictive element, an electrostrictive element or an electromagnetic coil type vibrator. In order to efficiently transfer these vibrational energy to the vibrating rod (6), an O-ring (7) with low contact resistance is used for the seal with the cylinder (2).
The distance between the nozzle (5) and the tip of the vibrating rod (6) is
It can be adjusted arbitrarily with the screw (11) of (2) and the nut (4) for fixing the cylinder. Nozzle (5) is a nut for fixing the nozzle
It is fixed to the cylinder (2) by (3), and the O-ring (8) is sealed between the nozzle (5) and the cylinder (2). The cylinder (2) is fixed to the fixed base (1) by a cylinder fixing nut (4).

A polymer solution of a cellulosic material sent from a gear pump or the like enters the cylinder (2) from the liquid inlet (9) and is periodically moved by the reciprocating motion of the vibrating rod (6) on the nozzle (5). It is ejected from the nozzle (5) under the pressure change. Using this device, the polymer solution can be applied to nozzles while applying pressure that changes periodically at various frequencies.
It can be ejected from (5). Further, in order to maintain the resonance frequency more stably, a cooling water inlet / outlet (10) can be provided on the fixed base (1) if necessary. The nozzle (5)
Usually a multi-hole nozzle is used. Nozzle (5) and vibrating rod (6)
The distance to the tip is preferably 5 mm or more, especially when the frequency is high enough to be included in the ultrasonic region. If this distance is less than 2 mm, cavitation may occur in some cases, and the tip of the vibrating rod (6) and the inner surface of the nozzle (5) may be roughened. The frequency of vibration for obtaining stable fine uniform droplets is several thousands to several tens of thousands Hz, preferably 3,000 to 5,000.
It is 40,000 Hz. The vibration frequency of the vibrating rod is about 300
If it is less than 0 Hz, uniform droplets will not be formed even if other ejection conditions such as the amplitude of the vibrating rod and the ejection speed are changed. On the other hand, in the region where the frequency is large, uniform droplets can be obtained by appropriately adjusting the jetting conditions of the solution even if a high viscosity polymer solution is used. However, if the frequency exceeds several tens of KHz, the distance between adjacent droplets becomes extremely small and the frequency of collision between droplets increases, making it difficult to obtain uniform droplets. Once formed, the uniform droplets move away from the nozzle (5) and move turbulently due to air resistance, and many droplets collide with each other and recombine. However, this recombination can be prevented for a relatively long time if each droplet is charged with the same sign. Whether or not the droplet diameter is uniform can be confirmed by a conventional method. That is, the flashing cycle of the stroboscope may be synchronized with the droplet generation cycle to take a photograph and measure the diameter of each droplet.

In the present invention, the viscosity of the polymer solution of the cellulosic material is 50 to 2000 cP. If this viscosity exceeds 2000 cP, the jet pressure will be too high, and not only will the device be specially designed,
In many cases, it is possible to obtain droplets that can be used in the application of the present invention without using a polymer solution having such a high viscosity. As described above, the viscosity is 50 to 2000 cP
By directly ejecting the solution of (3) from the nozzle while directly applying vibration with a frequency of 3000 to 40,000 Hz, droplets having a uniform particle size are formed.

The solvent used for preparing such a polymer solution is a solvent for cellulose, for example, an aqueous solution of copper ammonia, a mixed solution of dimethylsulfoxide and formamide, an aqueous solution of calcium thiocyanate, and typical cellulose. Examples thereof include solvents such as cellulose acetate, which is a derivative, such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, and acetone. Furthermore, in these solvents, methanol, ethanol, ethylene glycol, propylene glycol, glycerin, water,
Inorganic salts, polyethylene glycol, etc. may be added.
The polymer solution prepared in this manner has the same structure as that shown in FIG.
No. 62-191033 disclosed in Japanese Patent Application Laid-Open No. 62-191033, the droplets are ejected into the gas phase as uniform droplets, and are made to fly over a flight distance that is almost spherical, and then contacted with a coagulant. As the particles, the porous particles made of the cellulosic material are isolated from the coagulant to produce porous particles having 90% or more of the particles within ± 20% of the number average particle diameter. The porous particles produced here can be used for producing the drug-containing particles either in a state of being dispersed in water or a solvent or in a state of being dried after isolation.

The coagulant is composed of a non-solvent for the polymer, but it is preferable that the coagulant has a surface tension such that the coagulant dissolves in the solvent forming the droplet and the droplet naturally wets. Specific examples of such a coagulant include water, a mixed liquid of water and the good solvent or non-solvent, a mixed liquid of water and a surfactant, and the like.

The porous particles composed of regenerated cellulose are obtained by hydrolyzing particles composed of a cellulose derivative prepared by the above-mentioned method from a cellulose derivative such as cellulose acetate prepared from cellulose. Manufactured.

Conventionally, it has not been known that the porous particles produced as described above are used in the field of formulation. However, as a result of the study by the present inventors, the porous particles obtained by the above-mentioned production method have the ability to carry a sufficient drug in their pores, and even if the drug is carried in the pores. In addition, since it is uniform and has a particle shape with high sphericity,
It has been clarified that the drug-containing particles produced by using the present particles are extremely excellent in use as a granule or fine granule form.

The amount of the porous particles according to the present invention carried by the drug,
The particle strength is adjusted by the size of the pores inside the particles, that is, the pores of the network structure inside the particles. That is, the larger the network structure formed inside the particles when they are brought into contact with the coagulant, the larger the drug-carrying amount of the manufactured porous particles becomes, but the relative particle strength decreases. The size of the pores of the network structure is adjusted by adjusting the polymer concentration in the polymer solution, adding a poor solvent or an additive that can be easily extracted and removed into the polymer solution, and the like. Generally, the higher the polymer concentration in the polymer solution, the more
It is known that the pores of the three-dimensional network structure become smaller.
In addition, in the addition of a poor solvent for the purpose of adjusting the pore size of the network structure, or in the addition of an additive, the pore size of the network structure is adjusted depending on the type and amount of the additive used. It is possible. Specific examples of the poor solvent and additive include methanol, ethanol, ethylene glycol, propylene glycol, glycerin, water, inorganic salts, polyethylene glycol and dextran, and the viscosity of the polymer solution to be adjusted is in the range of 50 to 2000 cP. Can be added to.

Further, when the porous particles are isolated and dried from the coagulating liquid and then used, the drug loading amount and the particle strength of the porous particles are also controlled by the drying method. That is, the amount of the drug loaded and the particle strength are adjusted depending on the degree of retention of the network structure inside the particles during drying. That is, when the liquid contained in the porous particles made of a cellulosic material is replaced with alcohol or the like and then dried under slow conditions such as carbon dioxide gas critical point drying, it has a relatively high drug loading, A relatively low drug loading is obtained when particles with low particle strength are obtained, and after the liquid inside the particles is replaced with a solvent such as alcohol, or when drying is performed using reduced pressure or heating without replacement, or both, However, particles having a relatively high particle strength can be obtained.

Next, the loading of the drug on the porous particles made of the above cellulosic material will be described. The drug is dissolved or dispersed in a solvent or water, and the present solution or dispersion is impregnated inside the porous particles having pores. When the porous particles are in a wet state, that is, when the pores of the particles are filled with water or a solvent, the particles are immersed in a solution or dispersion containing a drug, and the drug-containing solution or dispersion is placed in the pores. After sufficiently permeating, the drug can be supported by isolating and drying. Further, in the dry state of the particles, as in the case of the wet particles, the particles are immersed in a solution containing a drug or the solution or dispersion is dropped to the particles, and the solvent is allowed to penetrate into the inside of the porous particles. It is possible by removing In the latter case,
Place the porous particles in a tumbling granulator, agitation granulator, fluidized granulator or centrifugal fluidized granulator, add the solution containing the drug, and then dry it to load the drug into the pores of the particles. can do. In the case of a liquid having a low viscosity, the drug can be loaded by performing the above operation without using a solvent. When increasing the amount of the drug loaded, the above steps are repeated. In order to dry the porous particles after impregnating or permeating the drug in this way, a drying method such as reduced pressure drying or freeze drying can be performed.

When the drug has low solubility in water or a solvent, it can be loaded by mechanical impact.
The method is to fill the fine particles in the pores of the porous particles. To fill it, the drug can be supported by mechanical impact, and specifically, it can be adsorbed by a ball mill type or rolling compaction type device in a dry method or by inserting an appropriate solvent. is there.

When the drug has a subliming property, the drug is sublimated by physically mixing the drug and the porous particles and leaving them in a sealed container, and the drug is adsorbed on the surface of the pores of the porous particles to carry the drug. To be done. In this case, depending on the sublimability of the drug, at least one of heating and depressurization can be performed to carry the drug in a short time.

The drug carried on the porous particles is not particularly limited as long as it can be administered as granules or fine particles. For example, as the central nervous system drug, diazepam, aspirin, ibuprofen, paracetamol,
Naproxen, piroxicam, diclofenac, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen, etenzamid, ketoprofen, azelastine, etc., as cardiovascular drugs diltiazem, molsidomine, vinpocetine,
Proluranol, methyldopa, dipyridamole, furosemide, nifedipine, atenolol, pindolol, captopril, etc., respiratory agents such as amrenoxax, dextromethorphan, theophylline, pseudoephedrine, salbutamol, etc., and digestive agents cimetidine, ranitidine , Pancreatin, 5
-Aminosalicylic acid, predzolone and the like, antibiotics and chemotherapeutic agents cephalexin, cefaclor, cefradine, amoxicillin, erythromachine, lincomycin, trimethoprim and the like, metabolic drugs serapeptase, glibenclamide and the like, vitamin-based drugs Is vitamin B1, vitamin B2, vitamin B
6, Vitamin B12, Vitamin C, fursultiamine, etc. are mentioned respectively. The amount of the drug loaded on these porous particles varies depending on the type of the drug, but can be generally 1 to 80% by weight. Further, various forms such as powder, fine powder and liquid can be used as the form of the drug used in the present invention.

As described above, the porous particles according to the present invention, that is, the cellulosic porous particles have a pore structure inside the particles capable of supporting a sufficient amount of the drug both in a wet condition and a dry condition, and Since the particle size is uniform and the sphericity is high, these characteristics are maintained even after the drug is loaded inside the pores, and therefore there is no need for a sizing step in the use as a formulation, and It is extremely useful in the production of coated granules or fine particles for the purpose of controlling drug release.

It is desirable that 90% or more of the cellulose-based porous particles used as the porous particles are within ± 20% of the number average particle diameter. The particle size distribution of the drug-containing particles produced by the porous particles having a wide particle distribution width of less than 90% is wide, and when the capsules are filled and used as granules or fine particles, the amount of the drug contained in the produced capsules is limited. There are variations. Further, when coating these drug-carrying particles for the purpose of controlling drug release, there is a problem that the uniformity of the coating layer is impaired.

The average particle size of the cellulosic porous particles used here is a number average particle size of 50 to 1 depending on the desired size of granules, fine particles or the kind and amount of the drug to be contained.
It can be appropriately selected within the range of 000 μm. 300 to 1000 μm for the purpose of producing a granular preparation,
It is desirable to use particles preferably in the range of 400 to 800 μm. 50 for the production of fine granules
It is desirable to use particles in the range ˜500 μm, preferably 100-300 μm.

When the porous particles are used as fine particles, if the particle size is smaller than 50 μm, the amount of the drug carried is not sufficient, and problems such as agglomeration occur during the process of preparation. On the other hand, when it is 500 μm or more, the drug-containing particles produced have a large particle size and are poor in miscibility with other excipients, which causes a problem when used as a dispersible powder which is difficult to take.

The sphericity of the cellulosic porous particles used here is preferably 1.2 or less. The sphericity is 1.
When it is higher than 2, the fine particles containing a drug produced by using the fine particles have a low sphericity, and in the uniform coating for the purpose of aesthetic appearance of the product or controlling the release of the drug, masking the taste and odor, the coating layer is It is not preferable because the uniformity is low and agglomeration between particles occurs.

Further, since the porous particles according to the present invention have water swelling property in a dry state, the drug component is rapidly eluted after a certain lag time, and the drug release is sustained for a certain time or more, It is possible to produce granular or fine granules with a so-called sigmoidal dissolution pattern. The degree of swelling in the present invention means that a graduated cylinder is filled with a certain amount of volume (apparent volume) while tapping porous particles made of a cellulosic material, a sufficient amount of water is added, and the swelled volume after leaving for 1 hour (apparent volume) The volume) is measured and the rate of increase in the volume is shown. Therefore, the swelling degree of the cellulosic porous particles is preferably 1.5 or more. If it is less than 1.5, the drug-containing particles produced have a swelling sufficient to destroy a coating layer formed by coating a water-insoluble non-melting substance such as talc with a small amount of a wax component as a binder on the surface after a predetermined time. The production of granular or fine granules with a certain degree is extremely difficult.

The drug-containing particles of the present invention obtained as described above may be used as they are as a granule preparation or a fine granule, or as a capsule containing these particles in a capsule or compressed with an excipient. It is also molded and used as tablets.

In the case of a capsule, it is produced by filling particles containing the above-mentioned drug into a capsule made of gelatin or the like by a known method. The capsules produced can be coated by a known coating agent and its coating method according to the purpose of taste masking, gastric solubility, enteric solubility, sustained release, etc. As the coating agent used at this time, ethyl cellulose, a water-insoluble coating agent such as shellac, an enteric coating agent such as hydroxypropylcellulose, hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose acetate, an acrylic acid polymer, or a colon-degradable coating agent. And so on.

Tablets may be prepared by using the particles described above and excipients such as lactose, crystalline cellulose and starch by a known method, or a mixture of these particles and excipients, if necessary, with a low-substituted hydroxypropylcellulose. , Disintegrants such as carboxymethyl cellulose, lubricants such as talc, 4th
It is produced by adding an absorption promoter such as a high-grade ammonium salt and sodium lauryl sulfate, a moisturizer such as glycerin, and other pharmaceutically acceptable additives, and compression-molding the mixture using a rotary tableting machine. The granules or tablets produced here can be coated with a known coating agent and its coating method depending on the purpose of taste masking, gastric solubility, enteric solubility, sustained release, etc. As the coating agent used at this time, ethyl cellulose, a water-insoluble coating agent such as shellac, an enteric coating agent such as hydroxypropylcellulose, hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose acetate, an acrylic acid polymer, or a colon-degradable coating agent. And so on.

The particles containing the drug thus produced are coated with a known coating agent and its coating method according to the purpose such as taste masking, gastric solubility, enteric solubility, and sustainability. Can be applied. As a coating agent used at this time, ethyl cellulose, a water-insoluble coating agent such as shellac, an enteric coating agent such as hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, an acrylic acid copolymer, or large intestine decomposition. Coating agents and the like.

In these coatings, since the particles containing the drug according to the present invention have a uniform particle size and a high sphericity, the coating layer formed has a uniform film thickness between granules, Also, when one granule is taken, it is possible to produce spherical drug-containing particles in which the outer surface having a uniform film thickness is coated with a coating agent. The uniform thickness of the coating layer among the particles enables a high degree of controlled release. That is, when controlling the release of the drug from the drug-containing particles by coating with the above-mentioned enteric coating agent, the selection of the coating agent having the pH solubility of the gastrointestinal site where the drug is desired to be released, and the thickness of the coating layer It is generally controlled by the thickness, but when the thickness of the coating layer is uniform among particles, the drug from the particles after reaching the site having the pH at which the coating agent used for coating dissolves in the digestive tract Has a constant emission pattern.
This is extremely useful in application to a sustained-release preparation in which particles having different coating film thicknesses are mixed, and to a preparation in which a drug is locally released to a specific site in the digestive tract. The uniformity of the coating layer when viewed as one particle can realize sufficient strength even at a relatively thin film thickness, and enables rapid drug release after the coating layer starts to dissolve. Further, the release rate can be adjusted by adjusting the film thickness.

The drug contained in the particles containing the coated drug is not particularly limited in the same manner as the drug contained in the above-mentioned granules, but in addition to the drugs exemplified above, calcitoniin, CSF (colony Stimulator), E
Protein drugs such as PO (erythropoietin), insulin and cyclosporin, and peptide drugs are added.

Further, these coated granules or fine granules may be directly used as a granule preparation or fine granule as in the case of the above-mentioned uncoated granules or fine granules, or a capsule or filler filled in a capsule. It is also used as a tablet that is compression-molded together with a shaping agent.

[0038]

EXAMPLES The present invention will be described below by taking fine particles containing diltiazem hydrochloride as an example, but the present invention is not limited to the following examples.

Example 1 Cellulose diacetate was added at a concentration of 1
Dimethylsulfoxide / propylene glycol was dissolved in a mixed solution of 4/6 by weight so that the concentration was 2.5% (% by weight, the same applies hereinafter). 2 5mm in front of the nozzle
A parallel plate electrode having a width of 5 cm and a length of 25 cm in the droplet advancing direction was placed at a distance of cm, and a direct current voltage of 800 V was applied between the electrode and the nozzle. From the 250 μm diameter orifice provided in this nozzle, 1
The solution held at 45 ° C. was ejected at a linear velocity of 7.8 m / sec while vibrating at 3850 Hz to form uniform droplets of the solution, and after flying in air for about 3 m,
Cellulose diacetate particles were obtained by infiltrating into a 10% aqueous methanol solution at 23 ° C. and coagulating. The obtained cellulose diacetate particles were dipped in methanol to replace the water in the cellulose diacetate particles with methanol, and then, at 50 ° C. under reduced pressure.
After being dried for 12 hours, the degree of water swelling is 2.5, the number average particle diameter is 300 μm, and 90% or more of the particles have a porosity of cellulose diacetate within ± 20 of the number average particle diameter. The particles were obtained. 500 g of these porous particles were placed in a planetary mixer, and a 30% diltiazem hydrochloride aqueous solution 20 was added.
After dropping 0 ml and mixing, the mixture was dried at 45 ° C. for 10 hours to obtain drug-containing particles having a number average particle diameter of 300 μm.

(Example 2) 500 g of the drug-containing particles obtained in Example 1 was charged into a centrifugal fluidizer, and 7 parts by weight of Eudragit S100, 3.5 parts by weight of talc and 0.7 parts by weight of polyethylene glycol were added. 70% ethanol / water containing the above was sprayed to form a coating layer to obtain drug-containing particles having a coating amount of 5% by weight, the outer surface of which was coated with a coating agent.

Therefore, regarding the releasability of diltiazem hydrochloride from the drug-containing particles obtained in Examples 1 and 2, artificial intestinal fluid first solution (0.1N hydrochloric acid (pH 1.2)), second solution (phosphoric acid) It evaluated using the buffer solution pH7.2).
The eluted diltiazem hydrochloride was measured by spectroscopic measurement after a certain period of time. Further, 500 mg of the granules obtained in Example 1 and Example 2 was added to 900 ml of the solution, and the amount of the drug eluted was measured at 37 ° C and a stirring speed of 100 rpm.

As a result, the drug-containing particles obtained in Example 1 contained 30 particles in both the first and second artificial intestinal fluids.
Within 90 minutes, drug release of 90% or more of the drug content was confirmed. On the other hand, the drug-containing particles of the granules obtained in Example 2 were all below the detection limit in the artificial intestinal fluid first liquid after 1 hour and 3 hours, while the artificial intestinal fluid second liquid was detected. In, the release of the drug was confirmed after 30 minutes,
By 2 hours, it was confirmed that 90% by weight or more of the drug content was released.

[0043]

As described above, since the drug-containing particles of the present invention have a uniform particle size and a high sphericity,
When used in the fields of medicine and food, uniform filling of the drug content in the capsule is possible when filling the capsule. In addition, for the purpose of imparting drug release controllability to the surface of the granule surface, for example, for the purpose of improving drug stability, masking taste, sustained release of drug, or delivering drug to a specific site of the digestive tract. Even when the drug-containing particles are coated with a water-insoluble film, a pH-dependent film, etc., uniform coating is possible, the taste and odor of the drug are masked, or the drug release controllability is excellent. Oral administration preparations and the like can be provided.

[Brief description of drawings]

1 is a cross-sectional view of a portion of an apparatus for producing porous particles of the present invention.

[Explanation of symbols]

 1. Fixed base 2. Cylinder 3. Nozzle fixing nut 4. Cylinder fixing nut 5. Nozzle 6. Vibration bar 7. O-ring 8. O-ring 9. Liquid inlet 10. Cooling water inlet / outlet 11. Screw 12. Nozzle hole

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 9/50 A61K 9/14 C

Claims (15)

[Claims] 1. Drug-containing particles in which a drug is supported inside porous particles made of a cellulosic material such as cellulose, a cellulose derivative or regenerated cellulose. 2. 90% or more of the porous particles are within ± of the number average particle size.
The drug-containing particle according to claim 1, which is within 20%. 3. The number average particle diameter of the porous particles is 50 to 1000.
The drug-containing particle according to claim 1, which has a diameter of μm. 4. The drug-containing particle according to claim 1, wherein the sphericity of the porous particle is 1.2 or less. 5. The drug-containing particles according to claim 1, wherein the swelling degree of the porous particles is 1.5 or more. 6. A drug-containing particle in which the outer surface of the drug-containing particle according to claim 1 is coated with a coating agent. 7. A granular preparation comprising the drug-containing particles according to claim 1 or 6. 8. A fine granule comprising the drug-containing particles according to claim 1 or 6. 9. A capsule preparation obtained by filling the drug-containing particles according to claim 1 or 6 into a capsule. 10. A tablet obtained by compression-molding the drug-containing particles according to claim 1 or 6, together with an excipient. 11. A drug is obtained by immersing porous particles made of a cellulosic material such as cellulose, a cellulose derivative or regenerated cellulose in a solution or dispersion liquid containing a drug, impregnating the drug inside the particle and drying. A method for producing drug-containing particles, which comprises: 12. A solution or dispersion containing a drug is dropped into porous particles made of a cellulosic material such as cellulose, a cellulose derivative or regenerated cellulose, and the drug is impregnated inside the particles to dry the particles. A method for producing drug-containing particles, which carries a drug. 13. A method for mixing a powdery drug with porous particles made of a cellulosic material such as cellulose, a cellulose derivative or regenerated cellulose, and filling the powdery drug in the pores of the porous particle. A method for producing drug-containing particles, wherein a drug is carried inside the particles. 14. A porous particle made of a cellulosic material such as cellulose, a cellulose derivative or regenerated cellulose and a drug having sublimability are mixed and housed in a closed container, and the drug is sublimated to form fine particles of the porous particle. A method for producing drug-containing particles in which a drug is carried inside porous particles by being adsorbed on the surface of pores. 15. The method for producing drug-containing particles according to claim 11, 12, 13 or 14, wherein after the drug is loaded inside the porous particles, the outer surface is further coated with a coating agent.