JP5813391B2 - Method for producing particle preparation - Google Patents

Description

The present invention relates to a method for producing a particle preparation, and more particularly, to a method for producing a particle preparation, which can produce a particle preparation with controlled drug elution using a spray drying method.

Conventionally, in pharmaceutical solid preparations, drug bulk powder is granulated by adding binders, excipients, etc. to control drug dissolution characteristics, etc., and drug-containing particles are coated with a water-insoluble coating substance. I do.
However, since the surface area of the particles generally increases as the particle size decreases, the method of applying a water-insoluble coating substance to the particles containing the drug, while controlling the dissolution of the drug (particularly the particles containing the drug) Suppression of elution and masking of bitterness were very difficult.

The spray drying method is widely used as a method that can be easily and efficiently made into particles and powders. However, fluidized bed coatings are often used for drug coatings for the purpose of drug elution control. The reason for this is that, in the spray drying method, it is difficult to give the coating film a sufficient thickness, and therefore, a coated particle preparation with highly controlled drug elution cannot be obtained.

As a drug coating technique using a spray drying method, for example, Patent Document 1 discloses that a drug particle having a monolayer coating structure in which bitterness is suppressed is produced by a spray drying method.
However, Patent Document 1 does not show a multi-layer coating method using a spray drying method, which is insufficient for control of drug dissolution characteristics.

For example, Patent Document 2 discloses a drug in which a polymer solution containing a drug and an aqueous solution of an aggregation inhibitor are sprayed into contact with each other in a spray dryer using different nozzles, and the film is coated with the aggregation inhibitor in a thin film. A method for producing a contained particle formulation is disclosed.
However, the method disclosed in Patent Document 2 has a problem that it is difficult to produce a product with stable quality because solutions of different compositions are sprayed simultaneously from two nozzles. In addition, due to the special structure having two nozzles, the equipment is expensive, and there is a problem that it takes time and money for cleaning and maintenance after use.
Furthermore, Patent Document 2 discloses spray-drying a multi-layer coated particle preparation with highly controlled drug elution, without using a complicated method in which two types of spray liquids are sprayed simultaneously from different nozzles. There is no disclosure of a method for simple production by the method.

For example, Patent Document 3 discloses an enteric granule in which a primary enteric layer and a second enteric layer are coated on elementary granules.
However, the method for producing an enteric granule disclosed in Patent Document 3 is not a spray drying method but a coating method by a fluidized granulation method, and water dispersion is used as a coating polymer for the first enteric layer and the second enteric layer. Emulsion polymer is used, and cellulosic enteric polymer (HPMCAS) is used for the first layer and the second layer, respectively (the dissolution pH of HPMCAS used for the second layer is lower than the dissolution pH of HPMCAS used for the first layer) Has been.

Japanese Patent No. 3415835 Japanese Patent No. 320584 JP 2007-332101 A

The present invention is a method for producing a particle preparation with highly controlled drug elution, and without using a complicated method in which two types of spray liquids are sprayed simultaneously from separate nozzles. It is an object of the present invention to provide a method for producing a particle preparation that can easily produce a particle preparation coated with multiple layers by spray drying.

As a result of intensive studies to solve the above problems, the present inventors formed a first coating layer on the drug particles by using a spray drying method, and then further used a spray drying method to form the second coating layer. And spray-drying a particle formulation with highly controlled drug elution by making the coating polymer contained in the first coating layer different from the coating polymer contained in the second coating layer. The present inventors have found that it can be easily produced by a method, and have completed the present invention.
The particle preparation produced by the method for producing a particle preparation of the present invention comprises drug particles and two coating layers containing a predetermined coating agent that coats the drug particles, and the average particle size is small. However, there is a feature that drug elution can be controlled effectively.

That is, the present invention includes a step of dissolving and / or suspending drug particles in a first coating solution containing a cellulosic enteric polymer, and forming a first coating layer on the drug particles by spray drying. The drug particles forming the first coating layer are suspended in a second coating solution containing a water-insoluble polymer different from the cellulosic enteric polymer, and the second coating layer is formed by spray drying. The first coating solution contains a first polar solvent, and the first polar solvent is a mixture of ketones, ketones and alcohols, or a mixture of ketones and halogenated alkanes. is a solvent, the second coating solution contains a second polar solvent, the second polar solvent, Ri alcohols der, the ketones, selected from the group consisting of acetone and methyl ethyl ketone Wherein the alcohol is at least one selected from the group consisting of ethanol, propanol and isopropanol, and the halogenated alkane is selected from the group consisting of dichloromethane, chloroform, trichloroethane and carbon tetrachloride. at least one der manufacturing method of particle formulation according to claim Rukoto being.
In the method for producing a particle preparation of the present invention, the ketone is preferably acetone.
The alcohol is preferably ethanol.
The cellulose-based enteric polymer preferably contains hydroxypropyl methylcellulose phthalate (HPMCP) and / or hydroxypropylmethylcellulose acetate succinate (HPMCAS).
The water-insoluble polymer is ethyl cellulose, methacrylic acid-methyl acrylate copolymer, methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, polyvinyl acetal diethylaminoacetate, ethyl acrylate-methacrylic acid. It is preferable to include at least one selected from the group consisting of a methyl-methacrylated trimethylammonium ethyl copolymer and an ethyl acrylate-methyl methacrylate copolymer.
Moreover, it is preferable that the particle size of the particle | grain formulation which formed the said 2nd coating layer is 0.1-200 micrometers.
Hereinafter, the present invention will be described in detail.

In the method for producing the particle preparation of the present invention, drug particles are dissolved and / or suspended in a first coating solution containing a cellulosic enteric polymer, and the first coating layer is formed on the drug particles by spray drying. Forming.
By this step, the drug particles become single-layer coated drug particles coated with the first coating layer. Here, in the case where the drug particles are dissolved in the first coating solution, particles in which the drug and the coating material of the first coating solution are naturally integrated (manufactured integrally particles) are produced by this step. Particles that apparently differ in structure from the monolayer-coated drug particles. However, even in the case of the above-described monolithic particles, a particle preparation that can sufficiently exhibit the above-described effects of the present invention can be produced by performing the step of forming a second coating layer described later. For this reason, in the present invention, the above-described monolithic particles are also particles in which drug particles are coated with the first coating layer.
In order to reliably form the first coating layer, it is preferable that the drug particles are not completely dissolved in the first coating solution (that is, the drug particles are partially suspended). More preferably, the drug particles do not dissolve in the first coating solution at all (that is, all drug particles are suspended).

The drug in the drug particles is not particularly limited as long as it is a physiologically or pharmacologically active active ingredient. For example, polypeptides and nucleic acids having physiological activity, antipyretic / analgesic / anti-inflammatory drugs, gout / high Uricemia treatment, hypnosis / sedation, sleep inducer, anti-anxiety, antiepileptic, antipsychotic, antidepressant, antiparkinson, autonomic nervous system, cerebral circulation metabolism, allergy , Antiallergic drugs, antianginal drugs, beta blockers, calcium antagonists, cardiotonic drugs, antiarrhythmic drugs, diuretics, antihypertensive drugs, vasoconstrictor drugs, vasodilators, hyperlipidemia drugs, pressor drugs, Bronchodilators / asthma drugs, antitussives, expectorants, peptic ulcer drugs, healthy stomach / digestants, laxatives, intestinal drugs, antacids, diabetes drugs, hormone preparations, vitamin preparations, antibiotics, osteoporosis Medicine, antibacterial drug, chemotherapeutic agent, antiviral drug, anti Ulcer, muscle relaxant, anticoagulant, hemostatic agent, antituberculosis agent, narcotic antagonist, bone resorption inhibitor, angiogenesis inhibitor, central nervous system agent, local anesthetic, antipruritic agent, cardiovascular agent , Respiratory stimulants, antidiarrheals, antibacterial agents, digestive organ drugs, urinary organ drugs, liver disease drugs, and the like. The said drug can be used individually or in combination of 2 or more types.
Of these, the drug is preferably a water-soluble drug. The water-soluble drug means a drug having a weight of 1 g or more that dissolves in 100 g of 25 ° C. water. Examples of such drugs include potassium guaiacol sulfonate (an expectorant).

The drug particles can be produced by a known grinding technique (hammer mill, sample mill, pin mill, jet mill, bead mill, etc.).
Further, as the drug particles, for example, a physiologically or pharmacologically acceptable formulation using a fluidized bed granulator, a stirring fluidized bed device, a rolling fluidized bed device, a centrifugal rolling device, or a spray drying device. Drug-containing particles formed by mixing an auxiliary agent and a drug, or drug-containing particles formed by coating a drug on the surface of core particles of an appropriate material may be used.

The drug particles preferably have an average particle size of 0.08 to 160 μm. If it is less than 0.08 μm, the surface area of the drug particles becomes large, and it may be difficult to control the dissolution of the drug in the particle preparation produced according to the present invention. On the other hand, when it exceeds 160 μm, there is a possibility that a feeling of roughness or a foreign body in the oral cavity may be felt when the particle preparation produced according to the present invention is taken. A more preferable average particle size of the drug particles is 0.4 to 80 μm, and a more preferable average particle size is 0.8 to 32 μm.
The average particle diameter of the drug particles refers to a particle diameter corresponding to 50% of the total particle volume, and more specifically means a volume-based median diameter.

In this step, the drug particles are dissolved and / or suspended in a first coating solution containing a cellulosic enteric polymer.
The method for dissolving and / or suspending the drug particles in the first coating solution is not particularly limited and can be performed by a conventionally known method.

As the cellulose-based enteric polymer, various physiologically or pharmacologically acceptable materials can be used. Among these, the cellulose-based enteric polymer is preferably water-insoluble. Examples of such a cellulose-based enteric polymer include hydroxypropylmethylcellulose acetate succinate (HPMCAS) and hydroxypropylmethylcellulose phthalate (HPMCP). ), Hydroxymethyl ethyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate propionate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, methyl cellulose phthalate and the like.
These cellulosic enteric polymers can be used alone or in combination of two or more.
Of these, hydroxypropylmethylcellulose acetate succinate (HPMCAS) and / or hydroxypropylmethylcellulose phthalate (HPMCP) are preferably used as the cellulose-based enteric polymer. When these cellulosic enteric polymers are used, it is easy to form a first coating layer for effective elution control.
The “enteric polymer” means a polymer that does not dissolve in an aqueous solution having a pH of less than 5 but dissolves in an aqueous solution having a pH value of 5 to 7 or higher.

The first coating solution may contain inorganic particles.
As the inorganic particles, various physiologically or pharmacologically acceptable materials can be used. Examples of such inorganic particles include silicon dioxide (hydrous silicon dioxide, light anhydrous silicic acid), titanium dioxide, talc, kaolin, magnesium stearate, calcium stearate, sodium stearyl fumarate, calcium carbonate, calcium phosphate, calcium silicate. , Magnesium silicate, aluminum silicate, magnesium aluminate silicate, magnesium aluminate metasilicate, magnesium aluminum silicate, light aluminum oxide and the like.
These inorganic particles can be used alone or in combination of two or more.

As the inorganic particles, light anhydrous silicic acid and titanium oxide are preferable, and lightly treated light anhydrous silicic acid (for example, Aerosil-R972 (manufactured by Nippon Aerosil Co., Ltd.)) and hydrophobically treated titanium oxide (for example, Aeroxide-T805). (Nippon Aerosil Co., Ltd.)) is more preferable, and lightly treated light anhydrous silicic acid (Aerosil-R972 (Nippon Aerosil Co., Ltd.)) is particularly preferable.
The term “hydrophobized” as used herein means that the surface is chemically alkylated. As a specific example of the hydrophobization treatment, in the case of lightly treated silicic anhydride, a method of hydrophobizing the surface of the light silicic anhydride with a methyl group is mentioned. In the case of hydrophobized titanium oxide, oxidation is performed. There is a method of chemically treating titanium with octylsilane to make it hydrophobic.

The inorganic particles can be produced by a known crushing / dispersing technique (hammer mill, sample mill, pin mill, jet mill, bead mill, high-pressure homogenizer, ultrasonic crushing / dispersing, etc.).
The average particle size of the inorganic particles is preferably 1 nm to 1000 nm, more preferably 100 to 500 nm. If it is less than 1 nm, the handleability during work is deteriorated, and there is a problem that there is no product that can be purchased as a pharmaceutical additive. On the other hand, if it exceeds 1000 nm, it is used in the method for producing the particle preparation of the present invention. It becomes difficult to uniformly and densely fill the first coating layer, and it may be impossible to control the dissolution of the drug.
The average particle size of the inorganic particles has the same meaning as the average particle size of the drug particles described above.

The content of the inorganic particles is appropriately determined according to the type of drug in the drug particles, the degree of dissolution control of the desired drug, etc., but is preferably 0 with respect to 2.4 parts by weight of the drug. .5 to 2.4 parts by weight, more preferably 1.0 to 2.0 parts by weight. If the amount of the inorganic particles is less than 0.5 parts by weight, a sufficient drug elution control effect may not be obtained. If the amount exceeds 2.4 parts by weight, the first coating layer may become brittle. May be.

If necessary, the first coating solution is a known component used in pharmaceutical preparations, such as water-soluble polymers, binders, disintegrants, waxes, plasticizers, sugars, acidulants, artificial sweeteners, flavors, Lubricants, colorants, stabilizers and the like may be included as additives. These additives can be used alone or in combination of two or more.

The first coating liquid is a solution (organic solvent solution) or dispersion (water dispersion) containing the above-described cellulose-based enteric polymer, inorganic particles and other additives (formulation ingredients) and a solvent. Can be used.
Examples of the solvent include water and organic solvents.
Examples of the organic solvent include alcohols (ethanol, propanol, isopropanol, etc.), hydrocarbons (n-hexane, cyclohexane, etc.), halogenated alkanes (dichloromethane, chloroform, trichloroethane, carbon tetrachloride, etc.), ketones, and the like. (Acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), ethers, nitriles (acetonitrile, etc.) and the like. These organic solvents may be used as a mixture of two or more kinds, and may be used as a mixed solvent with water when water-miscible.
Especially, as said organic solvent, it is preferable that it is a polar organic solvent (henceforth a 1st polar solvent), Specifically, ketones (for example, acetone), ketones, and alcohols (for example, ethanol, A mixed solvent of methanol) and a mixed solvent of ketones and halogenated alkanes (for example, dichloromethane) are preferable. Among these, acetone is particularly preferable as the first polar solvent.

The concentration of the cellulosic enteric polymer in the first coating solution is selected according to the viscosity, sprayability, etc. of the first coating solution, and is preferably 0.1 to 50% by weight, more preferably 0.00. It is about 2 to 40% by weight, more preferably about 0.5 to 25% by weight, and most preferably about 1 to 10% by weight. If the concentration of the cellulosic enteric polymer is less than 0.1% by weight, it may not be possible to produce a particle preparation with sufficient drug elution control. On the other hand, if the concentration exceeds 50% by weight, the first coating may be produced. The solution may become highly viscous and a uniform first coating layer may not be formed.

In the spray drying method, first, a first coating solution in which drug particles are dissolved or suspended by the above-described method is sprayed into a drying chamber of a spray dryer using a nozzle. Then, the first coating layer can be formed on the drug particles by volatilizing the water or the organic solvent in the atomized droplets in a very short time.
Examples of the nozzle include a two-fluid nozzle type, a multi-fluid nozzle type, a pressure nozzle type, and a rotating disk type.
The type of the nozzle and spraying conditions are not particularly limited as long as the first coating solution in which the drug particles prepared as described above are dissolved and / or suspended is sprayed. Such conditions can be appropriately selected according to the composition of the particle preparation to be produced and the spray dryer used. For example, in a two-fluid nozzle spray dryer, the intake air temperature is appropriately adjusted depending on the solvent used, but is usually 50 to 200 ° C, preferably about 80 to 150 ° C. The amount of the spray liquid is appropriately adjusted depending on the scale of the apparatus. For example, at the laboratory scale (chamber diameter 15.5 cm) level, it is usually about 1 to 30 mL / min. The spray gas flow rate is usually adjusted to about 50 to 900 L / hr, although it depends on the particle size and nozzle diameter of the particle preparation to be produced.
In this step, if necessary, the water or solvent in the drug particles can be completely removed under reduced pressure.

The average particle diameter of the particles formed with the first coating layer obtained through this step is preferably 0.09 to 180 μm, more preferably 0.45 to 90 μm, and 0.9 to 36 μm. More preferably it is. If it is less than 0.09 μm, it may be difficult to control the dissolution of the drug in the particle preparation produced according to the present invention. On the other hand, if it exceeds 180 μm, there is a possibility that a feeling of roughness or a foreign body in the oral cavity may be felt when the particle preparation produced according to the present invention is taken.

In the method for producing a particle preparation of the present invention, the drug particles on which the first coating layer has been formed are then suspended in a second coating solution containing a water-insoluble polymer different from the cellulosic enteric polymer, Forming a second coating layer by spray drying.
By performing this step, the second coating layer is formed by spray drying on the drug particles on which the first coating layer has been formed, and the intended particle formulation can be produced.

In this step, first, the drug particles on which the first coating layer has been formed are suspended in the second coating solution.
The second coating solution contains a water-insoluble polymer different from the above-described cellulose-based enteric polymer. As will be described later, the water-insoluble polymer contained in the second coating solution includes the same polymer as the above-described cellulose-based enteric polymer, but in the present invention, the cellulose-based enteric polymer and the present step A polymer different from the water-insoluble polymer used in is used. In the second coating solution, the type of the cellulosic enteric polymer may be different from the type of the water-insoluble polymer.
By using such a second coating solution containing a water-insoluble polymer, the particle preparation produced according to the present invention has a structure in which drug particles are coated in multiple layers, and drug elution control is highly controlled. can do.

As the water-insoluble polymer, various physiologically or pharmacologically acceptable materials can be used. Examples of such water-insoluble polymers include sustained-release polymers, gastric polymers, and enteric polymers.

Examples of the sustained-release polymer include water-insoluble cellulose derivatives such as ethyl cellulose, ethyl acrylate-methyl methacrylate-methacrylate trimethylammonium ethyl copolymer (for example, Eudragit RS and Eudragit RL, both of which are manufactured by Evonik Industries). And water-insoluble acrylic acid copolymers such as ethyl acrylate-methyl methacrylate copolymer (for example, Eudragit NE, manufactured by Evonik Industries).
Examples of the gastric polymer include a polyvinyl derivative such as polyvinyl acetal diethylaminoacetate, and a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer (for example, Eudragit E, manufactured by Evonik Industries). Examples include (meth) acrylic acid copolymers.
Examples of the enteric polymer include methacrylic acid copolymer L (for example, Eudragit L, manufactured by Evonik Industries), methacrylic acid copolymer LD (for example, Eudragit LD, manufactured by Evonik Industries), and methacrylic acid copolymer S (eudragit). (Meth) acrylic acid copolymers such as S, manufactured by Evonik Industries).
These water-insoluble polymers can be used alone or in combination of two or more. Preferably, water-insoluble cellulose derivatives, gastric polymers, enteric polymers and the like can be mentioned, and these are used alone or in combination of two or more.
In addition, the said (meth) acryl means acryl or methacryl.

Of these, ethyl cellulose, methacrylic acid copolymer S, polyvinyl acetal diethylaminoacetate, methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer are preferred as the water-insoluble polymer. In particular, ethyl cellulose is preferable. When ethyl cellulose is used as the water-insoluble polymer, it is easy to form a second coating layer for effective elution control.

The second coating solution may contain the same inorganic particles as the first coating solution described above.
The content of the inorganic particles is appropriately determined according to the type of drug in the drug particles described above, the desired degree of elution control, etc., but is preferably based on 2.4 parts by weight of the water-insoluble polymer. Is 0.5 to 2.0 parts by weight, more preferably 1.0 to 2.0 parts by weight. When the amount of the inorganic particles is less than 0.5 parts by weight, the elution control effect may not be obtained. When the amount exceeds 2.0 parts by weight, the second coating layer may be brittle. .

If necessary, the second coating solution is a known component used in pharmaceutical preparations, such as water-soluble polymers, binders, disintegrants, waxes, plasticizers, sugars, acidulants, artificial sweeteners, flavors, Lubricants, colorants, stabilizers and the like may be included as additives. These additives can be used alone or in combination of two or more.

The second coating solution preferably contains the above-mentioned water-insoluble polymer, inorganic particles, other additives (formulation components), and the like, and a second polar solvent different from the above-mentioned first polar solvent.
The second polar solvent is a solvent different from the first polar solvent described above. In particular, the second polar solvent differs in solubility characteristics from the first polar solvent. More specifically, the second polar solvent differs from the first polar solvent in that it does not substantially dissolve the enteric cellulose polymer used in the first coating layer. In addition, that it does not melt | dissolve substantially means that the weight of the enteric cellulose polymer melt | dissolved in 100 g of 2nd polar solvents is 1 g or less (room temperature 25 degreeC conditions).
As described above, the second polar solvent is different from the first polar solvent described above, so that it is possible to produce a two-layer coated particle preparation according to the present invention, and the dissolution of the particle preparation is highly controlled. It can be. When using the water-soluble drug described above, the second polar solvent is preferably a polar organic solvent from the viewpoint that it does not affect the water-soluble drug.

Examples of the second polar solvent include alcohols (for example, ethanol and methanol) and halogenated alkanes (for example, dichloromethane). Among these, ethanol is preferably used.
The concentration of the water-insoluble polymer in the second coating solution is selected according to the viscosity, sprayability, etc. of the second coating solution, and is preferably 0.1 to 50% by weight, more preferably 0.2 to 0.2%. It is 40% by weight, more preferably about 0.5 to 25% by weight, and most preferably about 1 to 10% by weight. If the concentration of the water-insoluble polymer is less than 0.1% by weight, it may not be possible to produce a particle preparation with sufficient drug elution control. The coating solution may become highly viscous and a uniform second coating layer may not be formed.

Examples of the spray drying method using the second coating solution described above include the same methods as the spray drying method using the first coating solution described above.

As described above, according to the method for producing a particle preparation of the present invention having the steps described above, a two-layer coated particle preparation in which drug particles are coated with the first coating layer and the second coating layer described above can be produced. The particle preparation having such a structure is one in which drug elution is highly controlled.
Further, in the step of forming the first coating layer and the second coating layer, it is not necessary to use a complicated method in which two types of spray liquids are sprayed simultaneously from different nozzles, and the particle formulation having the above-described configuration is used. It can be easily produced by spray drying.

The average particle diameter of the particle preparation forming the second coating layer is not particularly limited as long as the roughness in the mouth is reduced, but is preferably 0.1 to 200 μm, more preferably 0.5 to The thickness is 100 μm, more preferably 1.0 to 50 μm, and most preferably 1.0 to 40 μm.
When the average particle size of the above-mentioned particle preparation is less than 0.1 μm, the surface area may become large and elution control may be difficult. On the other hand, when the average particle size of the particle preparation exceeds 200 μm, there is a possibility that a feeling of roughness or a foreign object in the oral cavity may be felt. The average particle size of the particle preparation is a value measured in the same manner as the average particle size of the drug particles described above.

The particle preparation produced according to the present invention can be administered as it is to a living body as a fine granule, but can also be molded into various preparations and administered as a raw material for producing such preparations. Can be used.
Examples of the preparation include injections, oral administration preparations (eg, powders, granules, capsules, tablets, orally disintegrating tablets, dry syrups, suspensions / emulsions, film preparations), nasal preparations, sitting Agents (eg, rectal suppositories, vaginal suppositories) and the like.
The amount of the drug to be contained in these preparations can vary depending on the kind of drug, dosage form, target disease, etc., but it is usually preferably about 0.001 mg to 5 g per preparation. Preferably, it is about 0.01 mg to 2 g.

These various preparations can be produced by publicly known methods.
Specifically, for example, the particle preparation produced according to the present invention includes a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), carboxymethylcellulose, sodium alginate, etc.) , Preservatives (eg, methyl paraben, propyl paraben, benzyl alcohol, chlorobutanol, etc.), tonicity agents (eg, sodium chloride, glycerin, sorbitol, glucose, etc.), etc., in aqueous suspensions, or olive oil, sesame oil It can be dispersed in vegetable oils such as peanut oil, cottonseed oil and corn oil, propylene glycol and the like and molded into an oily suspension to give an injection.

Moreover, the said oral administration formulation can be comprised with the particle formulation manufactured by this invention, and the usual formulation adjuvant according to a well-known method.
Examples of the above-mentioned formulation aid include components commonly used for oral administration, such as water-soluble polymers or binders (for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, crystalline cellulose / carboxymethylcellulose) Sodium, polyvinylpyrrolidone, polyvinyl alcohol, gum arabic powder, gelatin, pullulan, etc.), excipients (crystalline cellulose, starches such as corn starch, sucrose, lactose, powdered sugar, granulated sugar, sugars such as glucose, mannitol, light Silicic anhydride, talc, magnesium carbonate, calcium carbonate, etc.), disintegrants (eg, starches such as corn starch, carmellose calcium, crospovidone, low substituted hydroxy) Propyl cellulose, etc.), lipids (eg, hydrocarbons, waxes, higher fatty acids and salts thereof, higher alcohols, fatty acid esters, hardened oils such as hardened castor oil), plasticizers (triacetin, triethyl citrate, dibutyl sebacate, etc.) ), Flavoring agents [for example, sweeteners (sugars such as sucrose, lactose, glucose, maltose, sugar alcohols such as mannitol, xylitol, sorbitol, erythritol, artificial sweeteners such as saccharin, sodium saccharin, aspartame, stevia); citric acid Acid flavors such as tartaric acid and malic acid; flavors such as lemon, lemon lime, orange and menthol], lubricants (eg, magnesium stearate, calcium stearate, talc, etc.), fluidizing agents (eg, light anhydrous silica) Acid), colorants (eg food colors, caramel, Non-ionic interfaces such as anionic surfactants such as sodium alkyl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, and polyoxyethylene castor oil derivatives. Active agents, etc.), wetting agents (polyethylene glycol (macrogol), etc.), fillers, extenders, adsorbents, preservatives or stabilizers such as preservatives, antistatic agents, disintegration extenders, etc. Good.
Moreover, the above-mentioned preparation for oral administration may be coated by a known method for the purpose of taste masking, solubility, enteric solubility or persistence, if necessary.

For example, in order to obtain a nasal preparation, the particle preparation obtained in the present invention can be made into a solid, semi-solid or liquid nasal preparation according to a known method. For example, as the solid product, the particle preparation is used as it is, or an excipient (eg, glucose, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg, natural gums, cellulose derivatives, acrylic acid) Polymer etc.) and the like are added and mixed to obtain a powdery composition.
The liquid form is almost the same as in the case of injections, and is oily or aqueous suspension. In the case of a semi-solid form, an ointment is preferred. In addition, these are all pH adjusters (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.), etc. May be added.

In addition, for example, to make a suppository, an oily or aqueous solid, semi-solid or liquid suppository is added to the particle preparation obtained in the present invention by adding an oily base or an aqueous base according to a known method. It can be used as an agent.
The oily base is not particularly limited as long as it does not dissolve the particle formulation. For example, higher fatty acid glycerides (eg, cacao butter, vitepsols, etc.), intermediate fatty acids (eg, miglyols, etc.), vegetable oils (eg, sesame oil). , Soybean oil, cottonseed oil, etc.). Examples of the aqueous base include polyethylene glycols and propylene glycol. Moreover, when setting it as the said suppository, you may use natural gums, a cellulose derivative, a vinyl polymer, an acrylic acid polymer etc. as an aqueous gel base, for example.

Moreover, the said oral administration agent can be obtained by formulating, after granulating or kneading the said particle formulation as needed, for example, according to the usual method according to the dosage form.
For granulation of the above-mentioned particle preparation, conventional granulation methods such as rolling type granulation method and fluidized bed type granulation method can be adopted, and granulation and kneading are usually excipients and binders. Etc. are carried out using a carrier such as. For example, in the case of a tablet, it is obtained by mixing or kneading the above-mentioned particle preparation and a carrier such as an excipient or a binder, granulating as necessary, and adding an additive such as a lubricant to make a tablet. be able to. For example, a capsule can be obtained by encapsulating the above-mentioned particle preparation or a granulated product thereof in a capsule.

According to the method for producing a particle preparation of the present invention, it is possible to produce a two-layer coated particle preparation which is easily and efficiently highly controlled by spray drying.

EXAMPLES The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to these examples.

In the following Examples and Comparative Examples, the following drugs and formulation ingredients were used.
(Drug)
Potassium guaiacol sulfonate (formulation component)
HPMCP: Hydroxypropyl methylcellulose phthalate (Shin-Etsu Chemical Co., Ltd., HP55)
Ethylcellulose (Edocel 10 manufactured by Dow Chemical)
Eudragit S100 (Evonik Industries, Eudragit-S100)
Lightly treated light anhydrous silicic acid (Aerosil-R972, manufactured by Nippon Aerosil Co., Ltd.)
Glyceryl monoisostearate (Nikko Chemicals, NIKKOL-MGIS)

Moreover, in the following Examples and Comparative Examples, particle preparations were produced and evaluated by the following methods.
(Manufacture of drug particles)
100 g of potassium guaiacol sulfonate was added to 900 g of water and dissolved. This solution is spray-dried with a spray dryer (Mini Spray Dryer B-290, manufactured by BUCHI Labortechnik AG) at a spray liquid amount of 2 mL / min, an intake air temperature of 120 ° C., and a spray air flow rate of 190 L / hr, and spherical guaiacol. Potassium sulfonate particles were obtained.

(Measurement of average particle size)
<Coated particle formulation>
Using an automatic particle image analyzer (Malvern Instruments, Morphologi (registered trademark) -G3), the average particle diameter was measured from 20,000 or more particles.
<Average particle size of inorganic particles>
The particle size of the inorganic particles was measured in advance prior to production of the particle formulation.
That is, an ethanol suspension of inorganic particles was prepared, and after ultrasonic treatment, the average particle size was measured with a particle size measurement system ELSZ-1 (manufactured by Otsuka Electronics Co., Ltd., dynamic and electrophoretic light scattering method). The average particle size of the inorganic particles used in the examples is shown below.
Hydrophobized inorganic particles: Aerosil-R972 (Nippon Aerosil Co., Ltd., average particle size 218.0 nm)

(Dissolution test)
According to the flow-through method described in the Japanese Pharmacopoeia, the test was conducted with both the dissolution test first solution (pH 1.2) and dissolution test second solution (pH 6.8), and the dissolution rate of the drug was measured.
However, Swinnex filter holder 25 mm (manufactured by Nihon Millipore) was used for the cell. In order to prevent the particle formulation from flowing out, a support screen (25 mm stainless steel, manufactured by Nihon Millipore), Durapore membrane filter (PVDF, Hydrophilic, 0.45 μm, 25 mm, manufactured by Nihon Millipore), silicon gasket 25 mm (Swinex ( (Swinnex) for filter holder, manufactured by Nihon Millipore). For the liquid feeding pump, Masterflex L / S (model 7524-50, manufactured by Cole Palmer Instrument Company) was used, and the test liquid was fed at 2.5 mL / min. Other than that, it followed the flow-through cell method of the Japanese Pharmacopoeia. The drug elution amount was quantified by HPLC.

(Comparative Example 1)
Hydroxypropyl methylcellulose phthalate (HP55, manufactured by Shin-Etsu Chemical Co., Ltd.), hydrophobic light anhydrous silicic acid (Aerosil-R972, manufactured by Nippon Aerosil Co., Ltd.), glyceryl monoisostearate (NIKKOL-MGIS, Nikko Chemicals) with the composition shown in Table 1 A suspension was prepared by suspending the drug particles in a first coating solution containing acetone). The prepared suspension was sprayed with a spray dryer (Mini Spray Dryer B-290, manufactured by BUCHI Labortechnik AG) at a spray liquid amount (5 mL / min), an intake air temperature (80 ° C.), and a spray air flow rate (470 L / hr). By spray-drying under the conditions, monolayer-coated drug particles in which a first coating layer was formed on drug particles having an average particle diameter of 10.4 μm were obtained. This monolayer-coated drug particle was used as a particle preparation, and a dissolution test was performed at pH 1.2 (dissolution test first liquid) and pH 6.8 (dissolution test second liquid). As a result, the respective 60-minute elution rates were 50.0% and 79.9%. The recovery rate of monolayer-coated drug particles was about 80%. The recovery rate is calculated by (actual recovery amount / theoretical recovery amount) × 100.

(Example 1)
In the composition shown in Table 2, Eudragit S100 (Evonik Industries), ethylcellulose (Dow Chemical, Ethocel 10), hydrophobic light silicic anhydride (Aerosil-R972, Nippon Aerosil), glyceryl monoisostearate A suspension was prepared by suspending monolayer coated drug particles (coated drug particles produced in Comparative Example 1) in a second coating solution containing (Nikko Chemicals, NIKKOL-MGIS) and ethanol. The prepared suspension was sprayed with a spray dryer (Mini Spray Dryer B-290, manufactured by BUCHI Labortechnik AG) at a spray liquid amount (5 mL / min), an intake air temperature (120 ° C.), and a spray air flow rate (470 L / hr). By spray-drying under conditions, a two-layer coated particle formulation with an average particle size of 15.5 μm was obtained. The particle formulation was subjected to a dissolution test at pH 1.2 (dissolution test first liquid) and pH 6.8 (dissolution test second liquid). As a result, the respective 60-minute elution rates were 19.4% and 30.8%. Further, the recovery rate of the obtained particle preparation was about 80%.
As a result of the two-layer coating, an increase in average particle diameter and a decrease (inhibition) in the average particle diameter are observed compared to the case of the single-layer coating (Comparative Example 1), and a particle formulation in which elution is effectively suppressed is obtained. I was able to.

(Comparative Example 2)
As shown in Table 3, an attempt was made to prepare a particle preparation coated with two layers under the same conditions as in Example 1 except that the solvent of the second layer coating solution was changed to acetone, and it was composed of hydroxypropylmethylcellulose phthalate. Since the first coating layer was dissolved in acetone used as the solvent for the second coating solution, the spray solution became highly viscous and spraying for the two-layer coating could not be performed.

According to the present invention, by using a spray drying method, the drug particles are divided into a first coating layer containing a cellulosic enteric polymer and a second water-insoluble polymer different from the cellulosic enteric polymer. A particle preparation coated with a coating layer can be produced. Thereby, even when the particle size is small, drug particles can be effectively coated, and drug elution can be effectively suppressed. Therefore, the produced particle preparation can be directly administered to a living body as a fine granule as it is, and can also be molded and administered into various preparations.
Also, since spray drying does not require special spraying processes or equipment (for example, a complicated method in which two types of spray liquids are sprayed simultaneously from different nozzles), equipment installation costs, cleaning and maintenance costs, etc. Can be reduced.

Claims (6)

Dissolving and / or suspending drug particles in a first coating solution containing a cellulosic enteric polymer, and forming a first coating layer on the drug particles by spray drying;
The drug particles forming the first coating layer are suspended in a second coating solution containing a water-insoluble polymer different from the cellulosic enteric polymer, and the second coating layer is formed by spray drying. A process,
The first coating solution contains a first polar solvent, and the first polar solvent is a ketone, a mixed solvent of a ketone and an alcohol, or a mixed solvent of a ketone and a halogenated alkane.
The second coating solution contains a second polar solvent, said second polar solvent, Ri alcohols der,
The ketones are at least one selected from the group consisting of acetone and methyl ethyl ketone,
The alcohol is at least one selected from the group consisting of ethanol, propanol and isopropanol,
The method for producing a particle preparation, wherein the halogenated alkane is at least one selected from the group consisting of dichloromethane, chloroform, trichloroethane, and carbon tetrachloride . The method for producing a particle preparation according to claim 1, wherein the ketone is acetone. The method for producing a particle preparation according to claim 1, wherein the alcohol is ethanol. The method for producing a particle preparation according to claim 1, 2 or 3, wherein the cellulosic enteric polymer contains hydroxypropylmethylcellulose phthalate (HPMCP) and / or hydroxypropylmethylcellulose acetate succinate (HPMCAS). Water-insoluble polymers are ethyl cellulose, methacrylic acid-methyl acrylate copolymer, methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, polyvinyl acetal diethylaminoacetate, ethyl acrylate-methyl methacrylate-methacrylic acid. The method for producing a particle preparation according to claim 1, 2, 3, or 4, comprising at least one selected from the group consisting of an acid trimethylammonium ethyl copolymer and an ethyl acrylate-methyl methacrylate copolymer. The method for producing a particle preparation according to claim 1, 2, 3, 4, or 5, wherein the average particle diameter of the particle preparation on which the second coating layer is formed is 0.1 to 200 µm.