JP2012250926A - Particulate formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a particulate formulation with effectively controlled dissolution characteristics of a drug even if the average particle diameter is small.SOLUTION: The invention provides a particulate formulation containing drug particles and a coating layer coating the drug particles and characterized in that the coating layer contains 0.5-2.4 wt.% of inorganic particles to 2.4 wt.% of a water-insoluble polymer.

Description

The present invention relates to particle formulations.

Conventionally, in pharmaceutical solid preparations, the drug substance powder is granulated by adding a binder, excipient, etc. to control the dissolution characteristics of drug particles, etc., or the drug substance powder is coated with a water-insoluble coating substance. Have been.
For example, Patent Document 1 discloses drug-coated particles coated with a water-insoluble polymer using a particle coating / granulating apparatus and a method for producing the same, and is 0.1 to 2% based on the drug weight. It is disclosed that the formulation particle size is 17 μm.
Further, for example, Patent Document 2 discloses that 1 to 5% of titanium oxide is contained in a coating layer obtained by coating a drug with ethyl cellulose or HPMC to form preparation particles of 200 to 300 μm.
For example, Patent Document 3 discloses that a drug is coated with HPC or ethyl cellulose, talc, silicon dioxide or the like is used, and the formulation particle size is 161 μm.

However, in general, since the surface area of a drug increases as the particle size decreases, it is very difficult to control drug elution (particularly, elution suppression and bitter masking) while making the drug-containing particles into particles.

JP 2008-013480 A Japanese Patent No. 3317444 JP 2008-81448 A

An object of the present invention is to provide a particle preparation in which the dissolution characteristics of drug particles are effectively controlled even when the average particle size is small.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have determined that the coating layer that coats the drug particles contains a water-insoluble polymer and inorganic particles at a predetermined weight ratio, thereby elution of the drug particles. The present inventors have found that the control can be suitably performed and have completed the present invention.

That is, the present invention is a particle preparation having drug particles and a coating layer that coats the drug particles, and the coating layer contains 0.2 part by weight of inorganic particles with respect to 2.4 parts by weight of the water-insoluble polymer. It is a particle | grain formulation characterized by containing 5-2.4 weight part.
In the particle preparation of the present invention, the average particle size of the inorganic particles is preferably 1-1000 nm.
The inorganic particles are preferably silica and / or titanium dioxide.
The water-insoluble polymer preferably contains an enteric polymer.
Moreover, it is preferable that the said inorganic particle is a thing hydrophobized.
Moreover, it is preferable that the particle | grain formulation of this invention contains 0.5-2.4 weight part of inorganic particles with respect to 2.4 weight part of drug particles.
In addition, the particle preparation of the present invention is preferably obtained by a spray drying method.
Hereinafter, the present invention will be described in detail.

The present invention is a particle preparation having drug particles and a coating layer covering the drug particles.
The particle formulation of the present invention having such a configuration has a feature that the elution of drug particles can be effectively controlled even when the average particle size is small.
The drug in the drug particle 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 uric acid Antihypertensive, hypnotic / sedative, sleep-inducing agent, anxiolytic, antiepileptic, antipsychotic, antidepressant, anti-parkinsonian, autonomic nervous system, cerebral circulation metabolism, allergy, Antiallergic drugs, antianginal drugs, β-blockers, calcium antagonists, cardiotonic drugs, antiarrhythmic drugs, diuretics, antihypertensive drugs, vasoconstrictor drugs, vasodilators, hyperlipidemic drugs, pressor drugs, bronchi Dilators, asthma drugs, antitussives, expectorants, peptic ulcer drugs, stomach and digestive drugs, laxatives, intestinal drugs, antacids, diabetes drugs, hormone preparations, vitamin preparations, antibiotics, osteoporosis Drugs, antibacterial drugs, chemotherapeutic drugs, antiviral drugs, antitumors Agent, muscle relaxant, anticoagulant, hemostatic agent, antituberculosis agent, narcotic antagonist, bone resorption inhibitor, angiogenesis inhibitor, central nervous system agent, local anesthetic, antipruritic agent, cardiovascular agent, Examples include respiratory stimulants, antidiarrheals, antibacterials, digestive organs, urinary organs, and liver diseases. The above drugs can be used alone or in combination of two or more.

The drug particles can be produced by a known grinding technique (hammer mill, sample mill, pin mill, jet mill, bead mill, etc.).
In addition, as the drug particles, for example, a physiologically or pharmacologically acceptable formulation aid 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 with an agent, or drug-containing particles formed by coating a drug on the surface of core particles of an appropriate material may be used.

In the particle preparation of the present invention, the drug particles preferably have an average particle size of 1 to 200 μm. If it is less than 1 μm, the surface area of the particle preparation of the present invention becomes large, and it may be difficult to control the dissolution of drug particles. On the other hand, when it exceeds 200 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 of the present invention is taken. A more preferable range of the average particle diameter of the drug particles is 1 to 15 μm.
The average particle diameter of the drug particles has the same meaning as the average particle diameter of a particle preparation described later.

The particle preparation of the present invention has a configuration in which the drug particles are coated with a coating layer.
The coating layer contains a water-insoluble polymer and inorganic particles.
In the following description, the components used in the particle formulation of the present invention together with the drug particles are collectively referred to as a formulation component.
As the water-insoluble polymer, various physiologically or pharmacologically acceptable materials can be used. Specific 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 cellulose derivatives such as hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate and carboxymethylethylcellulose, methacrylic acid copolymer L (Eudragit L, manufactured by Evonik Industries). (Meth) acrylic acid copolymers such as methacrylic acid copolymer LD (Eudragit LD, manufactured by Evonik Industries) and methacrylic acid copolymer S (Eudragit S, manufactured by Evonik Industries).
These water-insoluble polymers can be used alone or in combination of two or more. Preferably, a water-insoluble cellulose derivative, a water-insoluble acrylic acid copolymer, a gastric polymer, an enteric polymer, and the like are used, and these are used alone or in combination of two or more.
In addition, the said (meth) acryl means acryl or methacryl.

In the particle preparation of the present invention, the water-insoluble polymer preferably contains an enteric polymer. When the coating layer contains an enteric polymer and inorganic particles described later, the drug particles can be more effectively eluted in the intestine.
In addition, the said enteric polymer means the polymer which does not melt | dissolve in aqueous solution below pH 5, but melt | dissolves in aqueous solution more than a certain pH value within the range of pH 5-7.
Examples of the enteric polymer include those described above, among which hydroxypropylmethylcellulose phthalate and methacrylic acid copolymer S are preferably used. These enteric polymers are commercially available, for example, as HP55 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) or Eudragit S100 (manufactured by Evonik Industries).

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

Among them, silica and / or titanium dioxide is preferable because it is easy to obtain a commercial product having an average particle diameter in the range described below. In particular, 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, manufactured by Nippon Aerosil Co., Ltd.) are preferable. The term "hydrophobized" as used herein means that the surface is chemically alkylated.
As a specific example of the hydrophobic treatment, in the case of lightly treated silicic anhydride, the surface of the light silicic anhydride is covered with a methyl group to be hydrophobized, and the hydrophobically treated titanium oxide In this case, the titanium oxide is chemically treated with octylsilane to be hydrophobized.

The average particle diameter of the inorganic particles is preferably 1-1000 nm, more preferably a lower limit is 100 nm, and a more preferable upper limit is 500 nm. When the thickness is less than 1 nm, the handling property during work is deteriorated, and there is a possibility that there is no product that can be purchased as a pharmaceutical additive. It becomes difficult to uniformly and densely fill the layer, and the elution of drug particles may not be controlled.
The average particle diameter of the inorganic particle here has the same meaning as the average particle diameter of the particle preparation described later.

In the particle preparation of the present invention, the content of the inorganic particles with respect to the water-insoluble polymer described above is 2.4 parts by weight of the water-insoluble polymer depending on the kind of drug particles, the degree of elution control of the desired drug particles, and the like. On the other hand, it adjusts in the range of 0.5-2.4 weight part. Preferably, it is 1.0-2.0 weight part. If the content of the inorganic particles with respect to the water-insoluble polymer is less than 0.5 parts by weight, the drug particle elution control effect cannot be obtained, while if it exceeds 2.4 parts by weight, the coating layer becomes brittle. Cause.

In addition, the content of the inorganic particles with respect to the drug particles described above is appropriately adjusted according to the type of drug particles, the desired degree of elution control, etc., but preferably with respect to 2.4 parts by weight of the drug particles. 0.5 to 2.4 parts by weight, and more preferably 1.0 to 2.0 parts by weight. If the content of the inorganic particles relative to the drug particles is less than 0.5 parts by weight, a sufficient drug particle elution control effect may not be obtained, whereas if the content exceeds 2.4 parts by weight, the coating layer becomes brittle. It may cause a change.

In addition, the coating layer may be a known component used in a pharmaceutical formulation, for example, a water-soluble polymer, a binder, a disintegrant, a wax, a plasticizer, a saccharide, an acidulant, an artificial sweetener, a fragrance, 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 coating layer uses, for example, a solution (organic solvent solution or the like) or a dispersion (aqueous dispersion or the like) containing the above-described water-insoluble polymer, inorganic particles, and other additives (formulation ingredients) as a coating solution. Can be formed.
Examples of the solvent in the coating liquid include water and organic solvents. Examples of the organic solvent include alcohols (ethanol, propanol, isopropanol, etc.), hydrocarbons (n-hexane, cyclohexane, etc.), halogens, and the like. Alkanes (dichloromethane, chloroform, trichloroethane, carbon tetrachloride, etc.), ketones (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, and water-miscible organic solvents may be used as a mixed solvent with water.
Of these solvents, alcohols, ketones and water are preferred.

The concentration of the water-insoluble polymer in the coating liquid can be selected according to the viscosity, sprayability, etc. of the coating liquid, for example, 0.1 to 50% by weight, preferably 0.2 to 40% by weight, more preferably It is about 0.5-25 weight%, More preferably, it is about 1-10 weight%. Various additives described above may be added to the coating solution.

The coating layer can be formed on the surface of the drug particles by a known coating technique using, for example, a stirring fluidized bed device, a rolling fluidized bed device, a Wurster fluidized bed device, or a spray drying device. Especially, the spray-drying method using a spray-drying apparatus is suitable for manufacture of the particle formulation of this invention.
In the spray drying method, first, a coating liquid in which drug particles and each material constituting the coating layer are mixed or suspended is prepared and sprayed into a drying chamber of a spray dryer using a nozzle. The water or organic solvent in the atomized droplets formed by spraying volatilizes in a very short time, thereby producing a particle preparation in which drug particles are coated with a coating layer.
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 nozzle type and spraying conditions are not particularly limited as long as the coating liquid prepared as described above is sprayed. Such conditions can be appropriately selected according to the composition of the particle preparation 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 30 to 200 ° C, preferably about 40 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 diameter and nozzle diameter of the particle preparation to be produced.
If necessary, the above-mentioned particle preparation can completely remove the water or solvent in the drug particles under reduced pressure.

The average particle size of the particle preparation of the present invention is not particularly limited as long as the roughness in the oral cavity is reduced, but preferably 1 to 200 μm, more preferably 1 to 100 μm, still more preferably 1 to 50 μm, Most preferably, it is 1-15 micrometers. When the average particle size is less than 1 μm, the surface area of the particle preparation of the present invention increases, and it may be difficult to control the dissolution of drug particles. On the other hand, when the average particle size 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” as used herein refers to a particle size corresponding to 50% of the total particle volume, and is referred to as “automatic particle image analyzer”. And a “laser diffraction type particle size distribution measuring device” (or “laser diffraction scattering type particle size distribution measuring device”).

The particle preparation of 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 used as a raw material for producing such preparations. .
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 drug particles to be contained in these preparations can vary depending on the type of drug, dosage form, target disease, etc., but is usually preferably 0.001 mg to 5 g per preparation, It is preferably about 0.01 mg to 2 g.

The said formulation can be manufactured by the well-known method generally used.
Specifically, for example, the particle preparation of the present invention contains a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), carboxymethylcellulose, sodium alginate, etc.), storage Agents (eg, methyl paraben, propyl paraben, benzyl alcohol, chlorobutanol, etc.), isotonic 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, corn oil, propylene glycol, etc., and formed into an oily suspension to give an injection.

The oral preparation can be composed of the particle preparation of the present invention and a conventional preparation aid according to a known method.
The above formulation aids include components commonly used in oral formulations, 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 (starch such as crystalline cellulose, corn starch, sucrose, lactose, powdered sugar, granulated sugar, sugars such as glucose, mannitol, light anhydrous Silicic acid, talc, magnesium carbonate, calcium carbonate, etc.), disintegrants (eg starches such as corn starch, carmellose calcium, crospovidone, low substituted hydroxy) Propylcellulose, etc.), lipids (for example, 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 Acidulants such as tartaric acid and malic acid; flavors such as lemon, lemon lime, orange and menthol), lubricants (eg, magnesium stearate, calcium stearate, stearic acid, talc, etc.), fluidizing agents (eg, Light silicic acid anhydride, etc.), colorants (eg food Pigments, caramel, bengara, titanium oxide, etc.), surfactants (eg, anionic surfactants such as sodium alkyl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, and polyoxyethylene castor oil derivatives) Nonionic surfactants), wetting agents (polyethylene glycol (macrogol), etc.), preservatives or stabilizers such as fillers, extenders, adsorbents, preservatives, antistatic agents, disintegration extenders, etc. May be included.
Furthermore, the above oral preparation may be coated by a known method, if necessary, for the purpose of taste masking, solubility, entericity or persistence.

For example, in order to obtain a nasal preparation, the particle preparation of 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 state, the particle preparation of the present invention 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.) are added and mixed to obtain a powdery composition.

The liquid preparation is almost the same as in the case of injections, and is an 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.

Also, for example, to make a suppository, an oily or aqueous solid, semi-solid or liquid suppository is added by adding an oily base or an aqueous base to the particle preparation of the present invention according to a known method. be able to.
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 formulation can be obtained by formulating, after granulating or kneading the particle | grain formulation of this invention as needed, for example, according to the usual method according to the dosage form.
For granulation of the particle preparation of the present invention, a conventional granulation method such as a rolling granulation method or a fluidized bed granulation method can be adopted. It is carried out using a carrier such as a binder. For example, in the case of a tablet, the particle preparation of the present invention and a carrier such as an excipient or a binder are mixed or kneaded, granulated as necessary, and added with an additive such as a lubricant and compressed into tablets. Can be obtained. For example, a capsule can be obtained by encapsulating the particle formulation of the present invention or a granulated product thereof in a capsule.

The particle preparation of the present invention has a structure having drug particles and a coating layer covering the drug particles, and the coating layer is 0.5 to 2.4 wt.% With respect to 2.4 parts by weight of the water-insoluble polymer. By containing a part of the inorganic particles, even when the diameter of the drug particles is small, the drug particles can be effectively coated with the coating layer, and elution of the drug particles can be effectively suppressed.
In a preferred embodiment in which the water-insoluble polymer contains an enteric polymer, the coating layer contains inorganic particles, whereby the drug particles can be more effectively eluted in the intestine.
Further, in a preferred embodiment in which the coating layer includes hydrophobicized inorganic particles, the coating layer includes hydrophobicized inorganic particles, so that drug particles are more effectively eluted in the intestine. It becomes possible.

The present invention is specifically described by the following 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)
Ethylcellulose (Edocel 10 manufactured by Dow Chemical)
HPMCP; hydroxypropyl methylcellulose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd., HP55)
Eudragit S100 (Evonik Industries, Eudragit-S100)
Light anhydrous silicic acid (Aerosil-A200, Aerosil-R972, manufactured by Nippon Aerosil Co., Ltd.)
Titanium oxide (Nippon Aerosil Co., Ltd., Aeroxide-P25, Aeroxide-T805)
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 to obtain a solution. 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. As a result, spherical guaiacol potassium sulfonate particles were obtained.
(Coating)
All the formulation ingredients and drug particles were dissolved and suspended in a solvent. This suspension solution was spray-dried with a spray dryer (Mini Spray Dryer B-290, BUCHI Labortechnik AG) to obtain a particle preparation. Tables 1 to 3 show the composition of the formulation components, the spray liquid amount, the intake air temperature, and the spray air flow rate used in each example and comparative example.

(Measurement of average particle size)
<Average particle size of particle preparation>
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 average particle size of the inorganic particles was measured in advance prior to the 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.
Aerosil-A200 (average particle size 400.5 nm) as inorganic particles not subjected to hydrophobic treatment, Aerosil-R972 (average particle size 218.0 nm) as inorganic particles subjected to hydrophobic treatment, hydrophobic treatment Aeroxide-P25 (average particle size 128.2 nm) as inorganic particles, and Aeroxide-T805 (average particle size 111.4 nm) as hydrophobically treated inorganic particles.

(Dissolution test)
In accordance with the flow-through cell 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). A Masterflex L / S (model 7524-50, manufactured by Cole Palmer Instrument Company) was used as a liquid feed pump, 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.

(Examples 1-5)
As the water-insoluble polymer, ethyl cellulose as the sustained-release polymer was used, and the particle formulation was prepared by the above-mentioned method by changing the kind of the inorganic particles. The composition and various test results are shown in Table 1.

(Comparative Example 1)
A particle formulation was prepared in the same manner as in Example 1 except that inorganic particles were not added. The composition and various test results are shown in Table 1.

噴霧液量（５ｍＬ／ｍｉｎ）、吸気温度（１２０℃）、噴霧空気流量（４７０Ｌ／ｈｒ）

Spray liquid volume (5 mL / min), intake air temperature (120 ° C.), spray air flow rate (470 L / hr)

As shown in Table 1, the particle formulation according to the example containing a controlled release polymer as a water-insoluble polymer and inorganic particles in a predetermined weight ratio effectively controls (suppresses) drug elution. ) And showed characteristics as a sustained release formulation.
On the other hand, the particle formulation according to Comparative Example 1 containing no inorganic particles could not effectively control (suppress) drug elution.

(Examples 6 and 7)
A particle formulation was prepared using HPMCP as an enteric polymer and inorganic particles (Aerosil-R972) as the water-insoluble polymer. Table 2 shows the composition and various test results measured in the same manner as in Example 1.

(Comparative Example 2)
A particle formulation was prepared in the same manner as in Example 6 except that inorganic particles were not added. The composition and various test results are shown in Table 2.

噴霧液量（５ｍＬ／ｍｉｎ）、吸気温度（８０℃）、噴霧空気流量（４７０Ｌ／ｈｒ）

Spray liquid volume (5 mL / min), intake air temperature (80 ° C.), spray air flow rate (470 L / hr)

As shown in Table 2, the particle formulation according to the example containing an enteric polymer as a water-insoluble polymer and inorganic particles in a predetermined weight ratio is effective for drug elution under pH 1.2 conditions. Thus, the dissolution of the drug was promoted under the condition of pH 6.8, and the characteristics as an enteric agent were exhibited.
On the other hand, the particle formulation according to Comparative Example 2 not containing inorganic particles could not effectively control (suppress) drug elution.

(Examples 8 to 17)
Using water-insoluble polymer, ethyl cellulose as a release polymer and Eudragit S100 as an enteric polymer, particle preparations were prepared by changing the kind of inorganic particles. Table 3 shows the composition and various test results measured in the same manner as in Example 1.

(Comparative Example 3)
A particle formulation was prepared in the same manner as in Example 8 except that inorganic particles were not added. The composition and various test results are shown in Table 3.

噴霧液量（５ｍＬ／ｍｉｎ）、吸気温度（１２０℃）、噴霧空気流量（４７０Ｌ／ｈｒ）

Spray liquid volume (5 mL / min), intake air temperature (120 ° C.), spray air flow rate (470 L / hr)

As shown in Table 3, the particle formulations according to Examples 10, 11, and 15 to 17 using a combination of a water-insoluble polymer and hydrophobically treated inorganic particles are water-insoluble polymer, hydrophobic The enteric effect was particularly enhanced as compared with the particle preparations according to Examples 8, 9, and 12 to 14 that were used in combination with inorganic particles that had not been subjected to an organic treatment.
On the other hand, the particle formulation according to Comparative Example 3 containing no inorganic particles could not effectively control (suppress) drug elution.

In the present invention, by coating drug particles with a coating layer containing a water-insoluble polymer and inorganic particles, the drug particles can be effectively coated even when the particle diameter is small, and drug elution can be effectively suppressed.
Therefore, not only can it be administered to a living body as it is as a fine granule, it can also be molded into various preparations for administration.

Claims (7)

A particle formulation having drug particles and a coating layer covering the drug particles,
The particle formulation, wherein the coating layer contains 0.5 to 2.4 parts by weight of inorganic particles with respect to 2.4 parts by weight of the water-insoluble polymer. The particle preparation according to claim 1, wherein the average particle diameter of the inorganic particles is 1-1000 nm. The particle preparation according to claim 1 or 2, wherein the inorganic particles are silica and / or titanium dioxide. The particle formulation according to claim 1, 2 or 3, wherein the water-insoluble polymer comprises an enteric polymer. The particle preparation according to claim 1, 2, 3, or 4, wherein the inorganic particles have been subjected to a hydrophobic treatment. The particle formulation according to claim 1, 2, 3, 4, or 5 containing 0.5 to 2.4 parts by weight of inorganic particles with respect to 2.4 parts by weight of the drug particles. The particle formulation according to claim 1, 2, 3, 4, 5 or 6 obtained by a spray drying method.