JP2018044017A - Particulate preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a particulate preparation having an effectively controlled elution characteristic of the drug even when an average particle size is small.SOLUTION: The particulate preparation consists of drug particles and a coating layer that coats the drug particles. The coating layer contains 0.1-0.8 pts.wt. of lipid components against 2.4 pts.wt. of water-insoluble polymers, the water-insoluble polymers contain sustained-release polymers and enteric-coated polymers, and the lipid complements contain C15 or more fatty acids.SELECTED DRAWING: None

Description

The present invention relates to particle formulations.

Conventionally, in pharmaceutical solid preparations, drug bulk powder is granulated by adding a binder, excipient, etc., or the drug bulk powder is coated with a water-insoluble coating substance in order to control the drug dissolution characteristics, etc. It is.
For example, Patent Document 1 discloses a sustained-release fine-grain preparation in which a drug, a polymer compound (ethylcellulose and HPMCAS), stearic acid, and ethanol are melt-mixed. Patent Document 1 does not describe the particle size of the preparation, but fine granules produced by a conventional method are usually about 90 μm or more.
Further, for example, Patent Document 2 discloses a particle preparation in which a drug-containing particle (particle diameter: 50 to 250 μm) is coated with a lipid component and a polymer compound. In Example 4, a methacrylic acid copolymer ( Eudragit L) Coated drug particles coated with drug-containing particles by spraying a methanol solution containing 2% and 10% stearic acid are disclosed.

However, since the surface area of a drug generally increases as the particle size decreases, it is very difficult to control drug elution (particularly, elution suppression and bitterness masking) while miniaturizing the drug-containing particles. It was.

Japanese Patent Laid-Open No. 09-020663 Japanese Patent No. 3247511

In view of the above-described present situation, an object of the present invention is to provide a particle preparation in which the drug dissolution characteristics are effectively controlled even when the average particle size is small.

As a result of intensive investigations to solve the above problems, the present inventors have determined that the coating layer for coating drug particles contains a water-insoluble polymer and a lipid component in a predetermined weight ratio, thereby controlling drug elution. Has been found to be suitable, and the present invention has been completed.

That is, the present invention is a particle preparation having drug particles and a coating layer that coats the drug particles, wherein the coating layer has a lipid component of 0.1 with respect to 2.4 parts by weight of the water-insoluble polymer. A particle formulation comprising: -0.8 parts by weight, wherein the water-insoluble polymer comprises a sustained-release polymer and an enteric polymer, and the lipid component comprises a C15 or higher fatty acid. is there.
The sustained-release polymer preferably contains a water-insoluble cellulose derivative.
The enteric polymer preferably contains a (meth) acrylic acid copolymer.
Moreover, it is preferable that the said lipid component contains C15-C21 fatty acid.
The coating layer preferably further 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 inorganic particles preferably have an average particle diameter of 1 nm to 1000 nm.
The inorganic particles are preferably silica and / or titanium dioxide.
Moreover, it is preferable that the said inorganic particle is a thing hydrophobized.
In the particle preparation of the present invention, the coating layer preferably has a two-layer structure.
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 drug elution 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, antibacterial agents, drugs for 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 the drug. 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 size of the drug particles has the same meaning as the average particle size 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 a lipid component.
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 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 them, hydroxypropylmethylcellulose phthalate and methacrylic acid copolymer 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 lipid component constituting the coating layer, various physiologically or pharmacologically acceptable materials can be used.
Examples of such lipid components include fatty acids (palmitic acid, stearic acid, arachidic acid, behenic acid, etc.), higher alcohols (cetyl alcohol, palmityl alcohol, stearyl alcohol, etc.), fatty acid esters (glyceryl monostearate, glyceryl). Monopalmitate, glyceryl behenate, etc.), hardened oil (hydrogenated castor oil, etc.), solid fats and oils (cocoa butter, etc.), waxes (beeswax, white beeswax, carnauba wax, etc.). These lipid components are used alone or in combination of two or more.

In the particle formulation of the present invention, the lipid component contains a fatty acid of C15 or higher. When the lipid component is a fatty acid of less than C15, the drug elution control cannot be sufficiently performed.
Especially, it is preferable that the said lipid component contains C15-C21 fatty acid. By including C15-C21 fatty acid as the lipid component, drug elution can be effectively controlled even when the particle size of the particle preparation of the present invention is small.
The C15 or higher fatty acid means a fatty acid having 15 or more total carbon atoms contained in the molecule.
The C15-C21 fatty acid means a fatty acid having a total number of carbon atoms in the molecule of 15-21, and examples thereof include palmitic acid, stearic acid, arachidic acid, etc. Stearic acid is particularly preferred. By containing stearic acid as the lipid component, drug elution control can be performed to a high degree.

In the particle preparation of the present invention, the content of the lipid component with respect to the water-insoluble polymer described above is based on 2.4 parts by weight of the water-insoluble polymer depending on the type of drug particles, the degree of elution control of the desired drug, and the like. And within the range of 0.1 to 0.8 parts by weight. Preferably, the amount is 0.15 to 0.75 parts by weight, and more preferably 0.2 to 0.55 parts by weight with respect to 2.4 parts by weight of the water-insoluble polymer.
When the content of the lipid component with respect to the water-insoluble polymer is less than 0.1 parts by weight, when the particle preparation of the present invention is an enteric preparation, it becomes difficult for the drug to be eluted in a neutral region. The characteristics of will not be fully demonstrated. On the other hand, when it exceeds 0.8 parts by weight, it becomes difficult to form an effective coating layer, and the elution of the drug cannot be controlled.

The coating layer preferably further contains inorganic particles.
When the coating layer further contains inorganic particles, higher drug elution control is possible.

As the inorganic particles, 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.).

The inorganic particles are preferably those that have been subjected to a hydrophobic treatment. Since the inorganic particles are rendered hydrophobic, higher drug elution control is possible.
The term “hydrophobized” as used herein means that the surface is chemically alkylated.
As a specific example of the hydrophobizing treatment, in the case of light anhydrous silicic acid, the surface of the light silicic anhydride is covered with a methyl group to be hydrophobized. In the case of the treated titanium oxide, one obtained by chemically treating titanium oxide with octylsilane to make it hydrophobic.

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 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 may be difficult to uniformly and densely fill the layer, and drug elution may not be controlled.
The average particle diameter of the inorganic particles 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 relative to the water-insoluble polymer described above is based on 2.4 parts by weight of the water-insoluble polymer, depending on the type of drug particles, the desired level of drug elution control, and the like. It is preferable to adjust in the range of 0.5 to 2.4 parts by weight, and more preferably 1.0 to 2.0 parts by weight. When the content of the inorganic particles with respect to the water-insoluble polymer is less than 0.5 parts by weight, the drug elution control effect may not be obtained. On the other hand, when the content exceeds 2.4 parts by weight, the coating layer is brittle. It may cause a change.

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 with respect to the drug particles is less than 0.5 parts by weight, a sufficient drug 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.

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.

Moreover, the said coating layer may contain surfactant in order to improve the dispersibility of the drug particle in the coating liquid mentioned later as needed. These surfactants can be used alone or in combination of two or more. Examples of the surfactant include glyceryl monoisostearate.

In the particle preparation of the present invention, the coating layer may have a single-layer structure or a two-layer structure. When the coating layer has a two-layer structure, higher drug elution control is possible.
The coating layer having a two-layer structure means a structure in which another coating layer (second coating layer) is formed on the coating layer (first coating layer) coated with the drug particles. The first coating layer and the second coating layer may be composed of the same composition or may be composed of different compositions.

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 type spray dryer, the intake air temperature is appropriately adjusted depending on the solvent used, but is usually about 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.
In addition, the particle formulation coated with the above-described two-layer coating layer is formed by, for example, forming the first coating layer that coats the drug particles by the above-described spray drying method or the like, and then applying a coating solution having the same or different composition. And can be obtained by forming the second coating layer on the first coating layer formed by the above-described spray drying method or the like.

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 is increased, and drug elution control may be difficult. On the other hand, when the average particle diameter 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 refers to an “automatic particle image analyzer” (the particle image analyzer determines the particle size from the photographed particle image. 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, Preferably, it is 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.

Moreover, the said oral administration formulation can be comprised with the particle | grain formulation of 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 hydro Cypropylcellulose, etc.), lipids (eg, hydrocarbons, waxes, higher fatty acids and their salts, higher alcohols, fatty acid esters, hardened oils such as hardened castor oil, etc.), 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 anhydrous silicic acid, etc.), colorant (for example, Food coloring, caramel, bengara, titanium oxide, etc.), surfactant (for example, anionic surfactant such as sodium alkyl sulfate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, and polyoxyethylene castor oil derivative) Nonionic surfactants, etc.), wetting agents (polyethylene glycol (macrogol), etc.), fillers, extenders, adsorbents, preservatives and stabilizers such as preservatives, antistatic agents, disintegration extenders Etc. may be included.
Furthermore, the above-mentioned preparation for oral administration 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, for example, the particle formulation of the present invention and a carrier such as an excipient or a binder are mixed or kneaded, granulated as necessary, and an additive such as a lubricant is added to make a tablet. 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 0.1 to 0.8 weight with respect to 2.4 parts by weight of the water-insoluble polymer. By containing the lipid component in part, even when the diameter of the drug particles is small, the drug particles can be effectively coated with the coating layer, and drug elution can be effectively suppressed.
In a preferred embodiment in which the water-insoluble polymer contains an enteric polymer, the coating layer contains a lipid component, so that the drug can be more effectively eluted in the intestine. More preferably, the effect can be enhanced by containing 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 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)
Guayacol sulfonate potassium tamsulosin hydrochloride (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)
Myristic acid (Wako Pure Chemical Industries, reagent special grade)
Palmitic acid (Wako Pure Chemical Industries, reagent grade)
Stearic acid (made by Wako Pure Chemical Industries, special grade reagent)
Arachidic acid (Wako Pure Chemical Industries, reagent grade)
Behenic acid (manufactured by Wako Pure Chemical Industries, Ltd., for chemical use)
Hydrophobic light silicic anhydride (manufactured by Nippon Aerosil Co., Ltd., Aerosil-R972)
Glyceryl monoisostearate (Nikko Chemicals, NIKKOL-MGIS)

Moreover, in the following Examples and Comparative Examples, particle preparations were produced and evaluated by the following methods.
(Production of potassium guaiacol sulfonate 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.
(Production of tamsulosin hydrochloride drug particles)
Tamsulosin hydrochloride particles were obtained as drug particles by physical pulverization of tamsulosin hydrochloride using a jet mill (spiral jet mill 50AS manufactured by Hosokawa Micron Corporation).
(Coating)
The formulation ingredients and drug particles were suspended in a solvent. The obtained suspension was spray-dried with a spray dryer (Mini Spray Dryer B-290, manufactured by BUCHI Labortechnik AG) to obtain a particle preparation. The composition of the formulation component used in each example and comparative example is shown in the table.

(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 size 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 preparation.
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 diameter of the inorganic particles used in the examples is shown below.
Aerosil-R972 (average particle size 218.0 nm) as hydrophobically treated inorganic particles

(Dissolution test)
According to the flow-through cell method described in the Japanese Pharmacopoeia, Dissolution Test 1st liquid (pH 1.2), Dissolution Test 2nd liquid (pH 6.8), or pH 7.2 disodium hydrogen phosphate / citrate buffer Solution (7.1 g of anhydrous disodium hydrogen phosphate dissolved in water to 1000 mL. To this solution, 5.3 g of citric acid monohydrate dissolved in water to 1000 mL was added to adjust to pH 7.2. The test was carried out with any of the test solutions.
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 eluate was collected 60 minutes after the start of the test, and the elution amount of the drug in the collected eluate was measured by high performance liquid chromatography (HPLC) to calculate the elution rate relative to the initial drug content.

(Reference Example 1)
In the composition shown in Table 1, hydroxypropylmethylcellulose phthalate (HPMCP), hydrophobic light silicic anhydride (Aerosil-R972), glyceryl monoisostearate, stearic acid, and potassium guaiacol sulfonate were suspended in acetone.
The prepared suspension is spray-dried with a spray dryer (Mini Spray Dryer B-290, manufactured by BUCHI Labortechnik AG) under the conditions of a spray liquid amount of 5 mL / min, an intake air temperature of 120 ° C., and a spray air flow rate of 470 L / hr. A particle formulation was obtained. About this particle | grain formulation, the elution test was done with the test liquid of pH1.2 and pH7.2. The test results are summarized in Table 1.

(Comparative Example 1)
A particle formulation was obtained in the same manner as in Reference Example 1 except that stearic acid was not added. About this particle | grain formulation, the elution test was done with the test liquid of pH1.2 and pH7.2. The composition and test results are summarized in Table 1.

As shown in Table 1, the particle formulation according to Reference Example 1 containing HPMCP (enteric polymer) as a water-insoluble polymer and a lipid component in a predetermined weight ratio has an average particle size of 9.5 μm. The drug elution under pH 1.2 conditions can be effectively controlled (suppressed), the drug elution is promoted under pH 7.2 conditions, and elution at pH 7.2 and pH 1.2 The ratio of the ratio increased and showed the characteristics as an enteric preparation.
On the other hand, the particle formulation according to Comparative Example 1 containing no lipid component could not effectively promote drug elution under pH 7.2 conditions as compared with Reference Example 1.

(Example 2)
Ethyl cellulose, Eudragit S100, palmitic acid, hydrophobic light silicic anhydride (Aerosil-R972), glyceryl monoisostearate, and potassium guaiacol sulfonate drug particles having the composition shown in Table 2 were suspended in ethanol. The prepared suspension is spray-dried with a spray dryer (Mini Spray Dryer B-290, manufactured by BUCHI Labortechnik AG) under the conditions of a spray liquid amount of 5 mL / min, an intake air temperature of 120 ° C., and a spray air flow rate of 470 L / hr. A particle formulation was obtained. About this particle | grain formulation, the elution test was done with the test liquid of pH1.2 and pH7.2. The test results are summarized in Table 2.

(Example 3)
A particle formulation was obtained in the same manner as in Example 2 except that palmitic acid was changed to stearic acid. About this particle | grain formulation, the elution test was done with the test liquid of pH1.2 and pH7.2. The composition and test results are summarized in Table 2.

Example 4
A particle formulation having a two-layer coating layer was obtained in the same manner as in Example 3 except that the particle formulation obtained in Reference Example 1 was used in place of the potassium guaiacol sulfonate drug particles. About this particle | grain formulation, the elution test was done with the test liquid of pH1.2 and pH7.2. The composition and test results are summarized in Table 2.

(Example 5)
A particle formulation was obtained in the same manner as in Example 3 except that the amount of stearic acid was changed from 0.30 g to 0.60 g. About this particle | grain formulation, the elution test was done with the test liquid of pH1.2 and pH7.2. The composition and test results are summarized in Table 2.

(Example 6)
A particle formulation was obtained in the same manner as in Example 2 except that palmitic acid was changed to arachidic acid. About this particle | grain formulation, the elution test was done with the test liquid of pH1.2 and pH7.2. The composition and test results are summarized in Table 2.

(Example 7)
A particle formulation was obtained in the same manner as in Example 2 except that palmitic acid was changed to behenic acid. About this particle | grain formulation, the elution test was done with the test liquid of pH1.2 and pH7.2. The composition and test results are summarized in Table 2.

(Comparative Example 2)
A particle formulation was obtained in the same manner as in Example 3 except that the amount of stearic acid was changed from 0.30 g to 0.90 g. About this particle | grain formulation, the elution test was done with the test liquid of pH1.2 and pH7.2. The composition and test results are summarized in Table 2.

(Comparative Example 3)
A particle formulation was obtained in the same manner as in Example 2 except that palmitic acid was changed to myristic acid. About this particle | grain formulation, the elution test was done with the test liquid of pH1.2 and pH7.2. The composition and test results are summarized in Table 2.

As shown in Table 2, Eudragit S100 (enteric polymer) and ethyl cellulose (sustained release polymer) as water-insoluble polymers and fatty acids of C15 or more as lipid components are contained in a predetermined weight ratio. The particle preparations according to Examples 2 to 7 have an average particle size as small as 9.0 to 16.6 μm, and can effectively control (suppress) drug elution under pH 1.2 conditions. Under the condition of pH 7.2, elution of the drug was promoted, and the ratio of elution rate between pH 7.2 and pH 1.2 was increased, showing the characteristics as an enteric preparation. In addition, the particle formulation according to Example 7 using C22 behenic acid as a lipid component was slightly inferior in drug elution rate under other conditions than pH 7.2.
On the other hand, the particle formulation of Comparative Example 2 containing 0.90 part by weight of stearic acid as a lipid component and the particle formulation of Comparative Example 3 using myristic acid (C14) as a lipid component were subjected to pH 1.2 conditions. Drug elution control (suppression) was not possible, and the elution rate ratio between pH 7.2 and pH 1.2 became small.

(Example 8)
Ethyl cellulose, Eudragit S100, glyceryl monoisostearate, stearic acid, and tamsulosin hydrochloride drug particles having the composition shown in Table 3 were suspended in ethanol.
The prepared suspension is spray-dried with a spray dryer (Mini Spray Dryer B-290, manufactured by BUCHI Labortechnik AG) under the conditions of a spray liquid amount of 5 mL / min, an intake air temperature of 120 ° C., and a spray air flow rate of 470 L / hr. A particle formulation was obtained. About this particle | grain formulation, the elution test was done with the test liquid of pH1.2 and pH6.8. The test results are summarized in Table 3.

Example 9
A particle formulation was obtained in the same manner as in Example 8 except that hydrophobic light silicic anhydride (Aerosil-R972) was further added. About this particle | grain formulation, the elution test was done with the test liquid of pH1.2 and pH6.8. The composition and test results are summarized in Table 3.

(Comparative Example 4)
A particle formulation was obtained in the same manner as in Example 8 except that stearic acid was not blended. About this particle | grain formulation, the elution test was done with the test liquid of pH1.2 and pH6.8. The composition and test results are summarized in Table 3.

(Comparative Example 5)
A particle formulation was obtained in the same manner as in Example 9 except that stearic acid was not blended. About this particle | grain formulation, the elution test was done with the test liquid of pH1.2 and pH6.8. The composition and test results are summarized in Table 3.

(Comparative Example 6)
About the tamsulosin hydrochloride drug particle physically pulverized with a jet mill, an elution test was conducted with a test solution of pH 1.2 and pH 6.8. The test results are summarized in Table 3.

As shown in Table 3, the drug particles of Comparative Example 6 physically pulverized with a jet mill showed a high drug elution rate under the conditions of pH 1.2 and pH 6.8.
Particle formulation according to Example 8 containing Eudragit S100 (enteric polymer) and ethyl cellulose (sustained release polymer) as water-insoluble polymers and stearic acid which is C18 as a lipid component in a predetermined weight ratio. Has an average particle size as small as 10.6 μm, and can effectively control (suppress) the elution of the drug under the condition of pH 1.2, and the elution of the drug is promoted under the condition of pH 6.8, The elution rate ratio between pH 6.8 and pH 1.2 was increased, indicating the characteristics as an enteric preparation. On the other hand, the particle formulation according to Comparative Example 4 containing no lipid component cannot effectively promote the elution of the drug under the condition of pH 6.8, compared with Example 8, and the elution of pH 6.8 and pH 1.2. The rate ratio has become smaller.

In the case of tamsulosin hydrochloride, unlike the case of potassium guaiacol sulfonate, the elution of the drug under the condition of pH 6.8 is promoted without using hydrophobic light silicic acid, while the drug under the condition of pH 1.2 is used. Elution could be effectively controlled (suppressed). Moreover, drug elution under pH 1.2 conditions could be effectively controlled (suppressed) with a single layer coating without a two layer coating like potassium guaiacol sulfonate.

Contains Eudragit S100 (enteric polymer) and ethyl cellulose (sustained release polymer) as water-insoluble polymers, stearic acid C18 as a lipid component, and hydrophobic light anhydrous silicic acid in a predetermined weight ratio. The particle formulation according to Example 9 has an average particle size as small as 10.9 μm, and can effectively control (suppress) the elution of the drug under pH 1.2 conditions, and under pH 6.8 conditions. Elution of the drug was promoted, and the elution rate ratio between pH 6.8 and pH 1.2 was increased, indicating the characteristics as an enteric preparation. On the other hand, the particle formulation according to Comparative Example 5 containing no lipid component cannot effectively promote drug elution under the condition of pH 6.8 as compared with Example 9, and the elution of pH 6.8 and pH 1.2. The rate ratio has become smaller.

The particle formulation according to Example 8 that does not contain hydrophobic light silicic acid is a drug under pH 1.2 conditions compared to the particle formulation according to Example 9 that contains 0.60 parts by weight of hydrophobic light silicic acid. It was possible to control (suppress) drug elution under pH 6.8 conditions while effectively controlling (suppressing) elution. Thus, the dissolution of the drug under the pH 6.8 condition can be controlled while the drug elution under the pH 1.2 condition is effectively controlled (suppressed) by the addition of the hydrophobic light silicic acid. It was.

By changing the number of coatings, type of water-insoluble polymer, blending amount, blending amount of hydrophobic light anhydrous silicic acid, blending amount of lipid component according to the physical properties of the drug such as solubility, the acidic condition, neutrality It was possible to freely control the dissolution of the drug under the conditions.

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 as it is to a living body as a fine granule, but it can also be molded into various preparations for administration.

Claims (10)

A particle formulation having drug particles and a coating layer covering the drug particles,
The coating layer contains 0.1 to 0.8 parts by weight of a lipid component with respect to 2.4 parts by weight of the water-insoluble polymer.
The water-insoluble polymer includes a sustained-release polymer and an enteric polymer,
The particle component, wherein the lipid component contains a fatty acid of C15 or higher. The particle formulation according to claim 1, wherein the sustained-release polymer comprises a water-insoluble cellulose derivative. The particle preparation according to claim 1, wherein the enteric polymer contains a (meth) acrylic acid copolymer. The particle preparation according to claim 1, 2 or 3, wherein the lipid component contains C15-C21 fatty acid. The particle formulation according to claim 1, 2, 3 or 4, wherein the coating layer further 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 5, wherein the inorganic particles have an average particle diameter of 1 nm to 1000 nm. The particle preparation according to claim 5 or 6, wherein the inorganic particles are silica and / or titanium dioxide. The particle preparation according to claim 5, 6 or 7, wherein the inorganic particles have been subjected to a hydrophobic treatment. The particle preparation according to claim 1, 2, 3, 4, 5, 6, 7 or 8, wherein the coating layer has a two-layer structure. The particle preparation according to claim 1, 2, 3, 4, 5, 6, 7, 8, or 9 obtained by a spray drying method.