WO2010092925A1 - Dispersion solide, composition pharmaceutique comprenant celle-ci et procédés de production de la dispersion solide et de la composition pharmaceutique - Google Patents

Dispersion solide, composition pharmaceutique comprenant celle-ci et procédés de production de la dispersion solide et de la composition pharmaceutique Download PDF

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WO2010092925A1
WO2010092925A1 PCT/JP2010/051780 JP2010051780W WO2010092925A1 WO 2010092925 A1 WO2010092925 A1 WO 2010092925A1 JP 2010051780 W JP2010051780 W JP 2010051780W WO 2010092925 A1 WO2010092925 A1 WO 2010092925A1
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solid dispersion
water
weight
soluble
carrier
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PCT/JP2010/051780
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English (en)
Japanese (ja)
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一志 吉田
教道 大窪
純一 坂田
一 金澤
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あすか製薬株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention includes a solid dispersion using a powdered porous carrier and improved in the dissolution of an active ingredient hardly soluble in water (such as a fibrate active ingredient), and the solid dispersion.
  • the present invention relates to pharmaceutical compositions and methods for producing them.
  • Active ingredients that are sparingly soluble in water have a low elution or dispersibility, so that the bioavailability (bioavailability or bioavailability) is significantly reduced.
  • various pharmaceutical formulations such as refinement of active ingredients, solid dispersions in which active ingredients are dispersed in a carrier that solubilizes active ingredients, powdered porous carriers Solid dispersions in which active ingredients are impregnated and supported are being studied.
  • Non-patent Document 1 Colloidal silica, which is one of porous powders, is used as a carrier, and the solubility of poorly soluble drugs is improved by spray drying from an aqueous system.
  • Non-patent Document 2 carrier colloidal silica is added to indomethacin or tolbutamide to change the crystallinity of the active ingredient and improve the dissolution.
  • Patent Document 1 itraconazole is mixed with an inorganic porous substance (calcium silicate, light anhydrous silicic acid, etc.) to improve the dissolution property of itraconazole.
  • Patent Document 2 itraconazole solution is adsorbed and / or coated on a core substance made of silicic acid or a salt thereof to improve the bioavailability of itraconazole.
  • Patent Document 3 discloses a pharmaceutical composition and a cosmetic composition containing hydrophobic and highly dispersible silicon dioxide having a tamped density of 70 to 400 g / L of silicon dioxide.
  • Patent Document 4 discloses a tablet obtained by tableting a mixture of composite particles obtained by spray-drying a drug such as indomethacin and acetaminophen and silica and other components. .
  • Patent Document 5 International Publication No. WO 2004/096280 pamphlet is obtained by treating a composition containing an extremely poorly water-soluble drug and a porous material with a supercritical liquid or subcritical liquid of carbon dioxide.
  • a drug-containing composition is disclosed.
  • This document also describes an example using true spherical porous silica “Sunsphere H-51” (Asahi Glass Co., Ltd.) together with “Silicia” (Fuji Silysia Co., Ltd.) as silicic acid or a salt thereof. It is described that the dissolution property of the drug from the composition is improved.
  • Patent Document 6 describes a solid oral dosage form comprising a fibrate dissolved in a vehicle (vehicle such as polyethylene glycol) that is hydrophobic, hydrophilic or water miscible, and further enhanced.
  • a solid dosage form comprising a dosage form is disclosed and Aeroperl TM 300 (Degussa) is also described as a carrier or excipient (oil absorbing material).
  • the vehicle is in liquid form, the liquid vehicle is held at a temperature below the melting point of the fibrate, the desired amount of fibrate is dissolved in the vehicle, and the resulting solution is a solid having a temperature below the melting point of the vehicle.
  • a method is also described in which a solid oral dosage form is prepared by spraying on a carrier and mechanically treating the resulting composition to obtain particles, followed by subjecting the particulate material to conventional methods.
  • this method it is necessary to prepare a solid dispersion by heating and dissolving the fibrate in a vehicle, and to spray the molten solid dispersion on a carrier, which requires a special spray device, The operation is complicated. Also, in order to prepare a solid dispersion, a relatively large amount of vehicle is required for the fibrate.
  • the active ingredient is unevenly distributed on the surface of the carrier, and the dissolution property of the fibrate from the solid dosage form is It is dominated by the molten solid dispersion with the vehicle and the elution of fibrate cannot be greatly improved. Therefore, it is difficult to greatly improve the bioavailability of fibrates with a small content while miniaturizing the preparation.
  • the stability of the active ingredient may be impaired depending on the combination of the porous carrier and the active ingredient (such as a fibrate active ingredient).
  • the object of the present invention is to impregnate and support a porous carrier with an active ingredient (fibrate compound, etc.) that is sparingly soluble in water, and also relates to an active ingredient having a lower content than conventional preparations.
  • Another object of the present invention is to provide a solid dispersion capable of reducing the size of the preparation, a method for producing the same, and a pharmaceutical composition (or pharmaceutical preparation) composed of the solid dispersion.
  • Still another object of the present invention is to provide a solid dispersion that can improve the dissolution of an active ingredient even if it is compression-molded, a method for producing the same, and a pharmaceutical composition (or pharmaceutical preparation) composed of the solid dispersion.
  • Another object of the present invention is to provide a solid dispersion capable of improving the stability even if it is a poorly water-soluble active ingredient whose stability is impaired by the powdered porous silicon-based carrier, and a pharmaceutical composition comprising the solid dispersion To provide things.
  • Still another object of the present invention is to provide a method for easily and easily producing a solid dispersion and a pharmaceutical composition comprising the solid dispersion.
  • the inventors of the present invention have used a porous carrier (particularly, a low-viscosity active ingredient (such as a fibrate compound)) and a low-viscosity water-soluble additive ingredient.
  • a porous carrier particularly, a low-viscosity active ingredient (such as a fibrate compound)
  • a low-viscosity water-soluble additive ingredient such as a fibrate compound
  • the solid dispersion of the present invention comprises an active ingredient that is sparingly soluble in water, a water-soluble additive component that has a 2% display viscosity of 500 mPa ⁇ s or less (eg, 100 mPa ⁇ s or less) at 20 ° C., and It is comprised with the powdery porous silicon-type support
  • carrier which impregnates and carries an active ingredient and an additive component.
  • the porous silicon-based carrier may be at least one amorphous or spherical carrier selected from silicon dioxide and silicate compounds.
  • the porous silicon-based carrier may be a carrier with a small loss on heating.
  • the concentration of silanol groups is reduced by surface treatment with an organic or inorganic coupling agent or the like, or heat treatment such as firing.
  • the porous silicon-based carrier is reduced when it is heated at a temperature of 950 ° C. for 2 hours in accordance with a test method such as the Japanese Pharmacopoeia 2.43 “Ignition loss test method”. May be 10% by weight or less (for example, 7.5% by weight or less, particularly 4% by weight or less).
  • the weight loss (ignition weight loss) of the porous silicon-based carrier may be particularly 3.5% by weight or less (for example, 3.0% by weight or less).
  • the porous silicon-based carrier may be a spherical porous silicon-based carrier, or spherical silica having an oil absorption of 200 to 400 ml / 100 g and a specific surface area of 300 to 1000 m 2 / g.
  • the active ingredient may be a physiologically active ingredient or a pharmacologically active ingredient.
  • the pharmacologically active ingredient include hyperlipidemic agents, antihypertensive agents, antiobesity agents, diuretics, antithrombotic agents, antidiabetic agents, antidiabetic complications and the like.
  • the pharmacologically active ingredient is a fibrate compound such as bezafibrate, clinofibrate, clofibrate, fenofibrate, beclobrate, vinylibrate, ciprofibrate, etofibrate, gemfibrozil, nicofibrate, pilifibrate, lonfibrate, simfibrate, simfibrate , Theophibrate or a free acid thereof, or an active metabolite or a salt thereof.
  • the supported amount of the active ingredient may be about 0.01 to 5 parts by weight with respect to 1 part by weight of the powdery porous carrier. *
  • the crystalline active ingredient may be supported on a porous carrier in a crystalline, semi-crystalline or amorphous form. In many cases, the crystalline active ingredient is supported in an amorphous form.
  • the water-soluble additive component may be at least one selected from, for example, a water-soluble polymer, a saccharide, and a surfactant.
  • the water-soluble additive component is vinyl pyrrolidone homo- or copolymer, carboxy vinyl polymer, acrylic acid homo- or copolymer, polyvinyl alcohol, polyethylene glycol, cellulose ethers, saccharides, sugar alcohols, anionic interface It may be at least one selected from an active agent and a nonionic surfactant.
  • the water-soluble additive component may contain a combination of a water-soluble polymer and at least one selected from saccharides and surfactants, for example, a water-soluble polymer composed of at least cellulose ethers.
  • the amount of the water-soluble additive component used is 0.1 to 100 parts by weight, particularly 1 to 50 parts by weight (for example, 3 to 50 parts by weight), based on 100 parts by weight of the active ingredient hardly soluble in water. In particular, it may be about 5 to 30 parts by weight. Further, when a plurality of water-soluble additive components are used, the ratio of each water-soluble additive component is about 1 to 30 parts by weight with respect to 100 parts by weight of the active ingredient hardly soluble in water. Also good. Active ingredients and additive components (water-soluble additive components) that are sparingly soluble in water are usually impregnated and supported uniformly throughout the porous carrier.
  • the solid dispersion corresponds to at least one powdery porous carrier selected from amorphous silicate compounds, amorphous silica, spherical silicate compounds and spherical silica, and fenofibrate and fenofibrate.
  • fenofibrate components selected from free acids or active metabolites, at least one water-soluble cellulose ether selected from hydroxypropylcellulose and hydroxypropylmethylcellulose, anionic surfactants and nonionic surfactants
  • the water-soluble cellulose ethers based on 1 part by weight of the fenofibrate component, and the ratio of the fenofibrate component to 0.2 part by weight of 1 part by weight of the powdered porous carrier
  • the solid dispersion of the present invention can be prepared without treatment with a supercritical fluid or a subcritical fluid.
  • the solid dispersion of the present invention can be obtained without spraying the melt of the solid dispersion in which the active ingredient is dissolved or dispersed in the form of molecular or fine particles in the meltable organic matrix component onto the porous carrier.
  • the active ingredient may be impregnated and supported on a porous carrier, and is usually supported uniformly.
  • an active ingredient that is sparingly soluble in water is supported on a powdery porous carrier without treatment with a supercritical fluid (such as supercritical water) or a subcritical fluid (such as subcritical water).
  • a solid dispersion is produced.
  • an organic solvent solution room temperature, particularly a liquid solution at a temperature of 10 ° C.
  • a solid dispersion in which the active component and additive component are supported on the porous carrier can be produced.
  • the organic solvent solution is usually liquid at a temperature of 10 ° C., and the powdered porous silicon-based carrier is immersed in the organic solvent solution at room temperature, the powdered porous silicon-based carrier is impregnated with the organic solvent solution, and the mixture is dried. Then, the organic solvent may be removed. More specifically, the solid dispersion may be produced by spray-drying a mixed solution of an organic solvent solution of an active ingredient and a water-soluble additive component and a powdered porous silicon-based carrier.
  • the present invention also includes a pharmaceutical composition composed of the solid dispersion.
  • This pharmaceutical composition may further comprise at least one carrier component selected from excipients, binders, disintegrants and lubricants.
  • the pharmaceutical composition is preferably a preparation (solid preparation) in which a solid dispersion is compression-molded.
  • a pharmaceutical composition is produced through at least a step of compressing the solid dispersion.
  • the “solid dispersion” means a dispersion in which an active ingredient is dispersed and supported in a fine porous or molecular state on a solid porous carrier as a porous matrix, and is a meltable solid.
  • a meltable dispersion (solid dispersion) in which an active ingredient is dissolved or dispersed in a fine particle or molecular state in a matrix does not include a form supported on a solid porous carrier.
  • a porous silicon-based carrier having a small loss on heating (ignition loss) when heated at a temperature of 950 ° C. for 2 hours is simply referred to as “first porous carrier”, and a porous material having a large loss on heating (loss on ignition).
  • the silicon-based carrier may be simply referred to as “second porous carrier”.
  • the porous carrier is impregnated with a water-soluble additive component and an active ingredient that is sparingly soluble in water, the elution or dispersibility of the water-insoluble active ingredient can be greatly improved. Therefore, the bioavailability can be greatly improved regardless of the content of the active ingredient which is smaller than that of the conventional preparation.
  • the formulation pharmaceutical composition or pharmaceutical formulation
  • the elution property of the active ingredient can be greatly improved even by compression molding.
  • even a poorly water-soluble active ingredient such as fenofibrate
  • whose stability is impaired by the powdery porous silicon-based carrier can be improved by the water-soluble additive component.
  • a pharmaceutical composition composed of a solid dispersion and a solid dispersion can be obtained by a simple operation of impregnation and drying without treatment with a supercritical fluid (supercritical water, etc.) or a subcritical fluid (subcritical water, etc.). Easy to manufacture.
  • FIG. 1 is an infrared absorption spectrum of the first porous carrier A used in Examples 1 and 3.
  • FIG. 2 is an infrared absorption spectrum of the first porous carrier B used in Examples 2 and 5.
  • FIG. 3 is an infrared absorption spectrum of the second porous carrier used in Examples 3 and 4.
  • FIG. 4 is a graph showing the results of dissolution tests of the tablets of Examples 1 to 5 and the control preparation.
  • FIG. 5 is a graph showing the results of the absorbability test of the tablet of Example 1 and the control preparation.
  • the solid dispersion of the present invention comprises an active component that is sparingly soluble in water, a low-viscosity water-soluble additive component, and a powdery porous carrier (powdered porous silicon-based) that is impregnated and supported with these components Carrier).
  • the active ingredient and the water-soluble additive component are usually impregnated or infiltrated and supported on a powdered porous carrier as a porous matrix, and are uniformly impregnated and supported throughout the powdered porous carrier.
  • the solid dispersion of the present invention comprises a supercritical fluid (such as supercritical water) or a subcritical fluid containing a composition containing an active component hardly soluble in water, a water-soluble additive component, and a powdered porous carrier.
  • a meltable dispersion prepared without treatment with a fluid (such as subcritical water) and having active ingredients dissolved or dispersed in a meltable organic solid matrix in the form of fine particles or molecules.
  • the molten solid dispersion is prepared without being sprayed and supported on the solid porous carrier.
  • Powdered porous silicon-based carriers include inorganic silicon compounds such as silicon oxide (silicon dioxide, hydrous silicon dioxide, silica, etc.), silicate compounds [eg silicic acid (eg, light anhydrous silicic acid, etc.), silicates, etc. (For example, calcium silicate, magnesium silicate, aluminum silicate, magnesium aluminum silicate, magnesium aluminate silicate, magnesium magnesium metasilicate, synthetic magnesium sodium silicate, colloidal hydrous aluminum silicate, etc.)] it can.
  • the porous silicon-based support is composed of at least one selected from silicon dioxide (including hydrous silicon dioxide or silica) and a silicate compound (such as silicic acid) (particularly, silicon dioxide or silica, light anhydrous silicic acid, etc.).
  • the powdery porous silicon-based carrier is often at least one powdery porous carrier selected from amorphous silicate compounds, amorphous silica, spherical silicate compounds and spherical silica. These carriers can be used alone or in combination of two or more.
  • the porous silicon-based carrier may be untreated and has silanol groups (for example, about 0 to 5.5% by weight, preferably about 2.5 to 5% by weight of silanol groups). May be.
  • silanol groups for example, about 0 to 5.5% by weight, preferably about 2.5 to 5% by weight of silanol groups.
  • the carrier has a high binding ability (shaping ability) and is suitable for use as an excipient.
  • the silicon-based carrier has, for example, a silanol group concentration of 0.5 to 4% by weight, preferably 1 to 3.5% by weight, more preferably 1.5 to 3% by weight (for example, The carrier may be reduced or adjusted to about 1.5 to 2.5% by weight.
  • the silicon-based carrier is treated with a surface treatment agent or a surface modifier (such as a coupling agent) and / or heat treatment such as firing to produce a silanol group. May be reduced or adjusted.
  • the heat treatment such as firing is performed in an atmosphere containing oxygen-containing gas (air, etc.), inert gas (eg, rare gas such as nitrogen gas, helium gas, argon gas, carbon dioxide gas, etc.), hydrogen gas, etc., at a temperature of 500-2000.
  • the reaction can be performed at a temperature of about 0 ° C. (preferably 800 to 1700 ° C., more preferably 1000 to 1500 ° C.).
  • the heat treatment time may be, for example, about 10 minutes to 24 hours (eg, 30 minutes to 12 hours, particularly 1 to 6 hours).
  • the porous carrier may be calcined silica (fumed silica).
  • the porous carrier may be granulated.
  • a conventional granulation method such as rolling granulation or fluidized bed granulation can be used, and granulation may be performed in accordance with the surface treatment and / or heat treatment.
  • the loss on heating (loss on ignition) of the porous silicon-based carrier can be selected from the range of 15% by weight or less, usually 10% by weight or less (eg, 0 to 9% by weight), preferably Is 7.5% by weight or less (eg 0 to 6% by weight), more preferably 6% by weight or less (eg 0 to 5.5% by weight), in particular 5% by weight or less (eg 4.5% by weight or less). ). Even if granules and tablets are prepared by compression molding, it is advantageous to use a carrier having a low loss on heating (loss on ignition) in order to improve the dissolution of the active ingredient.
  • a preferred porous silicon-based carrier has a loss on heating (loss on ignition) of 4% by weight or less (eg, 3.5% by weight or less), preferably 3.0% by weight or less, more preferably 2.5% by weight or less ( For example, it may be 2% by weight or less.
  • the loss on heating (loss on ignition) may be about 0.3 to 3.5% by weight (for example, 0.5 to 3% by weight), or 0 to 2.5% by weight (for example, 0 to 2% by weight). %) Degree.
  • Such heat loss is dried (drying at 105 ° C. for 2 hours) to remove moisture (for example, adsorbed water), then the Japanese Pharmacopoeia 2.43 “Ignition Loss Test Method”, etc. In accordance with the test method, it can be measured by heating at a temperature of 950 ° C. for 2 hours and calculating the weight loss of the carrier after heating.
  • the form of the porous silicon-based carrier may be amorphous, spherical, ellipsoidal, polyhedral, prismatic or the like, and is usually spherical or elliptical (particularly spherical) in many cases.
  • a spherical porous carrier When a spherical porous carrier is used, the preparation can be miniaturized due to high fluidity and small bulk density, and the preparation workability of the preparation including processes such as handling and tableting can be improved.
  • a porous silicon-based carrier usually shows an absorption peak at a wave number of 3400 to 3500 cm ⁇ 1 (for example, a wave number of 3440 to 3480 cm ⁇ 1 ) in an infrared absorption spectrum. Depending on the measurement conditions, the absorption intensity may vary in the wave number range.
  • a preferable porous carrier (such as the carrier having the above-mentioned heat loss characteristics) has a wave number of at least 3100 to 3550 cm ⁇ 1 , particularly 3200 to 3400 cm ⁇ 1 (for example, 3300 to 3350 cm ⁇ ) in the infrared absorption spectrum as compared with light anhydrous silicic acid. It has a feature that the absorption intensity in the region 1 ) is small.
  • the absorption intensity at wave number 3800 cm -1 I 0, the absorption intensity at wave number 3650 cm -1 I 1, the absorption intensity at wave number 3600 cm -1 I 2, at wave number 3550 cm -1 absorption intensity of I 3, the absorption of the absorption intensity at wave number 3500 cm -1 in I 4, the absorption intensity at a wavenumber 3450cm -1 I 5, I 6 the absorption intensity at wave number 3400 cm -1, wave number 3350 cm -1 intensity I 7, when I 8 the absorption intensity at wave number 3300 cm -1, the absorption intensity at wave number 3200 cm -1 I 9, the absorption intensity at wave number 3100 cm -1 was I 10, at least one intensity ratio It may be as follows.
  • Intensity ratio to absorption intensity I 0 (1-1) Intensity ratio (I 1 / I 0 ): 1 to 15 (eg, 2 to 12), preferably 3 to 10 (eg, 3.5 to 9. 5), more preferably about 3.7 to 9 (for example, 4 to 8.5)
  • a preferable intensity ratio (I 1 / I 0 ) is 1 to 7 (for example, 2 to 6.7), preferably 3 to 6 0.5 (eg, 3.5 to 6.5), more preferably 3.7 to 6.3 (eg, 4 to 6.2), particularly 4.5 to 6.3 (eg, 5 to 6.2).
  • the preferred intensity ratio (I 3 / I 0 ) is 2.5 to 42 (eg 7.5 to 40), preferably 10 to 38 (eg 12 to 38), more preferably 15 to 37.
  • intensity ratio (I 4 / I 0 ) is 3-75 (e.g., 10-70), preferably 15 to 70 (e.g., 20 to 65), more preferably from 25 to 62 (For example, 27 to 61), usually 30 to 75 (for example, 35 to 73), particularly, for example, about 38 to 70 (1-5) intensity ratio (I 5 / I 0 ): 5 to 150 (for example, 10 To 145), preferably 20 to 140 (for example, 25 to 135), more preferably about 30 to 130 (for example, about 35 to 125)
  • the preferred intensity ratio (I 5 / I 0 ) is 5 to 105 (for example, 10 to 100).
  • I 6 / I 0 degrees preferable intensity ratio ( I 6 / I 0 ) is 3.5 to 75 (eg 10 to 75), preferably 15 to 75 (eg 20 to 73), more preferably 25 to 72 (eg 28 to 70), usually 35 ⁇ 85 (eg 40 to 80), especially about 45 to 75 (1-7)
  • the preferred intensity ratio (I 7 / I 0 ) is 2.5 to 47 (eg 5 to 45), preferably 10 to 45 (eg 12 to 42), more preferably 15 to 40 (eg 18 to 38).
  • 20 to 50 for example, 23 to 47
  • Preferred strength ratio (I 8 / I 0 ) is 1.5 to 27 (for example, 5 to 26), preferably 8 to 25 (eg 9 to 23), more preferably 10 to 22 (eg 11 to 21), usually 13 to 30 (eg 14 to 27), especially about 15 to 25 (1-9) intensity ratio (I 9 / I 0 ): 1-20 (eg, 3-18), preferably 4. 5 to 17 (for example, 5 to 16), more preferably about 5.5 to 15 (for example, 5.6 to 14).
  • Preferred strength ratio (I 9 / I 0 ) is 1 to 12 (for example, 3 to 11) , Preferably 4.5 to 10.5 (eg 5 to 10), more preferably 5.5 to 9.5 (eg 5.6 to 9), usually 6.0 to 12 (eg 6.
  • the preferred intensity ratio (I 10 / I 0 ) is 0.5 to 4.5 (for example, 1 to 4.5), preferably about 1.2 to 4.3 (eg, 1.3 to 4.2), more preferably about 1.3 to 4 (eg, 1.5 to 3.7). .
  • Intensity ratio to absorption intensity I 1 (2-1) Intensity ratio (I 3 / I 1 ): 3.5 to 10 (eg, 3.7 to 10), preferably 3.8 to 8 (eg, 3.9 to 7.5), more preferably about 4 to 7 (for example, 4.2 to 6.5).
  • the preferred intensity ratio (I 3 / I 1 ) is 3.5 to 5.8 (for example, 3.
  • the preferred intensity ratio (I 4 / I 1 ) is 6 to 10.5, preferably 6.3 to 10.3.
  • Preferred intensity ratio (I 5 / I 1 ) is 7 to 15, preferably 7.5 to 14.7 (eg, 8 to 14.5), more preferably 8.5 to 14.3 (eg, 9 to 14), usually 9.5 to 15 (for example, 9.8 to 14.8), particularly about 10 to 14.5 (2-4)
  • I 8 / I 1 is 2.3 to 3.8 (eg, 2.5 to 3.7), preferably 2.6 to 3.5 (eg, 2.7 to 3.5), and more preferably 2.8 to 3.4 (for example, 2.9 to 3.3) (2-7) Intensity ratio (I 9 / I 1 ): 1 to 1.7, preferably 1.1 to 1.6 ( For example, about 1.1 to 1.5).
  • Intensity ratio to absorption intensity I 2 (3-1) Intensity ratio (I 4 / I 2 ): 3 to 3.9 (eg, 3.2 to 3.9), preferably 3.2 to 3. 8 (for example, 3.1 to 3.7), particularly about 3.3 to 3.9 (for example, 3.4 to 3.8) (3-2) Intensity ratio (I 5 / I 2 ): 3. 5 to 5.6, preferably 3.7 to 5.5, more preferably 3.8 to 5.4 (eg 4 to 5.4), usually 4.2 to 5.6 (eg 4.
  • a preferred porous silicon-based support exhibits at least one strength ratio as follows.
  • Intensity ratio to absorption intensity I 0 (1-1) Intensity ratio (I 1 / I 0 ): 4.5 to 6.3 (for example, 5 to 6.2) (1-2) Intensity ratio (I 2 / I 0 ): 10 to 18 (for example, 11 to 17) (1-3) Intensity ratio (I 3 / I 0 ): 20 to 40 (for example, 22 to 37), particularly 23 to 36 (1-4) Intensity ratio (I 4 / I 0 ): 30 to 75 (for example, 35 to 73), particularly, for example, 38 to 70 (1-5) Intensity ratio (I 5 / I 0 ): 40 to 110 (eg 45 to 105), especially 50 to 100 (1-6) Intensity ratio (I 6 / I 0 ): 35 to 85 (for example, 40 to 80), particularly 45 to 75 (1-7) Intensity ratio (I 7 / I 0 ): 20-50 (for example, 23-47), especially 25-45 (1-8) Inten
  • an intensity ratio with respect to the absorption intensity I 2 (especially at least one of the intensity ratios (3-1) to (3-5), particularly the intensity ratios (3-1) to (3-3) (At least one strength ratio) can also be a useful indicator for identifying the first porous support.
  • the first porous carrier only needs to show at least one of the above-described strength ratios, and may be a plurality of strength ratios (for example, two strength ratios (I 2 / I 0 ) and strength ratio (I 3 / I 0 )). One intensity ratio) or all intensity ratios.
  • the intensity ratio based on the infrared absorption spectrum can be calculated based on the absorption intensity at each wave number by mixing and measuring about 200 mg of KBr and about 2 mg of carrier in a mortar according to the KBr method, preparing a plate.
  • the absorption intensity at a predetermined wave number can be represented by the height from the baseline in the infrared absorption spectrum chart.
  • a small absorption intensity value (for example, absorption intensity I 0 , I 1, etc.) can be measured accurately by expanding the infrared absorption spectrum, and in a region where the absorption intensity varies.
  • the value of the absorption intensity (for example, absorption intensity I 5 , I 6, etc.) averages the intensity of the fluctuation range of the infrared absorption spectrum, draws a gentle curve or straight line as a whole, and shows the intersection with a predetermined wave number as the intensity. Can be used as
  • the first porous carrier has a large number of fine pores, and the average pore diameter is, for example, 1 to 40 nm (eg, 5 to 40 nm), preferably 3 to 35 nm (eg, 7 to 35 nm), and The thickness is preferably about 5 to 30 nm (for example, 6 to 25 nm), particularly about 10 to 30 nm (for example, 15 to 25 nm).
  • the average pore diameter of the first porous carrier is preferably somewhat large, for example, 10 to 40 nm (for example, 12 to 35 nm), preferably 12 to 35 nm ( For example, it is about 13 to 30 nm), more preferably about 13 to 28 nm (for example, 15 to 25 nm), and may be about 15 to 20 nm.
  • the oil absorption of the first porous carrier is, for example, 75 to 500 (preferably 90 to 450, more preferably 100 to 400, particularly 150 to 380. (For example, about 170 to 350), usually about 200 to 320.
  • the preferred oil absorption is about 100 to 450, preferably about 150 to 400, particularly about 200 to 380 (eg, about 220 to 350), Usually, it is about 230 to 320.
  • the oil absorption amount of the porous carrier is preferably high, for example, 175 to 500 (for example, 200 to 500), Preferably 190 to 450 (eg 220 to 450), more preferably 200 to 400 (eg 230 to 400), especially 20-380 (e.g., 230-350) is about, may be about 230 to 320.
  • the average particle size of the first porous carrier by the laser diffraction method is, for example, 1 to 50 ⁇ m, preferably 2 to 45 ⁇ m (for example, 3 to 40 ⁇ m), more preferably 3 to 35 ⁇ m (for example, 5 to 30 ⁇ m). It may be a degree.
  • the average particle size of the first porous carrier is, for example, 1 to 25 ⁇ m (eg 7 to 25 ⁇ m), preferably 2 to 20 ⁇ m (eg 8 to 15 ⁇ m), more preferably 3 to 15 ⁇ m (eg 9 About 13 ⁇ m) or about 8 to 22 ⁇ m (for example, 10 to 12 ⁇ m).
  • the specific surface area (unit: m 2 / g) of the porous carrier by the BET method can be selected, for example, from the range of about 100 to 1200 m 2 / g (for example, 200 to 1000 m 2 / g), and usually 250 to 1200 ( For example, 300 to 1000), preferably 350 to 900 (for example, 400 to 900), more preferably 400 to 800 (for example, 400 to 600), particularly 450 to 850 (for example, 500 to 800). Good.
  • the pore volume (unit: ml / g) of the porous carrier can be selected, for example, from the range of about 0.1 to 5 ml / g, and is 0.5 to 5 (preferably 0.7 to 3, more preferably Is about 0.8 to 2.5, particularly about 1 to 2.
  • the sedimentation volume (apparent specific gravity, unit: ml / 5g) of the porous carrier by the stationary method is, for example, 10 to 120 (preferably 20).
  • a porous body having a high bulk density is preferred, and the bulk density of such a porous body is, for example, 10 to 50 (preferably 15 to 100). 45, more preferably about 20-40).
  • the first porous carrier has innumerable fine pores in the nanometer unit (the average pore diameter) inside, and is 50 to 85% (for example, 55 to 83%, preferably 60 to 80%) of the particle volume. More preferably, the space may occupy 65 to 80% (for example, about 70 to 80%).
  • the particle size distribution of the first porous carrier may be polydispersed, but is preferably monodispersed.
  • the first porous carrier is composed of monodisperse particles (for example, in a volume-based particle size distribution, the particle size distribution width D90 when the particle size having a cumulative frequency of 10% is D10 and the particle size having a cumulative frequency of 90% is D90.
  • / D10 may be about 1.2 to 3, preferably 1.3 to 2.7, and more preferably 1.5 to 2.5 (eg, 1.85 to 2.3).
  • the pH of the 5 wt% water slurry of the porous carrier may be about 4 to 8 (for example, 5 to 7).
  • porous carriers can be used alone or in combination of two or more.
  • a porous carrier especially spherical silica such as spherical silicon dioxide
  • ignition loss 4% by weight or less among the porous carrier
  • the bulk density is small, and the active ingredient is stably supported in a fine particle or molecular state.
  • the dissolution and bioavailability of the active compound can be greatly improved and the preparation can be miniaturized.
  • the dissolution of the active ingredient can be improved by preparing granules and tablets by compression molding.
  • Such a porous carrier (hereinafter, simply referred to as a first porous carrier) has a large loss in heating (loss in ignition) (for example, 4.5% by weight or more) (hereinafter simply referred to as a second porous carrier). May be used in combination with a carrier).
  • the former / the latter weight ratio
  • 20/80 to 100/0 for example, 30/70 to 100/0
  • the ratio of the second porous carrier is increased, the elution property of the active ingredient tends to be lowered.
  • the first porous carriers are “Cyrossphere” product numbers “C-1504” and “C-1510” (manufactured by Fuji Silysia Chemical Co., Ltd.), “Aero Pearl AEROPERL” product numbers “300/30” (Degussa) (Degussa)).
  • a preferred first porous carrier is a “thyrossphere”.
  • the first porous carrier can be obtained in a spherical form (a form such as spherical porous silica).
  • the second porous carrier may be amorphous or spherical (including a shape such as an ellipse). In many cases, amorphous light anhydrous silicic acid is used as the amorphous second porous carrier.
  • amorphous light anhydrous silicic acid examples include, for example, the Silicia series manufactured by Fuji Silysia Chemical Co., Ltd. (Silicia 250, Silicia 320, Silicia 350, Silicia 470, Silicia 440, Silicia 740, etc.), manufactured by Freund Corporation. Available as Adsolider series (AdSolider 101, AdSolider 102, etc.), Aerosil series (Aerosil 200, Aerosil 300, etc.) manufactured by Nippon Aerosil Co., Ltd. A spherical second porous carrier may be used.
  • Such a spherical second porous carrier is available, for example, as “Sunsphere” product numbers “H-51”, “H-52”, “H-53” (manufactured by Asahi Glass Co., Ltd.).
  • “Sunsphere” product numbers “H-51”, “H-52”, “H-53” manufactured by Asahi Glass Co., Ltd.
  • the spherical second porous carrier it is possible to improve the manufacturing workability of the preparation including processes such as handleability and tableting due to high fluidity and small bulk density.
  • the form of the active ingredient is not particularly limited, and may be crystallized or in an amorphous state.
  • the active ingredient even if the active ingredient is crystalline, it can be supported on the porous carrier (such as spherical porous silica) in an amorphous form. That is, even when the crystalline active ingredient is supported on a porous carrier (such as spherical porous silica) and subjected to X-ray diffraction and thermal analysis, no peak or endothermic peak due to crystals is observed. Therefore, in this invention, even if it is a crystalline active ingredient, an elution property can be improved effectively.
  • the porous silicon-based carrier functions as an excipient.
  • the powdery porous carrier may be composed of the porous silicon-based carrier alone, or may be used in combination with other porous carriers as necessary.
  • Such porous carriers include, for example, cellulose such as crystalline cellulose (porous cellulose, etc.), resins (ion exchange resins, thermoplastic resins, thermosetting resins, etc.), inorganic substances [activated carbon, minerals (zeolite, diatomaceous earth).
  • metal oxides alumina, zinc oxide, titanium dioxide, etc.
  • metal hydroxides alkaline earth metal hydroxides such as calcium hydroxide; aluminum hydroxide, etc.
  • metal carbonates Such as alkaline earth metal carbonates such as calcium carbonate
  • metal sulfates such as alkaline earth metal sulfates such as calcium sulfate
  • metal phosphates such as alkaline earth metal phosphates such as calcium phosphate
  • the hardly soluble active ingredient may have physiological activity or may have pharmacological activity.
  • the solubility of the poorly soluble active ingredient in water is 1 mg / ml or less, preferably 0.1 mg / ml or less, more preferably 0.01 mg / ml or less at a temperature of 25 ° C.
  • the kind of the poorly soluble active ingredient is not particularly limited, for example, hyperlipidemia treatment agent, angina treatment agent, hypertension treatment agent, hypotension treatment agent, anti-obesity agent, heart failure treatment agent, myocardial infarction treatment agent, Antiarrhythmic agent, antidiabetic agent, antidiabetic complication agent, peptic ulcer agent, antipyretic agent, analgesic agent, anti-inflammatory agent, healthy stomach / digestion / antacid / antiemetic agent, antitussive expectorant, bronchial asthma agent , Constipation treatment, diarrhea treatment, liver disease treatment, biliary / spleen treatment, acupuncture treatment, thyroid disease treatment, hyperuricemia treatment, rheumatism treatment, antibiotic, antidepressant, antiallergy Drugs, antituberculosis drugs, prostatic hypertrophy treatment drugs, osteoporosis treatment drugs, Alzheimer's disease treatment drugs and the like.
  • Antihyperlipidemic agents include HMG-CoA reductase inhibitors such as simvastatin, lovastatin, atorvastatin, pitavastatin, rosuvastatin, cerivastatin, itavastatin, ZD-4522 or salts thereof (eg, sodium salt, calcium salt, etc. )
  • Statin compounds fibrate compounds, probucol, nicotinic acid drugs (eg, nicomol, niceritrol, etc.), ethyl icosapentate, plant sterols (eg, soysterol), small intestine cholesterol transporter inhibitors (eg, Examples thereof include ezetimibe) and anion exchange resins (colestimide, cholestyramine).
  • Antihypertensive agents include, for example, angiotensin converting enzyme inhibitors (eg, temocapril, cilazapril, trandopril or salts thereof), angiotensin II antagonists (eg, candesartan cilexetil, eprosartan, valsantan, telmisartan, irbesartan, olmesartan medoxomil) , Tasosartan or salts thereof), calcium antagonists (eg, manidipine, nifedipine, nicardipine, amlodipine, efonidipine or salts thereof), potassium channel openers (eg, levucomacarim), clonidine hydrochloride, bunazosin hydrochloride, etc. It is done.
  • angiotensin converting enzyme inhibitors eg, temocapril, cilazapril, trandopril or salts thereof
  • Anti-obesity agents include, for example, central anti-obesity agents (for example, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex, etc.), pancreatic lipase Inhibitors (for example, orlistat), ⁇ 3 agonists, peptidic appetite suppressants (for example, leptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (for example, linchtripto), and the like.
  • central anti-obesity agents for example, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex, etc.
  • pancreatic lipase Inhibitors for example
  • therapeutic agents for heart failure include xanthine derivatives (for example, sodium salicylate theobromine, calcium salicylate theobromine), thiazide compounds (for example, ethiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penflutide , Polythiazide, methiclotiazide, etc.), non-thiazide compounds (methiclan, trypamide, etc.), anti-aldosterone compounds (eg spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg acetazolamide, etc.), chlorobenzenesulfonamide compounds (For example, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid, pire
  • heparin eg, heparin sodium, heparin calcium, dalteparin sodium
  • warfarin antithrombin drug (eg, argatroban)
  • thrombolytic drug eg, Urokinase, tisokinase,reteplase, nateplase, monteplase, pamitepase, etc.
  • platelet aggregation inhibitors for example, dibilidamole, cilostazol, icosapentate, etc.
  • Antidiabetic agents include, for example, insulin preparations, ⁇ -glucosidase inhibitors (eg, voglibose, acarbose, etc.), biguanides (eg, phenformin or salts thereof), insulin secretagogues [sulfonylurea agents (eg, Tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybsol, etc.), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate]], dipeptidyl peptidase IV inhibitor, ⁇ 3 Agonists, amylin agonists (eg, pramlintide), phosphotyrosine phosphatase inhibitors (eg, vanadic acid, etc.), gluconeogenesis inhibitors (eg, glycogen phospho) Lylase inhibitor
  • therapeutic agents for diabetic complications include aldose reductase inhibitors (for example, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, etc.), neurotrophic factors (for example, NGF, NT-3, etc.) , Neurotrophic factor production / secretion promoter, PKC inhibitor, AGE inhibitor, active oxygen scavenger (eg, thioctic acid), and cerebral vasodilator.
  • aldose reductase inhibitors for example, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, etc.
  • neurotrophic factors for example, NGF, NT-3, etc.
  • Neurotrophic factor production / secretion promoter for example, PKC inhibitor, AGE inhibitor, active oxygen scavenger (eg, thioctic acid), and cerebral vasodilator.
  • therapeutic agents for peptic ulcer include proton pump inhibitors (for example, omeprazole, lansoprazole, etc.), defense factor enhancers (for example, teprenone, metoclopramide, sofalcone, etc.) and the like.
  • proton pump inhibitors for example, omeprazole, lansoprazole, etc.
  • defense factor enhancers for example, teprenone, metoclopramide, sofalcone, etc.
  • therapeutic agent for rheumatism examples include immunosuppressants (for example, leflunomide, methotrexate, etc.), salazosulfapyridine, auranofin and the like.
  • antiallergic agents examples include antihistamines (for example, clemastine fumarate, loratadine, mequitazine, ebastine, oxatomide, pranlukast hydrate, bepotastine besylate, etc.).
  • antihistamines for example, clemastine fumarate, loratadine, mequitazine, ebastine, oxatomide, pranlukast hydrate, bepotastine besylate, etc.
  • vitamin A vitamin A
  • vitamin B vitamin B 12 (mecobalamin)
  • vitamin C vitamin D
  • vitamin E etc.
  • minerals amino acids and the like
  • These active ingredients may be optically active or racemic. These active ingredients can be used alone or in combination of two or more.
  • the fibrate compounds include, for example, bezafibrate, clinofibrate, clofibrate, fenofibrate, beclobrate, vinyl fibrate, ciprofibrate, etofibrate, gemfibrozil, nicofibrate, pilifibrate, lonfibrate, simfibrate Synfibrate, theofibrate, or a salt thereof (for example, clofibrate aluminum, etc.).
  • Fibrates include derivatives of active compounds (esters, hydrates, hydrates, etc.), prodrugs, free acids or active metabolites (fibric acid, clofibric acid, fenofibric acid, etc.) or their salts. It is.
  • the fibrate compound may be fenofibrate and the free acid or active metabolite (fenofibric acid) corresponding to fenofibrate.
  • the fibrate compound may be an optically active substance or a racemate.
  • the fibrate compounds can be used alone or in combination of two or more.
  • the fibrate compound may contain other active ingredients (for example, other antihyperlipidemic drugs excluding the fibrate compound (such as HMG-CoA reductase inhibitor (statin compound)), antihypertensive agent, anti-obesity agent , At least one selected from diuretics, antithrombotics, antidiabetics, diabetic complications, and the like.
  • Fibrate compounds reduce low density lipoprotein binding (LDL) cholesterol and triglyceride (TG) and increase high density lipoprotein binding (HDL) cholesterol by inhibiting triglyceride synthesis or secretion in the liver. It is useful as a prophylactic and / or therapeutic agent for hyperlipidemia.
  • LDL low density lipoprotein binding
  • TG triglyceride
  • HDL high density lipoprotein binding
  • Fibrate compounds reduce low density lipoprotein binding (LDL) cholesterol and triglyceride (TG) and increase high density lipoprotein binding (HDL) cholesterol by inhibiting triglyceride synthesis or secretion in the liver. It is useful as a prophylactic and / or therapeutic agent for hyperlipidemia.
  • fenofibrate having a large lipid improving action, particularly LDL cholesterol or triglyceride lowering action is preferable.
  • the active ingredient may be amorphous or crystalline. Even if it is a crystalline active ingredient, the solid dispersion of the present invention can greatly improve the dissolution property. Therefore, even if the amount of active ingredient used is small, the bioavailability can be greatly improved.
  • the dosage form can be miniaturized and the bioavailability can be increased even if the dose is reduced. it can. Therefore, the present invention is preferably applied to an active ingredient that is sparingly soluble in water and has low bioavailability, and an active ingredient with a small dose (for example, a single dose of 0.1 to 15 mg, preferably May be applied to about 0.5 to 10 mg, more preferably about 1 to 5 mg).
  • a small dose for example, a single dose of 0.1 to 15 mg, preferably May be applied to about 0.5 to 10 mg, more preferably about 1 to 5 mg.
  • active ingredients that are sparingly soluble in water have low bioavailability, and have a large dosage (for example, a single dose is 25 to 1000 mg, preferably 30 to 500 mg, more preferably about 50 to 300 mg) It is preferable to apply to.
  • high-dose active ingredients include antihyperlipidemic agents (eg, fibrate compounds (eg, fenofibrate), probucol, nicotinic acid agents), anti-obesity agents, heart failure agents, myocardium Examples include infarction treatment drugs, diabetes treatment drugs, diabetic complication treatment drugs, and the like.
  • a plurality of active ingredients may be supported on a porous carrier.
  • an active ingredient having a large dosage for example, a fibrate compound such as fenofibrate
  • an active ingredient having a small dosage for example, pitavastatin
  • Or a statin compound such as pitavastatin calcium may be supported on a porous carrier.
  • the hardly soluble active ingredient is supported on the porous carrier, and the hardly soluble active ingredient and the water-soluble active ingredient may be supported on the porous carrier.
  • the amount of the active ingredient supported on the powdery porous carrier is 0.01 to 10 parts by weight (for example, 0.01 to 10 parts by weight) of the active ingredient relative to 1 part by weight of the powdery porous carrier depending on the type of carrier and active ingredient.
  • the elution property of an active ingredient is high, and bioavailability can be improved greatly. Therefore, high bioavailability can be achieved while reducing the amount of active ingredient used.
  • the amount of active ingredient used is reduced by about 10 to 50% by weight, preferably 20 to 45% by weight (for example, 25 to 35% by weight) with respect to the amount of active ingredient used in the past. Even so, the same bioavailability as before can be obtained.
  • the powdery porous carrier functions as an excipient, the solid dispersion has high compression moldability. Therefore, the dosage form can be miniaturized, and the dosage and patient compliance can be improved.
  • the solid dispersion contains a water-soluble additive component.
  • a poorly water-soluble active ingredient such as a fibrate active ingredient
  • the water-soluble additive component has low affinity or compatibility with the active component (or hydrophobic active component) that is hardly soluble in water, and the active component is dissolved in a molecular form or dispersed in the form of fine particles. It may be a component that cannot be formed (an additive component that cannot form a meltable solid dispersion in which the active ingredient is dissolved or dispersed at the molecular level or fine particle level and does not function as an organic solid matrix of the solid dispersion).
  • the water-soluble additive component various additive components can be used as long as they have low viscosity and are water-soluble.
  • the 2% indicated viscosity of the water-soluble additive component is 500 mPa ⁇ s or less (eg, 400 mPa ⁇ s or less, 300 mPa ⁇ s or less, or 200 mPa ⁇ s or less) at 20 ° C., preferably 100 mPa ⁇ s or less (eg, 1 to 70 mPa ⁇ s), more preferably 50 mPa ⁇ s or less (for example, 1.5 to 30 mPa ⁇ s), particularly about 20 mPa ⁇ s or less (for example, 1.5 to 15 mPa ⁇ s), usually 10 mPa ⁇ s.
  • the porous carrier can be uniformly dispersed in the organic solvent solution, and the porous carrier can be smoothly impregnated with the active ingredient and the additive component.
  • a solid dispersion is obtained.
  • the indicated viscosity can be measured with a capillary viscometer at a 2% concentration of 20 ° C., and is usually said to vary within a range of 70 to 150% (particularly 80 to 130%) centering on the viscosity value. ing.
  • the value of the displayed viscosity includes such fluctuations.
  • the water-soluble additive component at least one selected from water-soluble polymers, saccharides and surfactants is often used.
  • most low-molecular-weight additive components saccharides and surfactants
  • a polymer having the above-mentioned display viscosity is preferably used as the water-soluble polymer.
  • water-soluble polymers examples include soluble starch; polysaccharides such as gum arabic, dextrin, sodium alginate, hyaluronic acid, sodium chondroitin sulfate; polyvinylpyrrolidone (povidone), vinylpyrrolidone-vinyl acetate copolymer (copovidone), etc.
  • Vinylpyrrolidone homo- or copolymer polyvinyl alcohol; carboxyvinyl polymer (Carbopol 934, 940, Carbomer etc.), polyacrylic acid polymer, polymethacrylic acid polymer (Eudragit L, LD, S etc.) ) Acrylic acid homopolymers or copolymers; Synthetic polymers such as polyethylene glycol (eg macrogol); methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose Loin potassium, hydroxyethyl cellulose (HEC), hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), cellulose ethers such as hydroxypropylmethylcellulose (HPMC) is exemplified.
  • Synthetic polymers such as polyethylene glycol (eg macrogol); methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose Loin potassium, hydroxyethyl cellulose (HEC), hydroxyethyl cellulose, hydroxypropyl cellulose (H
  • a water-soluble polymer can be used individually or in combination of 2 or more types.
  • vinylpyrrolidone homopolymers or copolymers such as polyvinylpyrrolidone (povidone), homopolymers or copolymers of acrylic acid such as carboxyvinyl polymers and polyacrylic acid polymers, polyethylene glycol (Macrogol) Etc.), and cellulose ethers such as HPMC and HPC are preferred.
  • polyvinylpyrrolidone (povidone) carboxyvinyl polymer, polyethylene glycol (such as macrogol), HPMC, and HPC are preferable.
  • HPMC includes HPMC 2208, HPMC 2906, HPMC 910, etc.
  • HPC includes about 53 to 78% HPC of hydroxypropoxy groups.
  • water-soluble polymer at least one water-soluble cellulose ether selected from HPC and HPMC is often used.
  • saccharide examples include lactose, sucrose, glucose, fructose, sucrose, maltose (malt sugar), reduced maltose, maltitol, mannitol, sorbitol, xylitol and other sugars (monosaccharides or oligosaccharides such as disaccharides) or sugars.
  • sugars examples include alcohols.
  • sugar alcohols such as mannitol are preferred.
  • surfactant examples include anionic surfactants (for example, sulfonic acids such as benzenesulfonic acid, dodecylbenzenesulfonic acid, and dodecanesulfonic acid or salts thereof; alkyl sulfates such as sodium dodecyl sulfate and sodium lauryl sulfate (SLS).
  • anionic surfactants for example, sulfonic acids such as benzenesulfonic acid, dodecylbenzenesulfonic acid, and dodecanesulfonic acid or salts thereof
  • alkyl sulfates such as sodium dodecyl sulfate and sodium lauryl sulfate (SLS).
  • sulfoaliphatic dicarboxylic acid ester salts for example, sulfosuccinates such as disodium lauryl sulfosuccinate); long chain fatty acid metal salts such as calcium stearate; bile acids or the like Salt; cholic acid such as cholic acid and deoxycholic acid), cationic surfactant (tetraalkylammonium salt such as tetraalkylammonium halide; benzethonium chloride, benzalkonium chloride, cetylpyridinium chloride, etc.), nonionic Surfactants (sucrose long chain fatty acid esters such as sucrose palmitate, sucrose stearate, sucrose oleate; ethylene glycol mono or distearate, polyethylene glycol mono or dioleate, polyethylene glycol mono Or (poly) ethylene glycol long chain fatty acid
  • polymeric surfactants polyoxyethylene polyoxypropylene glycols such as pluronics and poloxamers; polyethylene oxide- (meth) acrylate copolymers; polyethylene oxide-epichlorohydrin copolymers; polyether ester amides, polyether amides) Imide, polyether ester, etc.
  • long-chain fatty acid examples include C 8-26 saturated or unsaturated fatty acid, preferably C 12-20 saturated or unsaturated fatty acid.
  • anionic surfactants for example, C 10-24 sodium alkylsulfate such as SLS, sulfosuccinate, etc.
  • nonionic surfactants for example, sucrose C 8-26 fatty acid ester (Poly) glycerin C 8-26 fatty acid ester, sorbitan C 8-26 fatty acid ester, (poly) oxyethylene sorbitan long chain fatty acid ester such as polysorbate, etc.
  • polyoxyethylene polyoxypropylene glycol such as pluronic and poloxamer, etc. preferable.
  • polyoxyethylene polyoxypropylene glycol as a polymer type surfactant can be classified as a nonionic surfactant.
  • the water-soluble additive component in order to improve the uniformity of the solid dispersion, preferably contains a water-soluble polymer and at least one selected from saccharides and surfactants. It is also advantageous to use at least a water-soluble polymer and / or a surfactant.
  • the water-soluble additive component comprises a water-soluble polymer (particularly a water-soluble polymer composed of at least cellulose ethers) and a surfactant (particularly an anionic surfactant and a nonionic surfactant). And at least one surfactant selected from agents.
  • the amount of these components to be supported or used can be selected according to the characteristics of the solid dispersion, and is usually 0.1 to 100 parts by weight (for example, 1 to 50 parts by weight) with respect to 100 parts by weight of the active ingredient. Part), preferably 0.5 to 50 parts by weight, more preferably 1.5 to 30 parts by weight (for example, 2.5 to 25 parts by weight), usually 1.5 to 20 parts by weight. It may be about (for example, 1.5 to 15 parts by weight).
  • the amount of each additive component used can be selected from the range of 3 to 50 parts by weight, preferably 5 to 30 parts by weight (eg, 7 to 25 parts by weight) with respect to 100 parts by weight of the active ingredient. It may be about 5 to 20 parts by weight (for example, 5 to 15 parts by weight).
  • the additive component and the active component are heated and melt-mixed, and the solid component (the additive component as a vehicle or a solid matrix contains the active component in a molecular or fine particle form). It is not necessary to prepare a meltable dispersion (solid dispersion).
  • the powdery porous carrier composed of the first porous carrier functions as an excipient for the solid preparation, and the additive component includes the wettability and impregnation of the active ingredient to the powdery porous carrier. Improve sexiness. Furthermore, the dissolution property and bioavailability of the active ingredient can be improved. Therefore, the amount of the additive component used can be greatly reduced, and the dosage form can be miniaturized.
  • the ratio of each additive component (for example, a component selected from a water-soluble polymer, a saccharide, and a surfactant) carried on the porous carrier is, for example, 100 parts by weight of an active component that is hardly soluble in water.
  • 0.1 to 30 parts by weight for example, 0.5 to 25 parts by weight
  • preferably 1 to 20 parts by weight for example, 1.5 to 20 parts by weight
  • more preferably 2 to 15 parts by weight for example, 2.5 to 13 parts by weight
  • the amount of each additive component used is 1 to 30 parts by weight (for example, 2 to 25 parts by weight), preferably 3 to 20 parts by weight (for example, 5 to 20 parts by weight) with respect to 100 parts by weight of the active ingredient.
  • the total amount of the additive components is, for example, 1 to 100 parts by weight with respect to 100 parts by weight of the water-insoluble active ingredient (fenofibrate component and the like).
  • it can be selected from a range of about 1 to 50 parts by weight (eg 3 to 50 parts by weight), preferably 5 to 40 parts by weight (eg 5 to 30 parts by weight), more preferably 10 to 40 parts by weight ( For example, it may be about 10 to 30 parts by weight), particularly about 10 to 25 parts by weight.
  • the ratio of the water-soluble additive component to 100 parts by weight of the porous carrier is 0.1 to 100 parts by weight (eg 1 to 100 parts by weight), preferably 1 to 50 parts by weight (eg 3 to 50 parts by weight), More preferably, it may be about 5 to 40 parts by weight (for example, 10 to 40 parts by weight), particularly about 5 to 30 parts by weight (for example, 10 to 30 parts by weight).
  • lipids may be used in combination in order to control the dissolution of the active ingredient.
  • the solid dispersion may contain various pharmaceutically acceptable formulation components (or carrier components, additive components) such as excipients, binders, disintegrants and the like.
  • Lipids include waxes (beeswax, carnauba wax, cacao butter, lanolin, paraffin, petrolatum, etc.), long chain fatty acid esters (saturated or unsaturated fatty acid alkyl esters, fatty acids and polyhydric alcohols (poly C 2-4 alkylene glycol) , Esters with glycerin or polyglycerin) (oils and fats such as hardened oil such as glyceride and hardened castor oil), phospholipids, higher alcohols (saturated or unsaturated higher alcohols such as stearyl alcohol and oleyl alcohol), Examples include higher fatty acids (saturated or unsaturated higher fatty acids such as oleic acid, linoleic acid, linolenic acid and stearic acid), metal soaps (for example, fatty acid metal salts such as sodium coconut oil fatty acid and calcium stearate) and the like. Lipids alone or in combinations of two or more Can be used together.
  • the body can be manufactured. That is, by impregnating the powdered porous carrier composed of at least the first porous carrier with the organic solvent solution containing the hardly soluble active ingredient and the water-soluble additive component, and removing the organic solvent, A solid dispersion in which the active component and the water-soluble additive component are supported on the porous carrier can be produced.
  • a matrix component and an active component are heated and melted to prepare a meltable dispersion (solid dispersion) in which the active component is dissolved or finely dispersed in the matrix component, and the solid dispersion is melted to obtain a carrier.
  • a meltable dispersion solid dispersion
  • the active ingredient is not thermally deteriorated and can be applied to a wide range of active ingredients, and the elution property and bioavailability of the active ingredient can be improved simply and efficiently.
  • the organic solvent only needs to be able to dissolve the hardly soluble active ingredient (and the water-soluble polymer), for example, alcohols (methanol, ethanol, propanol, isopropanol, butanol, etc.), esters (ethyl acetate, acetic acid, etc.).
  • alcohols methanol, ethanol, propanol, isopropanol, butanol, etc.
  • esters ethyl acetate, acetic acid, etc.
  • An organic solvent can be used individually or in mixture of 2 or more types. If necessary, water may be used in combination as long as the solution
  • the concentration of the organic solvent solution is 1 to 50 wt / vol%, preferably 5 to 30 wt / vol% (for example, 10 to 25 wt / vol%), more preferably 7 to 20 wt / vol% (for example, in terms of solid content) 10-15 wt / vol%).
  • the organic solvent solution containing the hardly soluble active ingredient and the water-soluble additive component is usually at room temperature (temperature 15 to 25 ° C.), preferably 10 ° C., more preferably 5 ° C., particularly 0 ° C. Liquid (liquid form).
  • the porous carrier is impregnated in the form of an organic solvent solution
  • the active ingredient and the additive component are not carried unevenly on the surface of the porous carrier, and penetrate into the deep part of the porous carrier uniformly. , And can be supported uniformly throughout.
  • an organic solvent solution containing the additive component for example, at least one component selected from a water-soluble polymer, a saccharide, and a surfactant
  • the permeability or impregnation property of the sparingly soluble active component to the porous carrier is improved. It can be improved.
  • the organic solvent solution containing the hardly soluble active ingredient and the water-soluble additive component may be brought into contact with the powdered porous carrier, and the organic solvent solution is applied to the porous carrier by spraying or the like.
  • the porous support is usually left in the organic solvent solution with stirring or standing, or the organic solvent solution and the porous support are mixed and impregnated in many cases.
  • the powdered porous carrier is immersed in an organic solvent solution at room temperature, and the powdered porous carrier is impregnated with the organic solvent solution.
  • the active component and the water-soluble additive component in the organic solvent enter the pores of the porous carrier and are supported. It appears that most of the active ingredient and the water-soluble additive ingredient enter or adsorb into the pores of the porous carrier.
  • the impregnation operation is usually performed under normal pressure in many cases, but may be performed under reduced pressure or under pressure as necessary.
  • the impregnation operation can be carried out at a temperature lower than the boiling point of the organic solvent, and the temperature is usually 0 to 50 ° C., preferably 5 to 35 ° C. (for example, 10 to 30 ° C.), more preferably 15 to 25 ° C. Can be done to the extent.
  • the impregnation operation can be performed at room temperature (for example, about 10 to 35 ° C., preferably about 15 to 30 ° C., particularly about 15 to 25 ° C.). If necessary, it may be impregnated by heating or heating. Further, if necessary, the porous carrier impregnated with the active ingredient and the water-soluble additive component may be separated and washed by a method such as filtration or centrifugation.
  • the solid dispersion is obtained by drying the mixture (mixture containing the powdered porous carrier impregnated with the active ingredient and the water-soluble additive component) to remove the organic solvent. That is, by removing the remaining organic solvent from the powdery porous carrier, a dispersion (solid dispersion) in which the active component and the water-soluble additive component are dispersed in the porous carrier can be obtained.
  • the active component and the water-soluble additive component are usually uniformly dispersed and supported on a porous carrier.
  • the porous carrier is impregnated with the organic solvent solution without spraying and supporting the melt of the solid dispersion containing the meltable matrix and the active ingredient on the porous carrier, the active ingredient and the additive are added.
  • the components are usually supported throughout the porous carrier.
  • the removal of the organic solvent can be performed by a conventional method, for example, drying (air drying, heat drying), or can be performed under normal pressure or reduced pressure.
  • a solid dispersion can be efficiently produced by removing a solvent by freeze-drying or spray-drying a mixed solution of an organic solvent solution of an active ingredient and a powdered porous carrier.
  • a mixed liquid of the organic solvent solution and the powdered porous carrier is spray-dried, a homogeneous solid dispersion can be efficiently produced.
  • This freeze-drying or spray-drying can be performed by a conventional method.
  • spray-drying can be performed by spraying the mixture into an air stream and drying it with warm air / hot air.
  • the solid dispersion of the present invention is sufficient if the active component and the water-soluble additive component are impregnated and supported on the porous carrier, and may be a mixture of the active component and the water-soluble additive component and the porous carrier.
  • the active component and the water-soluble additive component are usually uniformly dispersed and supported on the porous carrier.
  • the active ingredient is dispersed in the pores of the porous carrier in a state where the active ingredient is incorporated together with the water-soluble additive ingredient, the elution of the active ingredient can be remarkably improved, and the amount of active ingredient used can be reduced. Even if it is reduced, the bioavailability can be improved.
  • the solid dispersion of the present invention may be used alone as a medicine, and is excellent in compression moldability. Therefore, it may be used as a granule by compression molding, crushing and sizing, and tableting It may be used as a tablet.
  • the solid dispersion of the present invention is often used as a pharmaceutical composition such as a solid preparation in combination with a pharmaceutically acceptable carrier or additive (such as the exemplified carrier or additive).
  • the pharmaceutical composition of the present invention only needs to contain the solid dispersion in which an active ingredient hardly soluble in water is supported on a powdery porous carrier composed of the first porous carrier, Multiple active ingredients may be included. It suffices that at least one of the plurality of active ingredients is an active ingredient that is sparingly soluble in water, and the plurality of active ingredients may be composed of a plurality of active ingredients that are sparingly soluble in water. It may contain a water-soluble active ingredient. In addition, all the plurality of active ingredients may be supported on a single porous carrier (first porous carrier), and each of the plurality of active ingredients is a plurality of porous carriers (at least the first porous carrier).
  • a plurality of powdered porous carriers are not necessarily the specific powdery porous carriers used in the present invention.
  • all or some of the active ingredients may be supported on the powdery porous carrier.
  • Other active ingredients not supported on the porous carrier can be contained in the pharmaceutical composition in various forms.
  • an active ingredient with a low dose (such as a poorly water-soluble active ingredient) may be supported on a porous carrier, but at least administered It is preferable that a large amount of the active ingredient is supported on a porous carrier (a powdery porous carrier composed of at least the first porous carrier, particularly the first porous carrier).
  • a porous carrier a powdery porous carrier composed of at least the first porous carrier, particularly the first porous carrier.
  • an active ingredient having a large dose and hardly soluble in water is supported on a porous carrier (a powdery porous carrier composed of at least the first porous carrier, particularly the first porous carrier).
  • a fibrate compound in a pharmaceutical composition containing a fibrate compound (eg, fenofibrate etc.) and a statin compound (pitavastatin or pitavastatin calcium etc.) Is preferably contained in the form of a solid dispersion supported on a powdered porous carrier, and the statin compound may be supported on a porous carrier, and is free from the solid dispersion (such as a mixture or a preparation). In the form) may be included in the pharmaceutical composition.
  • a preparation containing a small amount of active ingredient can be added in various steps of the pharmaceutical composition. For example, when a granule containing a solid dispersion is prepared and then tableted to produce a tablet, preparation of the granule It may be added in the process, or may be added to the granules and tableted.
  • Low-dose active ingredients include angina, antihypertensive, hypotensive, antiobesity, heart failure, myocardial infarction, antiarrhythmic, diabetes, and diabetic complications
  • Drugs peptic ulcer drugs, antipyretic drugs, analgesics, anti-inflammatory drugs, healthy stomach / digestion / antacid / antiemetic drugs, antitussives, bronchial asthma drugs, constipation drugs, diarrhea drugs, liver disease drugs , Biliary / spleen system, acupuncture, thyroid disease, hyperuricemia, rheumatism, antibiotic, antidepressant, antiallergic, antituberculosis, prostatic hypertrophy, osteoporosis Therapeutic agents, Alzheimer's disease therapeutic agents, and the like.
  • Antihyperlipidemic agents include HMG-CoA reductase inhibitors such as simvastatin, lovastatin, atorvastatin, pitavastatin, rosuvastatin, cerivastatin, itavastatin, pravastatin, fluvastatin or salts thereof (eg, sodium salt, calcium salt) And the like, and small intestine cholesterol transporter inhibitors (for example, ezetimibe).
  • HMG-CoA reductase inhibitors such as simvastatin, lovastatin, atorvastatin, pitavastatin, rosuvastatin, cerivastatin, itavastatin, pravastatin, fluvastatin or salts thereof (eg, sodium salt, calcium salt) And the like, and small intestine cholesterol transporter inhibitors (for example, ezetimibe).
  • Antihypertensive agents include, for example, angiotensin converting enzyme inhibitors (for example, captopril, enalapril, delapril, imidapril, quinapril, temocapril, cilazapril, trandopril, lisinipril, or salts thereof), angiotensin II antagonists (for example, candesartan cilexetil) , Losartan, valsantan, telmisartan, olmesartan medoxomil or salts thereof), calcium antagonists (eg, manidipine, nifedipine, nicardipine, amlodipine, efonidipine or salts thereof), clonidine hydrochloride, bunazosin hydrochloride and the like.
  • angiotensin converting enzyme inhibitors for example, captopril, enalapril, delapril, imidapril, quinapri
  • anti-obesity drugs examples include central anti-obesity drugs (for example, mazindol).
  • therapeutic agents for heart failure include thiazide compounds (for example, trichloromethiazide, hydrochlorothiazide, etc.), non-thiazide compounds (for example, tripamide), anti-aldosterone compounds (for example, spironolactone), chlorobenzenesulfonamide compounds (for example, , Mefluside, indapamide, etc.), azosemide, isosorbide nitrate, piretanide, bumetanide and the like.
  • thiazide compounds for example, trichloromethiazide, hydrochlorothiazide, etc.
  • non-thiazide compounds for example, tripamide
  • anti-aldosterone compounds for example, spironolactone
  • chlorobenzenesulfonamide compounds for example, Mefluside, indapamide, etc.
  • azosemide isosorbide nitrate, piretanide, bumetan
  • Examples of the therapeutic agent for myocardial infarction include warfarin (eg, warfarin potassium), antithrombin drug (eg, aragatroban), platelet aggregation inhibitor (eg, ethyl icosapentate, beraprostprosodium), aspirin And clopidogrel sulfate.
  • warfarin eg, warfarin potassium
  • antithrombin drug eg, aragatroban
  • platelet aggregation inhibitor eg, ethyl icosapentate, beraprostprosodium
  • aspirin And clopidogrel sulfate eg, aspirin And clopidogrel sulfate.
  • Examples of the therapeutic agent for diabetes include insulin preparations, ⁇ -glucosidase inhibitors (eg, voglibose, miglitol, etc.), insulin secretagogues (eg, tolbutamide, glibenclamide, gliclazide, glimepiride, etc.), insulin resistance improvers (pioglitazone hydrochloride) Etc.).
  • ⁇ -glucosidase inhibitors eg, voglibose, miglitol, etc.
  • insulin secretagogues eg, tolbutamide, glibenclamide, gliclazide, glimepiride, etc.
  • insulin resistance improvers pioglitazone hydrochloride
  • therapeutic agents for diabetic complications include active oxygen scavengers (for example, thioctic acid) and cerebral vasodilators (for example, thioprid).
  • active oxygen scavengers for example, thioctic acid
  • cerebral vasodilators for example, thioprid
  • peptic ulcer therapeutic agents examples include proton pump inhibitors (eg, omeprazole, lansoprazole, etc.), defense factor enhancers (eg, metoclopramide, etc.) and the like.
  • Examples of the therapeutic agent for rheumatism include immunosuppressants (for example, leflunomide, methotrexate, etc.), auranofin and the like.
  • antiallergic agents examples include antihistamines (eg, clemastine fumarate, loratadine, mequitazine, ebastine, oxatomide, bepotastine besylate, etc.).
  • antihistamines eg, clemastine fumarate, loratadine, mequitazine, ebastine, oxatomide, bepotastine besylate, etc.
  • the form of the pharmaceutical composition may be, for example, a single preparation or a kit preparation.
  • a pharmaceutical composition comprising a combination of a fibrate compound (eg, fenofibrate) and a statin compound (eg, pitavastatin)
  • at least the fibrate compound is a powdered porous carrier
  • it may be a single pharmaceutical composition (formulation) comprising (a) a solid dispersion in which a fibrate compound is supported on the powdery porous carrier and a statin compound.
  • both a fibrate compound and a statin compound may be a single pharmaceutical composition (formulation) comprising a solid dispersion supported on the powdery porous carrier, and (c) a fibrate compound.
  • a kit-form pharmaceutical composition comprising a preparation containing a solid dispersion supported on the powdered porous carrier and a preparation containing a statin compound. It may be a formulation).
  • the dosage form is not particularly limited, and is a semi-solid preparation (cream, jelly, gummi, ointment, gel, etc.), liquid (suspension, emulsion, syrup, etc.), etc.
  • semi-solid preparation cream, jelly, gummi, ointment, gel, etc.
  • liquid uspension, emulsion, syrup, etc.
  • solid preparations powder, granules (granules, fine granules, etc.), pills, pills, tablets (including sublingual tablets, orally disintegrating tablets, lozenges, chewable tablets, etc.)
  • capsules hard capsules, soft capsules, microcapsules, etc.
  • dry syrups suppositories, film-form preparations, sheet-form preparations, etc.
  • the capsule may be a liquid-filled capsule (soft capsule or the like), or a capsule filled with a solid agent such as a solid dispersion or a granule.
  • the powder and / or liquid may be an injection, a spray, or an aerosol.
  • the preparation may be an oral administration preparation or a parenteral administration preparation (eye drops, nasal drops, inhalants, patches (such as cataplasms)). Further, the preparation may be a topical preparation (such as a suppository).
  • the pharmaceutical composition of the present invention may be an immediate release preparation or a sustained release preparation, if necessary.
  • the preparations of the present invention are often solid preparations for oral administration, such as powders, tablets (bare tablets, etc.), granules, pills, capsules and films, and tablets, granules and capsules are preferred.
  • the carrier may be, for example, the Japanese Pharmacopoeia (Pharmacopeia), (1) Pharmaceutical Additive Handbook, Maruzen ), (1989), (2) “Pharmaceutical Additives Dictionary 2000” (Pharmaceutical Daily Journal, published in March 2002), (3) “Pharmaceutical Additives Dictionary 2005” (Pharmaceutical Daily Report, published in May 2005), (4) Ingredients (for example, excipients) listed in Pharmacology, Rev. 5th edition, Nanedo Co., Ltd. (1997), and (5) Pharmaceutical Additives Standard 2003 (Pharmaceutical Daily Newsletter, August 2003) Agent, binder, disintegrant, lubricant, coating agent, etc.).
  • the carrier of the pharmaceutical composition particularly, solid preparation
  • at least one carrier selected from excipients, binders and disintegrants is often used, and additives such as lipids may be used.
  • the solid dispersion of the present invention does not impair the elution of the active ingredient even when compression molded. More specifically, for example, when a solid dispersion is prepared using light anhydrous silicic acid (for example, “Silicia 350”) and compression-molded, the elution property of the active ingredient from the molded body (sized granule or tablet). Is greatly impaired. On the other hand, even if the solid dispersion of the present invention is compression molded, it can greatly improve the dissolution of the active ingredient.
  • the present invention is usually applied to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one carrier component selected from components subjected to a compression molding process, for example, an excipient, a binder, a disintegrant and a lubricant.
  • a carrier component selected from components subjected to a compression molding process, for example, an excipient, a binder, a disintegrant and a lubricant.
  • the present invention is advantageous when applied to a solid preparation in which a solid dispersion is compression molded.
  • excipient examples include saccharides or sugar alcohols such as lactose, sucrose, glucose, sucrose, mannitol, sorbitol, and xylitol; starches such as corn starch and potato starch; crystalline cellulose (including microcrystalline cellulose) and the like.
  • sugars examples include sugars; silicon oxides or silicates such as light anhydrous silicic acid and synthetic aluminum silicate; and phosphates such as anhydrous calcium hydrogen phosphate.
  • Binders include soluble starch such as pregelatinized starch and partially pregelatinized starch; polysaccharides such as agar, gum arabic, dextrin, sodium alginate, tragacanth gum, xanthan gum, hyaluronic acid, pectin, sodium chondroitin sulfate; polyvinylpyrrolidone, polyvinyl alcohol , Synthetic polymers such as carboxyvinyl polymer, polyacrylic acid polymer, polylactic acid, polyethylene glycol; cellulose ethers such as methylcellulose, ethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. It can be illustrated.
  • Disintegrators include calcium carbonate, carboxymethylcellulose or salts thereof (such as carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium), polyvinylpyrrolidone (polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone (crospovidone), etc.), low degree of substitution Examples thereof include hydroxypropylcellulose and sodium starch glycolate.
  • lipid examples include the waxes exemplified above, long chain fatty acid esters, higher alcohols, phospholipids, higher fatty acids, metal soaps, and the like.
  • Carriers can be used alone or in combination of two or more.
  • the proportion of the carrier is not particularly limited, and is, for example, 1 to 500 parts by weight, preferably 5 to 300 parts by weight, more preferably 10 to 250 parts by weight (for example, 25 to 200 parts by weight) with respect to 100 parts by weight of the active ingredient. Part) degree.
  • lubricants examples include talc, magnesium stearate, calcium stearate, polyethylene glycol 6000, and the like.
  • Additives include disintegration aids, antioxidants or antioxidants, surfactants, emulsifiers, dispersants, suspension agents, solubilizers, thickeners (carboxyvinyl polymer, polyvinyl alcohol, gelatin, etc.
  • Water-soluble polymers cellulose ethers such as carboxymethyl cellulose), pH adjusters or buffers (citric acid-sodium citrate buffer, etc.), preservatives or preservatives (parabens such as methyl paraben and butyl paraben), Bactericides or antibacterial agents (benzoic acids such as sodium benzoate), antistatic agents, corrigents or masking agents (for example, sweeteners), colorants (such as dyes and pigments such as Bengala), flavoring agents or fragrances (fragrances) Agents), cooling agents, antifoaming agents and the like.
  • An additive can be used individually or in combination of 2 or more types.
  • the solid preparation may be coated with a coating agent.
  • the coating agent include saccharides, cellulose derivatives such as ethyl cellulose and hydroxyethyl cellulose, polyoxyethylene glycol, enteric components (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methyl methacrylate- (meth) acrylic acid copolymer, Eudragit). (Methacrylic acid-acrylic acid copolymer) and the like, and gastric soluble components (polymers containing basic components such as dialkylaminoalkyl (meth) acrylate (such as Eudragit)).
  • the formulation (unit: mg) of a pharmaceutical composition (such as a solid preparation such as a tablet) in a typical unit dosage form containing at least a fibrate compound (particularly fenofibrate or its free acid or active metabolite) as an active ingredient is as follows: It is as follows.
  • carrier functions also as an excipient
  • the “range” column describes “0 to 30” for the water-soluble polymer and the surfactant, respectively. However, the amount of both components used is “0”. And at least one component contains at least 1 mg (preferably at least 2 mg).
  • the pharmaceutical composition of the present invention is prepared by a conventional method such as a solid dispersion containing an active ingredient, a carrier component (pharmaceutically acceptable formulation component), and additives as necessary, for example, the 15th revised Japanese pharmacy. It can be prepared by the production method described in this method or a method according to this production method.
  • a solid agent can be prepared using a carrier component (such as at least one carrier selected from a binder, an excipient, and a disintegrant) together with a solid dispersion containing an active ingredient.
  • a granule can be prepared by granulating an active ingredient-containing solid dispersion and a carrier component (pharmaceutically acceptable formulation component) by extrusion granulation, spray granulation or the like, and adjusting the size as necessary.
  • Tablets can be produced by mixing the granulated product with carrier components and / or additives as necessary and compression molding. Moreover, you may coat a compression molding agent as needed.
  • Capsules can be prepared by filling capsules with granules.
  • the solid dispersion of the present invention is excellent in compression moldability. Therefore, it is suitable for producing a pharmaceutical composition through at least a step of compressing the solid dispersion.
  • the solid dispersion can be compression-molded with carrier components (excipients, etc.), the molded body can be crushed and sized to obtain granules, and the mixture of solid dispersion and carrier components can be compressed. Tablets can be produced by molding (tabletting), and tablets can be produced by compression molding (tabletting) the mixture of the granule and carrier component.
  • the pharmaceutical composition of the present invention can be applied to non-human animals, but is usually used for humans.
  • the content of the active ingredient in the preparation, the dosage of the preparation and the administration schedule include the type of active ingredient, the subject of administration, the age, weight, sex and condition (general condition, medical condition, etc.), administration time, dosage form It can be appropriately selected depending on the administration method and the like.
  • the content of the active ingredient in the preparation is, for example, 0.01 to 90% by weight, preferably 0.05 to 80% by weight, more preferably 0.1 to 70% by weight in terms of solid content with respect to the whole preparation. % (For example, 0.5 to 50% by weight).
  • the content of the fibrate compound in the preparation is, for example, 1 to 90% by weight, preferably 5 to 80% by weight, more preferably 10 to 70% by weight (eg 15 to 50% by weight). %) Degree.
  • the dose of the fibrate compound is 1 to 500 mg, preferably 5 to 300 mg (eg 10 to 250 mg), more preferably 30 to 200 mg (eg 50 to 50 mg) per day for an adult (body weight of about 60 kg). About 150 mg).
  • the dosage of the statin compound may be about 0.1 to 50 mg, preferably 0.5 to 40 mg, more preferably about 1 to 30 mg (for example, 1 to 10 mg) per day for an adult.
  • the pharmaceutical composition of the present invention may be administered once per day, or may be administered a plurality of times (for example, about 2 to 5 times).
  • First porous carrier A spherical hydrous silicon dioxide (“Syrosphere C-1510” manufactured by Fuji Silysia Chemical Ltd.)
  • First porous carrier B spherical hydrous silicon dioxide (“Syrosphere C-1504” manufactured by Fuji Silysia Chemical Ltd.)
  • Second porous carrier amorphous light anhydrous silicic acid (“Silisia 350” manufactured by Fuji Silysia Chemical Ltd.)
  • Example 5 [Preparation of solid dispersion and tablets] Fenofibrate (5 g), sodium lauryl sulfate (SLS, 0.175 g) and hydroxypropyl cellulose (HPC-SSL (manufactured by Nippon Soda), display viscosity 2.0-2.9 mPa ⁇ s, 1 g) in ethanol / acetone mixture (Volume ratio 1: 1) was dissolved to prepare 50 ml of a solution (in the form of a solution at a temperature of 10 ° C.
  • the first porous carrier B spherical hydrous silicon dioxide (“Syrosphere C-1504” manufactured by Fuji Silysia Chemical Co., Ltd.)] was added at a ratio shown in Table 2 below and stirred. .
  • the characteristics of the spherical first porous carrier (“Cyrossphere C-1510” or “Cyrossphere C-1504”) and the amorphous second porous carrier (“Cylicia 350”) are as follows. It is.
  • FIG. 1 shows an infrared absorption spectrum of the first porous carrier A “Cyrossphere C-1510”.
  • the obtained suspension was spray-dried at 80 ° C. in a nitrogen atmosphere using a spray dryer (“GS31” manufactured by Yamato Scientific Co., Ltd.) to obtain a solid dispersion powder.
  • the obtained solid dispersion powder and disintegrant (croscarmellose sodium) were weighed and mixed in a mortar, and then compressed at 50 kN to produce a slug tablet.
  • the slug tablet was crushed and passed through a sieve having an opening of 710 ⁇ m to obtain granules.
  • a lubricant magnesium stearate
  • HPLC high performance liquid chromatography
  • Table 3 shows the formulation (ratio of each component: parts by weight).
  • Control preparation Fenofibrate micronized preparation obtained by co-micronizing fenofibrate and surfactant and containing 67 mg of fenofibrate (Asuka Pharmaceutical Co., Ltd., Lipidil (registered trademark) capsule 67) is used as a control preparation It was.
  • [Absorptive] Dogs male beagle, 21-24 months old were fasted overnight, fed for 30 minutes, and then about 15 minutes later, the tablet of Example 1 and the control preparation were each orally administered with 30 ml of water. Drinking water was free after administration. 0.5 to 25 hours (0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours and 24 hours) after administration Later, about 1 ml of blood was collected from the left and right forearm scalp veins.
  • Example 1 exhibited the same absorbability as the control preparation, although the content of the active ingredient was small.
  • Formulation Example 1 (tablet) Spray drying was performed in the same manner as in Example 1 to obtain a solid dispersion. This solid dispersion and the following carrier components were mixed, and then compressed and tableted at 5 kN to obtain tablets. In addition, the following ratio is the ratio (weight%) of the component in a tablet.
  • Example 2 41% by weight of solid dispersion of Example 1 Lactose 39% by weight 9% by weight of crystalline cellulose Crospovidone 9% by weight Talc 1% by weight Sucrose fatty acid ester 1% by weight Formulation Example 2 (tablet) Spray drying was performed in the same manner as in Example 5 to obtain a solid dispersion. This solid dispersion and the following carrier components were mixed, and then compressed and tableted at 5 kN to obtain tablets. In addition, the following ratio is the ratio (weight%) of the component in a tablet.
  • Example 5 54% by weight of solid dispersion of Example 5 D-mannitol 22% by weight Crospovidone 22% by weight Magnesium stearate 2% by weight Formulation Example 3 (Capsule) Spray drying was performed in the same manner as in Example 5 to obtain a solid dispersion powder.
  • the obtained solid dispersion powder, D-mannitol and croscarmellose sodium were mixed, and the mixture was compressed at 20 kN to produce slug tablets.
  • the slug tablet was crushed and granules were obtained through a sieve having an opening of 710 ⁇ m.
  • the obtained granules were filled with about 197 mg of gelatin capsules to prepare capsules.
  • the following ratio is a ratio of the component with respect to 100 weight% of capsule contents.
  • the solid dispersion and the pharmaceutical composition of the present invention the elution or dispersibility of the active ingredient and the bioavailability are remarkably improved, and the content of the active ingredient in the pharmaceutical preparation can be reduced.
  • the shape can be miniaturized. Therefore, the pharmaceutical composition is excellent in ingestibility and effective in improving patient compliance.
  • the solid dispersion and pharmaceutical composition of the present invention can be used as a preventive and / or therapeutic agent for various diseases such as metabolic syndrome, hyperlipidemia, diabetes, diabetic complications, etc., depending on the type of active ingredient. .

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Abstract

L'invention concerne une dispersion solide et une composition pharmaceutique (ou une préparation pharmaceutique) permettant d'améliorer la dissolution et la biodisponibilité d'un composant actif faiblement soluble dans l'eau (p. ex. un composé de fibrate). Un support de silicium poreux pulvérulent est imprégné d'un composant actif faiblement soluble dans l'eau et d'un composant d'additif soluble dans l'eau présentant une viscosité nominale de 2% égale ou inférieure à 500 mPa·s à 20˚C, afin que le support comporte le composant actif et l'additif soluble dans l'eau et forme ainsi une dispersion solide. Le support de silicium poreux peut être du dioxyde de silicium ou un composé d'acide silicique, ou peut être un support sphérique qui présente une perte de poids égale ou inférieure à 10% en poids (en particulier égale ou inférieure à 4% en poids) quand il est chauffé à 950˚C pendant 2 heures. Le composant d'additif soluble dans l'eau est sélectionné dans le groupe comprenant un polymère soluble dans l'eau, un saccharide et un tensioactif. Une composition pharmaceutique (p. ex. un comprimé, un granule ou une capsule) peut être préparée à l'aide de la dispersion solide et d'un excipient pharmaceutiquement acceptable.
PCT/JP2010/051780 2009-02-12 2010-02-08 Dispersion solide, composition pharmaceutique comprenant celle-ci et procédés de production de la dispersion solide et de la composition pharmaceutique WO2010092925A1 (fr)

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JP2015005376A (ja) * 2013-06-20 2015-01-08 信越化学工業株式会社 非水電解質二次電池活物質用粉砕助剤及び粉砕方法
WO2017073221A1 (fr) * 2015-10-29 2017-05-04 住友理工株式会社 Rouleau de charge pour appareil électrographique
WO2017188222A1 (fr) * 2016-04-26 2017-11-02 あすか製薬株式会社 Médicament contenant du fénofibrate
EP3549578A1 (fr) * 2018-04-06 2019-10-09 Bio Minerals N.V. Formulation d'acide silicique et son utilisation
US10835495B2 (en) 2012-11-14 2020-11-17 W. R. Grace & Co.-Conn. Compositions containing a biologically active material and a non-ordered inorganic oxide material and methods of making and using the same
US11878031B2 (en) 2018-10-05 2024-01-23 Bio Minerals N.V. Silicic acids for use in the treatment of periodontitis

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