WO2008016260A1 - Composition pharmaceutique d'administration par voie orale comprenant du fénofibrate et son procédé de préparation - Google Patents

Composition pharmaceutique d'administration par voie orale comprenant du fénofibrate et son procédé de préparation Download PDF

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Publication number
WO2008016260A1
WO2008016260A1 PCT/KR2007/003705 KR2007003705W WO2008016260A1 WO 2008016260 A1 WO2008016260 A1 WO 2008016260A1 KR 2007003705 W KR2007003705 W KR 2007003705W WO 2008016260 A1 WO2008016260 A1 WO 2008016260A1
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Prior art keywords
solid dispersion
fenofibrate
weight
pharmaceutical composition
parts
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PCT/KR2007/003705
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English (en)
Inventor
Seung-Hee Baek
Sung-Kyun Han
Eun-Jong Shin
Woo-Young Lee
Joon-Seug Park
Original Assignee
Sam Chun Dang Pharm. Co., Ltd.
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Application filed by Sam Chun Dang Pharm. Co., Ltd. filed Critical Sam Chun Dang Pharm. Co., Ltd.
Priority to BRPI0715538-7A priority Critical patent/BRPI0715538A2/pt
Publication of WO2008016260A1 publication Critical patent/WO2008016260A1/fr

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    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to an oral pharmaceutical composition
  • an oral pharmaceutical composition comprising fenofibrate which is called isopropyl-2-(4-(4-chlorobenzoyl)phenoxy)-2- methylpropionate as a chemical name and a preparation method thereof. More specifically, the present invention provides an oral pharmaceutical composition comprising the fenofibrate with an increased bioavailability, because fenofibrate is amorphous form, and in a dosage form of solid dispersion.
  • Fenofibrate is one of therapeutic agents which are mostly used in worldwide for endogenous hypercholesterolaemia and hypertriglyceridemia in adult.
  • the fenofibrate has a molecular structure of C 20 H 2 iClO 4 , and a molecular weight of 360.84 g/mol, and is white powder.
  • the fenofibrate has a low solubility in water in general. However, the fenofibrate is dissolved in methanol and ethanol partly, and is well dissolved in acetone, ether and benzene.
  • WO 01/80828 discloses an improved water-insoluble drug particle process, and more particularly a process for preparation of small particles containing a poorly water-soluble drug.
  • the process comprises the steps of mixing at high shear an admixture of a poorly water soluble drug and one or more than one surface active substance, heating the mixture to temperature at or above the melting point of the poorly water soluble drug, and homogenizing said heated suspension.
  • the heating of drug to temperature at or above the melting point is not desired, because the heating disrupts the crystalline structure of the drug.
  • the structure of drug is changed to non-crystalline form or is recrystallized to a different isoform, thereby forming a different composition in physical and structural aspects.
  • EP 0 904 781 discloses a process of making a solid dispersion of fenofibrate to granules, and more specifically the process comprises the steps of melting the fenofibrate, blending the disintegrant into the molten fenofibrate, and solidifying the mixture.
  • the solid disintegrant is polymer such as starch, croscarmellose sodium, sodium starch glycolate and cross-linked crospovidone (PVP). PVP is dissolved poorly in the molten fenofibrate and has a problem of phase compatibility, which was supported by M. T. Sheu et al, Int. J. Pharm. 1994, 103 (2), 137-146.
  • the preparation method of a pharmaceutical composition by using melting and solidifying processes makes dispersion and composition be undesirable in granule of fenofibrate, thereby affecting the bioavailability of active materials.
  • "co-melting" process requires a special equipment (see WO 2004/000279).
  • WO 1998/031361 discloses a method of preparing a pharmaceutical composition including fenofibrate comprising the steps of suspending fenofibrate in micronized form in a solution containing hydrophilic polymer, solvent, and optionally surfactant to make a suspension, and spraying the suspension on inert support.
  • the hydrophilic polymer is polyvinylpyrrolidone
  • the inert support is lactose
  • surfactant is sodium laurylsulfate.
  • the preparation method was used widely, and improves solubility and bioavailability compared to the conventional method.
  • the fenofibrate as an active agent must be micronized according to the complex processes for a long time, thereby reducing productivity and heat-stability of heat-labile drug in the microinizing process.
  • the sodium laurylsulfate stimulates mucous membrane of gastro intestine disadvantageously.
  • the object of the present invention is to provide a dosage form of solid dispersion of amorphous fenofibrate as poorly water-soluble therapeutic agent for hyperlipidemia by using the spray-drying method.
  • Another object of the present invention is to provide orally-administered pharmaceutical composition with improved bioavailability and the preparation method thereof.
  • Fig. 1 shows graphs of fenofibrate, solid dispersions of Example 2 and particles prepared by mechanical milling in Comparative Example 1 obtained by using X-ray Diffractometer to determine crystal structures of the fenofibrate.
  • Fig 2 is a graph showing the result of Comparative Dissolution test of fenofibrate and solid dispersions of Example 2.
  • Fig. 3 is a graph showing the result of Comparative Dissolution test of commercial drug and the compositions of Examples 6 to 7.
  • Fig. 4 shows a graph of particle diameter distribution of solid dispersion obtained by Example 2.
  • the present invention provides a solid dispersion comprising an amorphous fenofibrate dispersed in drug carrier, and a oral pharmaceutical composition for treating hyperlipidemia comprising the solid dispersion.
  • the present invention provides a method of increasing bioavailability, solubility, and/or dissolution rate of fenofibrate by preparing solid dispersion comprising an amorphous fenofibrate dispersed in drug carrier.
  • the present invention provides a method of preparing a solid dispersion comprising an amorphous fenofibrate dispersed in drug carrier.
  • the solid dispersion is prepared by spray-drying a mixture of 100 parts by weight of fenofibrate dispersed in 20-200 parts by weight of a water-soluble polymer, and 5-50 parts by weight of a surfactant.
  • the pharmaceutical composition further comprises at least an additive selected from the group consisting of an excipient, a binder, a disintegrant, a plasticizer, a lubricant and a mixture thereof.
  • the present invention provides a method of preparing a solid dispersion comprising the steps of: dissolving fenofibrate in an organic solvent, and mixing with 20-200 parts by weight of a water-soluble polymer and 5-50 parts by weight of a surfactant on the basis of 00 parts by weight of fenofibrate to produce a mixed solution, and spray-drying the mixed solution to obtain a solid dispersion comprising an amorphous fenofibrate dispersed in a drug carrier.
  • the solid dispersion further comprises at least one selected from the group consisting of excipient, binder, plasticizer, disintergant, and lubricant.
  • fenofibrate, fenofibrate, water-soluble polymer and surfactant is dissolved and mixed in an organic solvent and spray-dried to make fenofibrate be amorphous, thereby increasing solubility of fenofibrate.
  • solid dispersion means at least an active agent dispersed in solid state in an inert support or a matrix.
  • the crystalline property of drug remains after pulverizing.
  • the amorphousness can be achieved sufficiently by appropriately controlling the composition of drug and hydrophilic polymer, and the condition of spray-drying.
  • the spray- drying method does not change the crystalline property of drug without affecting the drug by making a particle with evaporation of optimized temperature and operating condition.
  • the fenofibrate which has a low melting point (79-82 " C) and is poorly water soluble dissolved in an organic solvent, and dried under the condition which is optimal for making a particulate without changing the melting point, to produce a solid dispersion.
  • the present invention provides an improved productivity, stability, solubility and bioavailability.
  • the reduced particle size of water-insoluble drug obtained by pulverizing increases theoretically soluble surface area, but aggregates the particles together so as to make the drug dissolve difficultly.
  • a process of preparing dispersion with partly increased solubility in solid dispersion and a process of maximizing the contact surface of solute and solubility of support.
  • a poorly water soluble drug is dispersed in a polymer at a molecular level to achieve optimization for oral administration.
  • the present invention relates to a solid dispersion comprising an amorphous fenofibrate (hereinafter, solid dispersion), which is prepared by mixing a fenofibrate, a water-soluble polymer, a surfactant and an organic solvent, and then spray-drying.
  • the particle diameter of fenofibrate in the solid dispersion of the present invention is 1 to 220 ⁇ m.
  • the solid dispersion shows 5 -15 ⁇ g/m£ of solubility of fenofibrate at pH 6.5 to 7.5 and at 25 ° C, which is 25 times as high as fenofibrate untreated according to the present invention.
  • the initial dissolution rate for 30 minutes is about 72 w/w% (percentage of dissolved drug amount to initial drug amount).
  • the water-soluble polymer includes cellulose polymers, polyalkenylpyrrolidon, polyalkyene glycol, and metaacrylate copolymer.
  • the examples of water-soluble polymer being capable of mixing with fenofibrate are at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxybutylcellulose, hydroxypentylcellulose, hydroxypropylbutylcellulose, hydroxypropylalkylcellulose, polyvinylpyrrolidone, polyvinylalcohol and a mixture thereof.
  • the amount of water-soluble polymer is 20 to 200 parts by weight on the basis of 100 parts by weight of fenofibrate. In the present invention, the water-soluble polymer is used in a small amount relatively, thereby reducing the weight of composition and causing inconvenient administration.
  • the amount of water-soluble polymer is less than 20 parts by weight, the structure of fenofibrate cannot be changed to amorphous form, and thus has low solubility. If the amount of water-soluble polymer exceeds 200 parts by weight, increased size and volume of preparation causes inconvenience for administration.
  • the surfactant can be amphoteric, non-ionic, cationic, and anionic, but not limited thereto.
  • the surfactant includes pH-dependent hydrophilic polymer.
  • the examples of surfactant are at least one selected from the group consisting of monooleic ester, monolauryl ester, monopalmitic ester, monostearic ester, polyoxyethylene, sorbitan ester, sodium dioctylsuccinate, lecitin, stearylalcohol, cetostearylalcohol, cholesterol, polyoxyethylen ricin oil, polyoxyethylene glyceride fatty acid, polyoxyelthylene-polyoxypropylene block copolymer (example, poloxamer) and polyethyleneglycol derivatives (for example, cremophor).
  • the amount of surfactant is 5 to 50 parts by weight, and preferably 10 to 50 parts by weight on the basis of 100 parts by weight of fenofibrate in consideration of drug solubility improvement and weight of solid dispersion. If the surfactant is contained less than 5 parts by weight, it does not provide desirable solubility. If the amount of surfactant exceeds 50 parts by weight, the amorphous property of produced solid dispersion is reduced and weight of solid dispersion must increase.
  • the organic solvent used for preparation of the solid dispersion can be various solvent being capable of dissolving the fenofibrate, and the amount is not limited because it is used for dissolve an active agent, surfactant and water-soluble polymer.
  • the preferred examples of the solvent are at least one selected from the group consisting of ethanol, dichloromethane, acetone, and methanol. More preferably, the solvent is a mixture of ethanol and dichloromethane in the ratio of 1 : l(v/v).
  • the solid dispersion is prepared by spray-drying method, and more specifically can be performed as below.
  • fenofibrate, hydroxypropylmethylcellulose, and surfactant such as Poloxamer or Cremophor are dissolved in an organic solvent to obtain a mixed solution (8%(w/v)), and then dried with a spray-drier to produce solid dispersion. That is, in a spray-drying process, after setting an optimal temperature for making particle without affecting a melting point of fenofibrate, the mixed solution is sprayed and immediately dried under the optimal condition the present invention. In the combined spraying and drying process of the present invention, spraying and drying is carried out simultaneously, and thus quick drying deprives the crystal of an sufficient time of rearranging. Thus, the amorphous fenofibrate is obtained is solid dispersion.
  • the spray-drying is carried out with a spray-drier under the condition of a feeding temperature of 75 - 77 ° C, chamber temperature of 55 - 58 ° C, disc rotating number of 7,000 - 10,000 rpm/min and a fluid rate of 16 - 20 kg/h.
  • the produced solid dispersion can be granulated to dry granules before being prepared for a pharmaceutical composition.
  • the present invention provides an oral pharmaceutical composition comprising the solid dispersion.
  • composition is referred to a pharmaceutical composition comprising solid dispersions of fenofibrate as an active agent.
  • the oral pharmaceutical composition further includes pharmaceutically-acceptable additives such as liquid or solid carrier, and excipient in general.
  • the composition includes 30.0 to 70.0 wt% of the solid dispersion; and 30.0 to 70.0 wt% of at least an additive selected from the group consisting of excipient, disintegrant, plasticizer, binder, and lubricant. If the amount of solid dispersion is less than 30 wt%, the weight of composition increases excessively, thereby causing inconvenience for administration. If the amount exceeds 70 wt%, the sufficient dissolution rate cannot be achieved.
  • The is at least one selected from the group consisting of lactose, white sugar, glucose, fructose, mannitol, corn starch, potato starch, wheat starch, pregelatinized starch, microcrystalline cellulose or cellulose derivatives, dextrin, monobasic calcium phosphate, dibasic calcium phosphate, calcium carbonate, polacrilin potassium, acetic acid, ammonium carbonate, ammonium phosphate, boric acid, lactic acid, citric acid, potassium phosphate, sodium phosphate, sodium acetate, sodium citrate, sodium lactate, ascorbic acid, and ascorbyl palmitate.
  • the amount of excipient is 20.0 to 60.0 wt% in reference to total content of additives contained in the pharmaceutical composition.
  • the disintegrant is at least one selected from the group consisting of microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium croscarmellose, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, crospovidon and a mixture thereof.
  • the amount of disintegrant is 0.1-20.0 wt% in reference to total content of additives contained in the pharmaceutical composition.
  • the plasticizer is at least one selected from the group consisting of colloidal anhydrous silica, silicon dioxide precipitate, magnesium stearate, stearic acid, polyethyleneglycol (PEG), and a mixture thereof.
  • the amount of plasticizer is 0.1-3.0 wt% in reference to total content of additives contained in the pharmaceutical composition.
  • the dosage form of oral pharmaceutical composition can be solid dosage forms, liquid dosage form, and etc.
  • the oral pharmaceutical composition is formulated to the oral dosage forms such as tablet, granule, powder, pill, and dry syrup, and more preferably to table or capsule for oral administration.
  • the preferred formulation is a unit form of administration.
  • the composition is divided into unit administration form containing an active agent in a suitable amount.
  • the unit administration form is a wrapped formulation containing a divided amount of active agent, for examples tablet, capsule or powder wrapped in vial or ampoule. More preferably, the formation is in a capsule form.
  • the effective dosage is 160mg per day.
  • Fenofibrate was dissolved in a mixture of ethanol and dichloromethane in a ratio l :l(v/v), and added with hydroxypropylmethylcellulose as a water-soluble polymer to obtain 8%(w/v) of mixed solution.
  • the mixed solution was added with Poloxamerl88, Poloxamer 407, CremophorRH-40, and Soybean Lecithin as a surfactant, respectively to produce each solution.
  • Each solution was spray-dried with disc-typed spray-drier to obtain a solid suspension where fenofibrate was dispersed in hydroxypropylmethylcellulose.
  • the spray-drying was performed under the condition of feed temperature of 75 - 77 ° C , a chamber temperature of 55 - 58 ° C, disc rotating number of 7,000 - 10,000 rpm/min, and fluid rate of 16 - 20 kg/h.
  • Fenofibrate, hydroxypropylmethylcellulose as a water-soluble polymer and each additive were mixed, and frozen for 5 minutes and pulverized for 5 minutes with a Freezer-mill.
  • the prepared sample was dehydrated with a vacuum pump for a day in consideration of the hygroscopic property of water-soluble polymer contained in the sample.
  • Example 2 The fenofibrate solid dispersion of Example 2 was granulated according to dry granulating method, well mixed with microcrystalline cellulose, lactose and Crospovidone in a same amount, mixed colloidal anhydrous silica as a plasticizer, Magnesium stearate as a lubricant, and then produced to tablet.
  • the fenofibrate solid dispersion was granulated with Crospovidone as a disintegrant for Example 6, but without adding Crospovidone for Example 7.
  • the solubility was measured by adding an excessive amount of solid dispersion to the solution (pH 6.8), agitating at 25 ° C for 2 hours, sonicating for 2 hours, filtering with 0.45 ⁇ m PVDF syringe filter, and then analyzing the filtrate with HPLC.
  • the analyzed result is shown in Table 4.
  • the solubility of solid dispersion of the present invention was 25 times or 50 times or higher than raw material.
  • the present invention provides an active agent with increased solubility, resulting in improved bioavailability.
  • the crystal structures of fenofibrate, and the solid dispersions obtained by Example 2 and Comparative Example 1 were determined by using X-ray Diffractometer (Rigaku), and the results were shown in Fig. 1.
  • X-ray diffraction type was measured by sufficiently laminating an amount of sample on transparent glass slide with 0.3mm of width so as to prevent the orientation from generating, and was detected at interval 0.5 ° C of in the range of 5-40 ° C .
  • the X-ray diffraction type was measured under the condition of voltage 40kv, current 7OmA, and wavelength 1.542 A.
  • a crystalline peak of untreated fenofibrate was very high and sharp, which meant a high crystalline property.
  • the untreated fenofibrate and the solid dispersion of Example 2 were tested for the comparative dissolution according to second dissolution method (paddle dissolution method) described in Korea Pharmacopeia.
  • the content of fenofibrate was performed by quantitative analysis using a dissolving solution (pH 6.8, added by 1% Tween 80) at a paddle speed of 50 rpm with HPLC.
  • the result was shown in Fig. 2.
  • the dissolution rate of solid dispersion obtained by EXAMPLE 2 increased notably.
  • compositions of Examples 6 to 7 suggested the dissolution rate of the present invention equivalent to the commercial drug.
  • the present invention provides an orally-administered pharmaceutical composition prepared by dissolving a poorly water-soluble fenofibrate, hydroxypropylmethylcellulose, surfactant such as Poloxamer or Cremophor in an organic solvent, and spray-drying the drug, water-soluble polymer and surfactant in a short time.
  • the composition can be prepared in a short time, and have an amorphous form with improved bioavailability advantageously.
  • amorphous solid suspension of the present invention is mixed with appropriated carrier and granulated, the conventional granulating process can be applied for the present invention.
  • the present invention can be a simple and convenient process, be commercialized easily and economically.

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Abstract

La présente invention concerne une composition pharmaceutique d'administration par voie orale comprenant du fénofibrate et son procédé de préparation. La présente invention concerne plus particulièrement une composition pharmaceutique d'administration par voie orale possédant une biodisponibilité améliorée pour le traitement de l'hyperlipidémie et son procédé de préparation, la dispersion solide étant préparée par séchage par atomisation d'un mélange de 100 parties en poids de fénofibrate dispersées dans 20-200 parties en poids d'un polymère hydrosoluble, et 5-50 parties en poids d'un tensioactif. La composition pharmaceutique d'administration par voie orale a une biodisponibilité élevée en raison de la solubilité accrue du fénofibrate amorphe. En plus, l'atomisation et le séchage peuvent être effectuées en même temps et à faible température, puis une perte d'activité du médicament peut être réduite au minimum, par opposition au procédé de broyage mécanique.
PCT/KR2007/003705 2006-08-01 2007-08-01 Composition pharmaceutique d'administration par voie orale comprenant du fénofibrate et son procédé de préparation WO2008016260A1 (fr)

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KR10-2006-0072550 2006-08-01
KR1020060072550A KR100767349B1 (ko) 2006-08-01 2006-08-01 페노피브레이트를 함유하는 경구용 약제 조성물 및 그의제조방법

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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
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WO2009085766A2 (fr) * 2007-12-19 2009-07-09 Mutual Pharmaceutical Company, Inc. Dispersion amorphe d'acide fénofibrique ; procédé de préparation ; et procédé d'utilisation
WO2011034396A2 (fr) * 2009-09-21 2011-03-24 주식회사 삼양사 Dispersion solide comprenant un médicament de type fibrate, et procédé de préparation de la dispersion solide
JP2013512948A (ja) * 2009-12-08 2013-04-18 イル・ファ・カンパニー・リミテッド ２０−Ｏ−β−Ｄ−グルコピラノシル−２０（Ｓ）−プロトパナキサジオールを含む固体分散体
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