CN101351191A - Fenofibrate medicinal preparation with improved bioavailability - Google Patents

Fenofibrate medicinal preparation with improved bioavailability Download PDF

Info

Publication number
CN101351191A
CN101351191A CNA2005800524449A CN200580052444A CN101351191A CN 101351191 A CN101351191 A CN 101351191A CN A2005800524449 A CNA2005800524449 A CN A2005800524449A CN 200580052444 A CN200580052444 A CN 200580052444A CN 101351191 A CN101351191 A CN 101351191A
Authority
CN
China
Prior art keywords
fenofibrate
solid oral
agent type
pharmaceutical composition
oral agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CNA2005800524449A
Other languages
Chinese (zh)
Inventor
E·I·莱尔纳
V·罗森伯格
M·弗拉什纳巴拉克
A·德拉布金
N·莫尔达夫斯基
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Industries Ltd
Original Assignee
Teva Pharmaceutical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Teva Pharmaceutical Industries Ltd filed Critical Teva Pharmaceutical Industries Ltd
Publication of CN101351191A publication Critical patent/CN101351191A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • 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
    • A61K9/20—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
    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; 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

Abstract

Provided are pharmaceutical compositions of fenofibrate, and dosage forms containing them, that include fenofibrate, a polyethylene glycol, and a polethylene-polypropylene glycol; wherein the compositions are made by subliming a sublimable carrier from a combination of fenofibrate, the polyethylene glycol, and the polethylene - polypropylene glycol with the sublimable carrier, for example menthol.

Description

The fenofibrate medicinal preparation that bioavailability improves
Invention field
The present invention relates to comprise the pharmaceutical composition of fenofibrate, Polyethylene Glycol and poly-second-polypropylene glycol, wherein this pharmaceutical composition is by containing fenofibrate, Polyethylene Glycol, poly-second-polypropylene glycol and making by the distillation of the carrier that can distil as the solid solution of menthol and so on distillation carrier.
Background technology
Fenofibrate, (2-[4-(4-chlorobenzoyl) phenoxy group]-the 1-methyl ethyl ester of 2-methyl-propanoic acid is one of fibrate class medicine.It both can capsule also can the tablet form supply.Fenofibrate obviously is a kind of prodrug.Its active part it is reported it is the metabolite fenofibric acid, and the latter it is said in vivo by the effect of esterase and generates.When fenofibrate bedding and clothing following times, in blood plasma, can not find tangible complete fenofibrate (Physician ' s Desk Reference 58 ThEd.2004 522-525 page or leaf (PDR)).
The water solublity of fenofibrate is very poor.In other words, it is the very poor medicine of a kind of water solublity.Although its dissolubility in water is very poor, it is said that its absorption reaches the acceptable degree of therapeutics, if take medicine, if but take medicine at " fasting state " then absorb relatively poor at " feed state ".Real " bioavailability (bioavailability) " of metabolite fenofibric acid is uncertain, because according to understanding, it was metabolised to glucosiduronic acid with the position major part of passing through at first before system.
The absolute bioavailability of fenofibrate it is believed that and can't measure, and is fit to the medium that vein injects because it is insoluble to.After oral by the healthy volunteer, about 60% of radiolabeled single dose fenofibrate appears in the urine, mainly is the form of fenofibric acid and glucosiduronic acid conjugated body thereof, discharges with feces for 25% simultaneously.(PDR) absorption of fenofibrate it is believed that when taking with food and will improve.The degree of absorption of oral tablet, (PDR, Martindale 33 to improve about 35% when tablet is taken with food RdEd. the 889th page).
Making great efforts to improve fenofibrate formulations, especially at the bioavailability of fenofibrate always.United States Patent (USP) 4,895,726 and 5,880,148 disclose a kind of with fenofibrate and surfactant altogether-micronized method.United States Patent (USP) 6,074,670,6,277,405 disclose a kind of being applied on the water-solubility carrier, randomly together with surfactant, the micronization fenofibrate.United States Patent (USP) 6,814,977 disclose the fenofibrate in a kind of medium chain glyceride that is dissolved in fatty acid.United States Patent (USP) 6,719,999 openly are dissolved in glycerol, propylene glycol, or the fenofibrate in the Isosorbide dimethyl ether; And United States Patent (USP) 5,827,536 discloses a kind of fenofibrate that is dissolved in the diethylene glycol monoethyl ether.
Several pieces of patent disclosures have a micronization fenofibrate particular formulations of particular polymers or surfactant additive; Other then describe the Emulsion and the suspended substance of fenofibrate.For example, U.S. Patent Application Publication No. 20040087656 discloses a kind of granularity that bioavailability improves fenofibrate less than 2000nm that it is said.U.S. Patent Application Publication No. 20030224059 disclose a kind of active pharmaceutical ingredient microgranule, contain the medicine of this microgranule-send excipient and method for making thereof.
The combination appropriateness of the micronization of fenofibrate and micronization fenofibrate and surfactant has improved the bioavailability of fenofibrate, thereby make the drug prescription dosage of authorities-allowance, in the bioavailability that keeps the feed state, be reduced to the every dosage of 67mg from the every dosage of 100mg, subsequently again and then be reduced to the every dosage of 54mg.The nanoparticle formulations of this medicine further allows dosage is reduced to the every dosage of 48mg, and meanwhile the bioavailability of " fasting state " it is said near the feed state.At present, still have significant improvement leeway, because by inference, the real bioavailability of fenofibrate is still relatively low.
Summary of the invention
One aspect of the invention relates to a kind of pharmaceutical composition, and it comprises the fenofibrate microgranule of on-mechanical micronization (micronized), especially with the distillation micronized fenofibrate microgranule of menthol as the carrier that can distil; Polyethylene Glycol, especially polyethylene glycol 6000; With poly-second-polypropylene glycol, especially poloxamer (poloxamer) 407.This pharmaceutical composition also can comprise the medicine disintegrating agent, is selected from crospovidone (crospovidone), carboxymethyl cellulose, especially cross-linking sodium carboxymethyl cellulose (croscarmellose sodium), bicarbonate or carbonate; Especially alkali metal hydrogencarbonate or carbonate are as sodium bicarbonate; Organic carboxyl acid, especially citric acid, tannic acid, ascorbic acid, benzoic acid, citric acid, fumaric acid, lactic acid, malic acid, sorbic acid and tartaric acid; And above-mentioned combination in any.
Another aspect of the present invention relates to a kind of solid oral agent type, and it comprises a kind of pharmaceutical composition, and the latter comprises about 15wt%～about 25wt% on-mechanical micronized fenofibrate microgranule, and the micronization fenofibrate especially distils; About 7wt%～about 13wt% poloxamer 407; About 7%～about 13% polyethylene glycol 6000; About 15wt% microcrystalline Cellulose; About 18wt% crospovidone; About 12wt% sodium bicarbonate; With about 12wt% citric acid or tartaric acid.
The further aspect of the present invention relates to a kind of solid oral agent type, and it comprises a kind of pharmaceutical composition, and the latter comprises about 15wt%～about 25wt% on-mechanical micronized fenofibrate microgranule, and the micronization fenofibrate especially distils; About 7wt%～about 13wt% poloxamer 407; About 7%～about 13% polyethylene glycol 6000; About 15wt% microcrystalline Cellulose; About 18wt% crospovidone; About 12wt% sodium bicarbonate; With about 12wt% citric acid or tartaric acid; Wherein this dosage form has the time dependent release in vitro curve of a kind of fenofibrate, so that at least about 51wt%, especially about 51%～about 81% fenofibrate discharges in about 10min, at least about 73%, especially about 73wt%～about 93wt% fenofibrate discharges in about 15min, at least about 85wt%, especially about 85wt%～all fenofibrate discharges in about 30min basically.
Another aspect of the present invention relates to a kind of solid oral agent type, especially a kind of compressed tablets, it comprises a kind of pharmaceutical composition, the latter comprises about 145mg distillation micronization fenofibrate, wherein human body giving drugs into nose that this dosage form is taked the fasting state administration for dynamics research in, the area (AUC below the 48h AUC curve 48) be about 121367h*ng/g～about 287539h*ng/g; Be extrapolated to the area (AUC below the AUC curve of infinitely great time ∞/ AUC Inf) be about 134750h*ng/g～about 345390h*ng/g; And maximal plasma concentration (C Max) be about 6357ng/g～about 14627ng/g.With regard to the typical case, this kind solid oral agent type will show the average A UC of about 175335h*ng/g 48, the average A UC of about 213652h*ng/g ∞Average C with about 10570ng/g Max
The further aspect of the present invention relates to a kind of solid oral agent type, especially a kind of compressed tablets, and it comprises a kind of pharmaceutical composition, and the latter comprises about 145mg distillation micronization fenofibrate; Wherein this dosage form take to take food the human body giving drugs into nose of state administration for dynamics research in, the area (AUC below the 48h AUC curve 48) be about 91601h*ng/g～about 217512h*ng/g; Be extrapolated to the area (AUC below the AUC curve of infinitely great time ∞) be about 97182h*ng/g～about 308070h*ng/g; And average A UC wherein in addition, 48, about 150511h*ng/g, and average A UC ∞Be about 185149h*ng/g.This dosage form can comprise disintegrating agent.
Another aspect of the present invention relates to a kind of pharmaceutical composition, and the latter has the high amount of drug carrier granular, and especially the microcrystalline cellulose crude granule has deposition following combination thereon: fenofibrate, especially about 15wt%～about 25wt% fenofibrate; Polyethylene Glycol, especially about 7wt%～about 13wt% polyethylene glycol 6000; Poly-second-polypropylene glycol, especially about 7wt%～about 13wt% poloxamer 407; Wherein this combination is by the carrier that can distil, and the especially distillation of menthol is deposited up by the solid solution that comprises fenofibrate, Polyethylene Glycol, poly-second-polypropylene glycol and the carrier that can distil.Compositions also can comprise the medicine disintegrating agent, is selected from crospovidone, cross-linked carboxymethyl cellulose salt (especially cross-linking sodium carboxymethyl cellulose), bicarbonate or carbonate; Especially alkali metal hydrogencarbonate or carbonate are as sodium bicarbonate; Organic carboxyl acid, especially citric acid, tannic acid, ascorbic acid, benzoic acid, citric acid, fumaric acid, lactic acid, malic acid, sorbic acid and tartaric acid; And above-mentioned combination in any.
The further aspect of the present invention relates to a kind of solid oral agent type, it comprises a kind of pharmaceutical composition, the latter comprises about 145mg fenofibrate, and it is deposited on a large amount of microcrystalline cellulose crude granules by the distillation of the solid solution that comprises the fenofibrate and the carrier that can distil by the carrier that can distil; Wherein human body giving drugs into nose that this dosage form is taked the fasting state administration for dynamics research in, the area (AUC below the 48h AUC curve 48) be about 121367h*ng/g～about 287539h*ng/g; Be extrapolated to the area (AUC below the AUC curve of infinitely great time ∞) be about 134750h*ng/g～about 345390h*ng/g; And maximal plasma concentration (C Max) be about 6357ng/g～about 14627ng/g.With regard to its some details, this solid oral agent type shows the average A UC of about 175335h*ng/g 48, the average A UC of about 213652h*ng/g ∞Average C with about 10570ng/g Max
Detailed Description Of The Invention
In one embodiment, the invention provides a kind of pharmaceutical composition, it comprises on-mechanical micronized fenofibrate microgranule, Polyethylene Glycol and poly-second-polypropylene glycol.
The average-size of on-mechanical micronized microparticles (mean dimension) is about 0.1 μ m～about 10 μ m, is to adopt the on-mechanical crushing technology to produce.The on-mechanical crushing technology is the technology except that grinding (ball milling, impact, high energy), spray drying and high pressure homogenize.With regard to the application's purpose, the technology of lyophilization (lyophilization) is regarded as a kind of mechanical micronization technology, and therefore, the microgranule of being produced by lyophilization is not at the row of on-mechanical micronized microparticles.It is well known to those skilled in the art that granularity (particlesize) is measured, and can adopt, and for example, the famous technology of laser light scattering is finished.
On-mechanical micronization fenofibrate microgranule of the present invention can adopt, and for example, the distillation micronization technology obtains.So the microgranule that obtains is known as " distillation micronization " microgranule, and the material that constitutes this kind microgranule is known as " distillation micronization ".The distillation micronization technology is described in the U.S. Patent Application Publication No. US 2003/0224059 that delivers people such as () Lerner, receives it for referencial use in full at this.
Fenofibrate microgranule of the present invention is by the distillation micronization, removes the carrier that can distil and obtain from the solid solution of fenofibrate the carrier that can distil.Fenofibrate can be discrete molecule with the distilled carrier in the solid solution and exist, perhaps it can hundreds of, several thousand or more polymolecular aggregate form exist.This medicine only needs to be dispersed to and is small enough to the final yardstick enough little, discrete particles that obtains.Preferably, the fenofibrate in the solid solution is dissolved in the carrier that can distil.
The carrier that can distil has measurable vapour pressure at it below the fusing point.The vapour pressure of carrier of preferably can distilling is at least about 10Pa, more preferably at its below normal fusing point 10 ℃ or be at least about 50Pa more.Preferably, the fusing point of the carrier that can distil is between-10 ℃～about 200 ℃ approximately, more preferably between about 20 ℃～about 60 ℃, most preferably between about 40 ℃～about 50 ℃.Preferably, the carrier that can distil is a kind of classification (that is material GRAS), that It is generally accepted to safety that incorporated into by food and drug administration.The example of suitable distilled carrier comprises menthol, thymol, Camphora, the tert-butyl alcohol, the three chloro-tert-butyl alcohols, imidazoles, coumarin, acetic acid (glacial acetic acid), dimethylsulfone, urea, Rhizoma et radix valerianae element, camphene, salicylamide and 2-aminopyridine.Menthol is the particularly preferred carrier that distils.
Microgranule of the present invention is to form by shift out the carrier that can distil in the temperature that is lower than the solid solution fusing point from the solid solution of preparation as mentioned above.This solid solution must maintain the temperature that is lower than its fusing point, so that preserve this solid solution during the processing of shifting out the carrier that can distil.The carrier that can distil can pass through, and for example, at air flow, preferably at heated air flow, for example, handles the solid solution that is deposited on the pharmaceutical carrier granule in fluidized bed dryer, if situation discussed below is suitable for, shifts out from solid solution.
Pharmaceutical composition of the present invention also comprises poly alkylene glycol.Preferably, pharmaceutical composition of the present invention comprises at least a Polyethylene Glycol (PEG) and at least a poly-second-polypropylene glycol.
The Polyethylene Glycol that can be used in the invention process has general formula-(CH 2-CH 2-O-) x-, and can be by the arithmetic mean of instantaneous value (＜X of X N) or molecular weight characterization correspondingly, as, for example, Polyethylene Glycols, 23National Formulary describes in 3052 (United States Pharmacopeial Convention, 2005).Polyethylene glycol 6000 is to be preferred for Polyethylene Glycol of the invention process.
Can be used for poly-second-polypropylene glycol of the invention process and have general formula-(O-CH 2CH 2-) a-O-(CH (CH 3) CH 2-) b-(O-CH 2CH 2-) n-OH is commonly referred to as " poloxamer (poloxamers) ".Be preferred for implementing poloxamer of the present invention and be described in picture U.S.National Formulary.Poloxamers, 23National Formulary is in 3051 (United States Pharmacopeial Convention, 2005) in the monograph of the same name.Poly-second-the polypropylene glycol that is commonly referred to as " poloxamer 407 " is to be particularly preferred for implementing poly-second-polypropylene glycol of the present invention.
Pharmaceutical composition of the present invention can by, and in preferred embodiments, be deposited on the high amount of drug carrier granular.Be used for pharmaceutical preparation of the present invention, can be used as the pharmaceutical carrier granule of carrier (support), base material or carrier (carrier), constitute and technically know by edible material.The particulate example of useful pharmaceutical carrier comprises such granule, and it can be the non-pariel pill, and diameter is generally between about 0.1mm～about 2mm, by, for example, starch, microcrystalline cellulose crude granule, lactose granule or, particularly, the sugar grain constitutes.Suitable sugar grain (pill, for example, non-pariel 103, and Nu-core is Nu-pariel) with 35～40 orders to 18～14 purpose granularity available commercial.Preferred pharmaceutical carrier granule is by non-water soluble material, and for example, microcrystalline Cellulose constitutes.Comprise that microcrystalline Cellulose (for example,
Figure A20058005244400111
) carrier granular be particularly preferred pharmaceutical carrier granule.Those skilled in the art will know that other pills or the bead of useful as drug carrier granular.
Pharmaceutical composition of the present invention can be made by the combination of fenofibrate, Polyethylene Glycol, poly-second-polypropylene glycol and the carrier that can distil.Above all compositions can respective pure form combination, perhaps, in the embodiment that compositions is deposited on the high amount of drug carrier granular, combine with appropriate solvent.Suitable dissolution with solvents fenofibrate, Polyethylene Glycol, poly-second-polypropylene glycol and the carrier that can distil, but dissolved substance carrier granular not, and further any composition all is chemical inertness, and can shift out easily in suitable temperature, especially＜100 ℃ temperature, randomly by adding vacuum.Ethanol is the example of suitable solvent.
The combination of all compositions is incorporated in together and heats with the formation homogeneous mixture, preferred a kind of solution, and cooling is to obtain solid solution.Fenofibrate can exist with distilled carrier in the solid solution form with discrete molecule, perhaps it can hundreds of, several thousand or more polymolecular aggregate form exist.This medicine only needs to be dispersed to and is small enough to the final yardstick enough little, discrete particles that obtains.
Preferably, with the medicine dissolution in the solid solution in the carrier that can distil.Deposit in the embodiment that the high amount of drug carrier granular gets in the micronized microparticles that will distil, the warm solution of all compositions in the carrier that can distil passes through, and for example, mixes, merge with the pharmaceutical carrier granule, and make mixture cool off the solid solution that is formed on the pharmaceutical carrier granule.Alternatively, the pharmaceutical carrier granule and carrier, fenofibrate, Polyethylene Glycol and the poly-second-polypropylene glycol solution in appropriate solvent (for example, ethanol) that can distil are merged.Shift out solvent, randomly by heating and evacuation, the result obtains to have deposited on it pharmaceutical carrier granule of fenofibrate, Polyethylene Glycol and the poly-second-polypropylene glycol solid solution in the carrier that can distil (for example, menthol).
Form after the solid solution,, thereby make pharmaceutical preparation of the present invention by from the solid solution of preparation as mentioned above, shifting out the carrier that to distil subsequently in the temperature that is lower than the solid solution fusing point no matter whether it is deposited on the pharmaceutical carrier granule.This solid solution must maintain the temperature that is lower than its fusing point, so that preserve solid solution during the processing of shifting out the carrier that can distil.The carrier that can distil can pass through, and for example, at air flow, preferably at heated air flow, for example, handles the solid solution that is deposited on the pharmaceutical carrier granule in fluidized bed dryer, if situation discussed above is suitable for, shifts out from solid solution.
In preferred embodiments, the shifting out of carrier that can distil causes the formation of on-mechanical micronization fenofibrate microgranule, and this microgranule also can comprise at least a portion Polyethylene Glycol and poly-second-polypropylene glycol.In addition, at least a portion fenofibrate can be in solution, perhaps with not necessarily will with the tight associating Polyethylene Glycol of on-mechanical micronized microparticles and poly-second-polypropylene glycol the two one or both of closely associate.
The applicant's invention is not limited to a certain particular theory of operation.But the applicant believes that after shifting out the carrier that can distil, at least a portion fenofibrate is dissolved in the poly alkylene glycol or closely associates with it.The simple physical mixture do not contained in term " closely associate ", as passing through, for example, do blending, do pelletize, or the wet pelletize in the presence of the liquid that does not dissolve all compositions at least in part formed those.
Pharmaceutical composition of the present invention in the time of especially on being deposited on the high amount of drug carrier granular, is fit to liquid state, the especially manufacturing of solid oral agent type such as compressed tablets and capsule charge well.In another embodiment, the invention provides a kind of peroral dosage form that comprises pharmaceutical composition of the present invention, especially solid oral agent type, preferably compressed tablets.
Compressed tablets perhaps adopts the pharmaceutical carrier granule that has this kind microgranule by the microgranule that comprises pharmaceutically active substance or medicine, with the pharmaceutical composition preparation of pharmacology's inertia (medicine can be accepted) additive or excipient.
Be to make tablet, satisfying usually is, comprises 1 or multiple optimum drug excipient in pharmaceutical composition.Pharmaceutical composition of the present invention can comprise 1 or plurality of diluent, and the purpose that adds it is that tablet is done more, therefore also be more convenient for patient or nursing staff's taking and placing.Diluent commonly used be microcrystalline Cellulose (for example, ), (pregelitinized) starch, calcium carbonate, calcium sulfate, sugar, dextrates (dextrates), dextrin, glucose, the Bibasic Calcium Phosphate of fine cellulose, lactose, starch, pre-gelatinizing (for example close two water (dibasic calcium phosphatedihydrate), three alkali calcium phosphates (tribasic calcium phosphate), Kaolin, magnesium carbonate, magnesium oxide, maltodextrin (maltodextrin), mannitol, polymethacrylates ), potassium chloride, powdery cellulose, sodium chloride, sorbitol and Pulvis Talci.
Binding agent also can be included in the tablet formulation and keep together after helping making tablet press.Some typical binding agent be arabic gum, alginic acid, carbomer (carbomer) (for example, Carbopol), sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl-cellulose, hydroxypropyl cellulose are (for example
Figure A20058005244400131
), hydroxypropyl emthylcellulose (for example,
Figure A20058005244400132
), liquid glucose, Magnesiumaluminumsilicate, maltodextrin, methylcellulose, polymethacrylates, polyvidone (povidone) (for example,
Figure A20058005244400133
Figure A20058005244400134
), pre-gelatinized starch, sodium alginate and starch.
Tablet can comprise also that in addition disintegrating agent is to quicken the disintegration of tablet in patient's stomach.Disintegrating agent comprises alginic acid, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, silica sol, cross-linking sodium carboxymethyl cellulose or calcium, and (croscarmellose sodium (for example, Or croscarmelose calcium), crospovidone (for example,
Figure A20058005244400136
), guar gum, Magnesiumaluminumsilicate, methylcellulose, microcrystalline Cellulose, polacrilin potassium (polacrilinpotassium), powdery cellulose, pre-gelatinized starch, sodium alginate, Explotab (for example,
Figure A20058005244400137
) and starch.
In addition or alternative alginic acid, other organic carboxyl acids also can be included in the prescription.This organic acid comprises tannic acid, citric acid, fumaric acid, tartaric acid, lactic acid, malic acid, ascorbic acid, benzoic acid, sorbic acid etc.Tannic acid and citric acid are the organic carboxyl acids that is particularly preferred for the present invention this and other embodiment.
Pharmaceutical composition of the present invention is passable, and contains bicarbonate or carbonate in preferred embodiments really, especially alkali metal hydrogencarbonate or carbonate.The example of preferred alkali carbonate and bicarbonate comprises sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate.Alkaline earth metal carbonate also can use as calcium carbonate and magnesium carbonate.
The pharmaceutical composition that is used to make compressed tablets also can comprise slipping agent (glidants), lubricant, spice, coloring agent and other normal excipient that uses.
It is mobile and can directly use that the pharmaceutical carrier granule that has drug microparticles made in accordance with the present invention has excellent body (bulk), separately or with the carrier granular combination that does not have medicine, make capsule formulation.When the glue capsule, necessary, diluent such as lactose, mannitol, calcium carbonate and magnesium carbonate are only lifted numerical example, can prepare burden with the pharmaceutical carrier granule that has this microgranule.
The liquid combination of oral medication of the present invention comprises microgranule or has the pharmaceutical carrier granule of microgranule, and liquid carrier such as water, vegetable oil, alcohol, Polyethylene Glycol, propylene glycol or glycerol, most preferably water.
Liquid combination of oral medication can comprise emulsifying agent, so that make active component, drug delivery vehicle, or the excipient that has low-solubility in liquid carrier disperses in whole compositions equably.The emulsifying agent that can be used for fluid composition of the present invention comprises, for example, gelatin, egg yolk, casein, cholesterol, arabic gum (acacia), Tragacanth (tragacanth), chondrus ocellatus Holmes (chondrus), pectin (pectin), methylcellulose, carbomer, spermaceti-stearyl alcohol and spermol.
The liquid combination of oral medication of the present invention also can comprise mouthfeel and/or the covering gastrointestinal tract inner surface of viscosifier to improve product.Examples of such additives comprises arabic gum, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, spermaceti-stearyl alcohol, methylcellulose, ethyl cellulose, gelatin guar gum, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, maltodextrin, polyvinyl alcohol, polyvidone, propylene carbonate (propylene carbonate), propylene glycol alginic acid ester, sodium alginate, Explotab, starch Tragacanth and Xanthan gum (xanthan gum).
Liquid combination of oral medication also can comprise sweeting agent such as sorbitol, glucide, saccharin sodium, sucrose, aspartame (aspartame), fructose (fructose), mannitol and Nulomoline; Antiseptic and chelating agen are as alcohol, sodium benzoate, Yoshinox BHT, butylatedhydroxyanisole and ethylenediaminetetraacetic acid; And buffer agent such as gluconic acid (guconic acid), lactic acid, citric acid or acetic acid, gluconic acid sodium salt, sodium lactate, sodium citrate or sodium acetate.
Prepare and blended solid oral agent type with Polyethylene Glycol and poly-second-polypropylene glycol with distillation micronization fenofibrate microgranule, as top prepared, provide the improvement of fenofibrate bioavailability, as what showed for kinetics (plasma concentration) test at dissolution in vitro (release) and human body giving drugs into nose.External and in vivo test result disclosed herein is by comprising about 145mg fenofibrate and having the tablet acquisition of every nominal weight of 792mg.
Time dependent release in vitro disclosed herein (dissolving) curve is to adopt USP model-II dissolution testers at 37 ℃, operates in 50rpm and pours into that 1000mL0.5wt% lauryl sulfate sodium water solution obtained.The concentration of fenofibrate in experimental liquid is to adopt HPLC to measure.
Pharmacokinetic data disclosed herein is to pass through to measure metabolite in testing in human body--the variation of the plasma concentration versus time of fenofibric acid obtains, and the result obtains famous Boltzmann shape accumulation plasma concentration (AUC) curve.Each point is reported with reference to the time point of selected reality or extrapolation on the AUC curve.
Therefore, the area of 48h AUC curve below, AUC 48, be meant accumulation haemoconcentration (blood concentration) until 48h time point (last measuring point).AUC ∞Refer to the area below the AUC curve that is extrapolated to the infinity time.C MaxBe meant the maximum absolute plasma concentration of in the 48h test, measuring (plasma concentration) (that is the maximum point on the 48-h AUC curve).Average A UC (＜AUC 〉) be the arithmetic average plasma concentration of the fenofibric acid that (about 48h) measures during determination of plasma concentration.
In its some embodiment, the present invention will be illustrated by following non-limiting example.In the following embodiments, fasting state refers to, and is taking medicine preceding 10 hours in, and object is feed not.The feed state refers to, and the precontract of taking medicine half an hour, object is taken food.
Embodiment
A. fenofibrate pill
Menthol (1.333kg) carries out fusion under 50 ℃ of stirrings in glass reactor.In reactor, add fenofibrate (133.3gm), poloxamer 407 (Lutrol F127,76gm) and ethylene glycol 6000 (76gm).The menthol melt stirs until all the components at 50 ℃ and all dissolves.(Avicel PH 101 106.7gm), stirs subsequently until obtaining symmetric suspension to add microcrystalline Cellulose in melt.
The menthol melt is classified in three categories part and be poured into 3 pallets (rustless steel, 0.133m 2Each) in, pallet is cooled to-40 ℃ in advance so that the menthol suspended substance is solidified rapidly.Take out the solid material on the pallet and adopt the Erweka mill by the rough lapping of 2.5mm screen cloth.The powder that obtains is further divided into 3 parts and turn back in the pallet.By in fine vacuum tray dried device, shifting out menthol the material from pallet at 0.2mbar and 36 ℃ of about 53h of distillation.The powder that generates is taken out from pallet, and adopts the Erweka mill to grind by the 1.6mm screen cloth so that the substance pulverizing of shaped particles does not take place.So the pill that obtains obtains 88% yield through weigh (346.4gm).
B. fenofibrate tablet (145mg)
Fenofibrate pill from steps A adopts the Erweka mill to grind by the 0.8mm screen cloth.The pill (336gm) that grinds is added into Polythene Bag (in 50 * 70cm).Add crospovidone (108gm), sodium bicarbonate (72gm) and anhydrous citric acid (72gm) and blending 5min.In sack, add magnesium stearate (12gm) and blend is further mixed 1/2min.So the blend total amount that obtains is 600g.
On Manesty F3 single punching tablet machine, (8.8mm * 17.6mm) common depression punch die is pressed into tablet to adopt ellipse with blend.The design weight of tablet is 785mg ± 39.3mg, hardness 5～7Kp.The average weight of the tablet that obtains is 792mg, hardness 6Kp.Several and be labeled as MAZ149B, MAZ149B1 and MAZ149B2 have respectively been made.
C. release in vitro
USP model II dissolution tester is adopted in the release (dissolving) of fenofibrate from tablet, and perfusion, 1000mL0.5wt% sodium lauryl sulfate (SLS) (w/v) aqueous solution are tested with 50rpm at 37 ℃.Employing HPLC measures the amount of the fenofibrate in each sample, as mentioned above.The result of this 3 batch of material is stated from table C1～C3.
Table C1. fenofibrate release in vitro result (% marks) MAZ149B
Time (min) Container 1 Container 2 Container 3 Container 4 Container 5 Container 6 Container 7
10 80.2 69.2 75.2 76.2 78.0 75.5 71.8
15 92.7 86.9 90.5 90.5 90.8 88.6 87.5
30 99.3 94.8 96.6 97.7 96.9 93.0 95.6
Time (min) Container 8 Container 9 Container 10 Container 11 Container 12 Avg ％RSD
10 80.1 75.2 73.9 80.5 80.3 76.3 4.75
15 89.6 88.9 88.3 89.1 89.2 89.4 1.76
30 95.2 95.4 94.6 95.4 94.4 95.7 1.74
Table C2. fenofibrate release in vitro result (% marks) MAZ149B1
Time (min) Container 1 Container 2 Container 3 Container 4 Container 5 Container 6 Avg ％RSD
10 58.6 55.8 51.4 55.2 51.5 61.5 55.7 7.11
15 79.5 77.3 73.6 77.5 74.4 79.2 76.9 3.16
30 90.7 88.9 86.5 88.5 89.1 89.5 88.9 1.56
Table C3. fenofibrate release in vitro result (% marks) MAZ149B2
Time (min) Container 1 Container 2 Container 3 Container 4 Container 5 Container 6 Avg ％RSD
10 69.0 66.3 68.9 71.0 72.4 63.8 68.6 4.54
15 80.2 79.6 81.1 81.1 81.0 77.6 80.1 1.72
30 86.9 87.8 88.0 87.1 87.1 86.9 87.3 0.56
D. the body giving drugs into nose is for dynamic test
MAZ149B and
Figure A20058005244400161
The pharmacokinetics test of 145mg
Adopt MAZ149B (145mg, as mentioned above) and
Figure A20058005244400162
(145mg) carry out 4 tunnel intersection (four way crossover) bioequivalence pharmacokinetics tests as two volunteers in the test arm to 12 health.Other 2 arms are other test preparations according to the present invention's preparation.Between each test arm, carry out 1 week cleaning (washout).Blood sample is 0,1,2,3,3.5,4,4.5,5,5.5,6,6.5,7,8,9,10,12,16,24 and 48h gathers (19 duplicate samples/test) and adopt effective method to analyze fenofibric acid.The test of 4 arms was both also implemented under the state on the feed in fasting.
The result
The fasting state data are from volunteer 1～11, just test that MAZ149B (N=11) obtains; And from volunteer 2～11, with regard to object of reference
Figure A20058005244400171
(N-10) obtain.The result is stated from table D1.Meansigma methods shows that the bioavailability of this test is 97.4% of an object of reference, according to AUC 48(175334 couples of 180010h*ng/g); With 97.7% of object of reference, according to AUC ∞(213653 couples of 218628h*ng/g).Corresponding geometrical mean shows 97.5%, according to AUC 48(169481 couples of 173880h*ng/g); With 97.5%, according to AUC ∞(205217 couples of 210558h*ng/g).Each test (sample) is to object of reference AUC ∞The geometric average ratio of ratio be 1.006.C MaxMeansigma methods show: test is 99% (10570 couples of 10624ng/g) of object of reference, and geometrical mean is 100.7% (10340 couples of 10270ng/g) simultaneously.Each volunteer's test is 1.021 to the geometrical mean of the ratio of object of reference.The variability of bioavailability (variability) is with regard to AUC 48The value %CV (variability of variable) and the opinion very close: 28.95% pair 27.16%.The average terminal point half-life (the terminal point half-life of disappearance) is 20.0h, for test products; And 19.9h, object of reference, and average T MaxBe 2.5h, test; And 2.1h, object of reference.Can draw to draw a conclusion: 2 kinds of preparations are bioequivalent at fasting state.
The feed status data be from volunteer 1～5,7～10 and 12 (N=10) just test MAZ149B and
Figure A20058005244400172
Obtain with reference to product.The result is stated from table D2.Meansigma methods shows that the bioavailability of test is 107.1% of an object of reference, according to AUC 48112.0% of (150511 couples of 140627h*ng/g) and object of reference is according to AUC ∞(185149 couples of 165310h*ng/g).Corresponding geometrical mean shows 106.8%, according to AUC 48(145402 couples of 136134h*ng/g) and 111.2% is according to AUC ∞(174021 couples of 156459h*ng/g).Each test is to object of reference AUC ∞The geometric average ratio of ratio be 1.112.C MaxMeansigma methods show: test is 79.0% (7557 couples of 9567ng/g) of object of reference, and geometrical mean is 77.5% (7147 couples of 9217ng/g) simultaneously.Each volunteer's test is 0.775 to the geometric average ratio of the ratio of object of reference.The variability of bioavailability is with regard to AUC 48The value %CV (variability of variable) and the opinion very close: 27.16 pairs 26.41%.The average terminal point half-life is 17.4h, for test products; And 16.1h, object of reference, and average T MaxBe 8.0h, test; And 3.6h, object of reference.The bioavailability combination that improves is with low C MaxSlower (later) T MaxShow the improvement of state on the feed of product effect.
Figure A20058005244400191
Figure A20058005244400201
Figure A20058005244400211

Claims (36)

1. pharmaceutical composition that comprises on-mechanical micronization fenofibrate microgranule, Polyethylene Glycol and poly-second-polypropylene glycol.
2. the pharmaceutical composition of claim 1, wherein on-mechanical micronization fenofibrate microgranule utilization distillation micronization manufacturing.
3. the pharmaceutical composition of claim 2, wherein the on-mechanical micronized microparticles is deposited on the high amount of drug carrier granular.
4. the pharmaceutical composition of claim 3, wherein menthol is the distilled carrier in the distillation micronization step.
5. the pharmaceutical composition of claim 1, wherein Polyethylene Glycol is a polyethylene glycol 6000.
6. the pharmaceutical composition of claim 1, wherein poly-second-polypropylene glycol is a poloxamer 407.
7. the pharmaceutical composition of claim 6, wherein this pharmaceutical composition is the form of solid oral agent type, and this dosage form comprises about 15wt%～about 25wt% fenofibrate, about 7%～about 13% poloxamer 407 and about 7%～about 13% polyethylene glycol 6000.
8. the solid oral agent type of claim 7 also comprises the medicine disintegrating agent, is selected from crospovidone, cross-linking sodium carboxymethyl cellulose, bicarbonate, organic carboxyl acid and above-mentioned combination in any.
9. the pharmaceutical composition of claim 8, wherein organic carboxyl acid is citric acid or tartaric acid.
10. solid oral agent type, it comprises a kind of pharmaceutical composition, and the latter comprises about 15wt%～about 25wt% on-mechanical micronized fenofibrate microgranule, about 7wt%～about 13wt% poloxamer 407, about 7%～about 13% polyethylene glycol 6000, about 15wt% microcrystalline Cellulose, about 18wt% crospovidone, about 12wt% sodium bicarbonate and about 12wt% citric acid or tartaric acid.
11. the solid oral agent type of claim 10 comprises about 12wt% citric acid.
12. the solid oral agent type of claim 10, has the time dependent release in vitro curve of a kind of fenofibrate, so that in about 10min, discharge at least about the 51wt% fenofibrate, discharge in about 15min at least about the 73wt% fenofibrate, in about 30min, discharge at least about the 85wt% fenofibrate.
13. the solid oral agent type of claim 10, has a kind of time dependent release in vitro curve, so that about 51wt%～about 81wt% fenofibrate discharges in about 10min, about 73wt%～about 93wt% fenofibrate discharges in about 15min, and about 85wt%～approximately all fenofibrate discharges in about 30min.
14. a solid oral agent type, it comprises a kind of pharmaceutical composition, and the latter comprises about 145mg distillation micronization fenofibrate, wherein human body giving drugs into nose that this dosage form is taked the fasting state administration for dynamics research in, the area (AUC below the 48 h AUC curves 48) be about 121367h*ng/g～about 287539 h*ng/g; Be extrapolated to the area (AUC below the AUC curve of infinitely great time ∞) be about 134750 h*ng/g～about 345390 h*ng/g; And maximal plasma concentration (C Max) be about 6357 ng/g～about 14627 ng/g.
15. the solid oral agent type of claim 14, wherein human body giving drugs into nose that this dosage form is taked the fasting state administration for dynamics research in, average A UC 48Be about 175335 h*ng/g, average A UC ∞Be about 213652h*ng/g and average C MaxBe about 10570 ng/g.
16. the solid oral agent type of claim 14, wherein the solid oral agent type is a compressed tablets.
17. a solid oral agent type, it comprises a kind of pharmaceutical composition, and the latter comprises about 145mg distillation micronization fenofibrate; Wherein this dosage form take to take food the human body giving drugs into nose of state administration for dynamics research in, the area (AUC below the 48 h AUC curves 48) be about 91601h*ng/g～about 217512 h*ng/g; Be extrapolated to the area (AUC below the AUC curve of infinitely great time ∞) be about 97182 h*ng/g～about 308070 h*ng/g.
18. the solid oral agent type of claim 17, wherein average A UC 48Be about 150511h*ng/g and average A UC ∞Be about 185149 h*ng/g.
19. the solid oral agent type of claim 18, wherein the solid oral agent type is a compressed tablets.
20. a pharmaceutical composition comprises the high amount of drug carrier granular, the latter has the combination of thereon fenofibrate of deposition, Polyethylene Glycol, poly-second-polypropylene glycol; Wherein this combination is deposited by the solid solution that comprises fenofibrate, Polyethylene Glycol, poly-second-polypropylene glycol and the carrier that can distil by the distillation of the carrier that can distil.
21. the pharmaceutical composition of claim 20, the carrier that wherein can distil is a menthol.
22. the pharmaceutical composition of claim 20, wherein Polyethylene Glycol is a polyethylene glycol 6000.
23. the pharmaceutical composition of claim 20, wherein poly-second-polypropylene glycol is a poloxamer 407.
24. the pharmaceutical composition of claim 20, wherein this pharmaceutical composition is the form of solid oral agent type, and this dosage form comprises about 15 wt%～about 25 wt% fenofibrate, about 7%～about 13% poloxamer 407 and about 7%～about 13% polyethylene glycol 6000.
25. the solid oral agent type of claim 24 also comprises the medicine disintegrating agent, is selected from crospovidone, cross-linking sodium carboxymethyl cellulose, bicarbonate, organic carboxyl acid and above-mentioned combination in any.
26. the pharmaceutical composition of claim 25, wherein organic carboxyl acid is citric acid or tartaric acid.
27. solid oral agent type, it comprises a kind of pharmaceutical composition, the latter comprises about 15wt%～about 25 wt% fenofibrate, about 7 wt%～about 13 wt% poloxamers 407, about 7%～about 13% polyethylene glycol 6000, about 15 wt% microcrystalline Cellulose, about 18 wt% crospovidones, about 12 wt% sodium bicarbonate and about 12 wt% citric acid or tartaric acid, wherein fenofibrate at least, poloxamer 407 and polyethylene glycol 6000 by the distillation of the carrier that can distil by fenofibrate at least, the solid solution of poloxamer 407 and polyethylene glycol 6000 and the carrier that can distil is deposited on the microcrystalline Cellulose.
28. the solid oral agent type of claim 27 comprises about 12 wt% citric acids.
29. the solid oral agent type of claim 27, has the time dependent release in vitro curve of a kind of fenofibrate, so that in about 10 min, discharge at least about 51 wt% fenofibrate, discharge in about 15 min at least about 73 wt% fenofibrate, in about 30 min, discharge at least about 85 wt% fenofibrate.
30. the solid oral agent type of claim 27, has a kind of time dependent release in vitro curve, so that about 51 wt%～about 81 wt% fenofibrate discharge in about 10 min, about 73 wt%～about 93 wt% fenofibrate discharge in about 15 min, and about 85 wt%～approximately all fenofibrate discharges in about 30 min.
31. a solid oral agent type, it comprises a kind of pharmaceutical composition, and the latter comprises about 145mg fenofibrate, and it is deposited on a large amount of microcrystalline cellulose crude granules by the distillation of the solid solution that comprises the fenofibrate and the carrier that can distil by the carrier that can distil; Wherein human body giving drugs into nose that this dosage form is taked the fasting state administration for dynamics research in, the area (AUC below the 48 h AUC curves 48) be about 121367 h*ng/g～about 287539 h*ng/g; Be extrapolated to the area (AUC below the AUC curve of infinitely great time ∞) be about 134750 h*ng/g～about 345390 h*ng/g; And maximal plasma concentration (C Max) be about 6357 ng/g～about 14627 ng/g.
32. the solid oral agent type of claim 31, wherein human body giving drugs into nose that this dosage form is taked the fasting state administration for dynamics research in, average A UC 48Be about 175335 h*ng/g, average A UC ∞Be about 213652h*ng/g and average C MaxBe about 10570 ng/g.
33. the solid oral agent type of claim 31, wherein the solid oral agent type is a compressed tablets.
34. a solid oral agent type, it comprises a kind of pharmaceutical composition, and the latter comprises about 145mg fenofibrate, and it is deposited on a large amount of microcrystalline cellulose crude granules by the distillation of the solid solution that comprises the fenofibrate and the carrier that can distil by the carrier that can distil; Wherein this dosage form take to take food the human body giving drugs into nose of state administration for dynamics research in, the area (AUC below the 48 h AUC curves 48) be about 91601 h*ng/g～about 217512 h*ng/g; Be extrapolated to the area (AUC below the AUC curve of infinitely great time ∞) be about 97182 h*ng/g～about 308070 h*ng/g.
35. the solid oral agent type of claim 34, wherein average A UC 48Be about 150511h*ng/g and average A UC ∞Be about 185149 h*ng/g.
36. the solid oral agent type of claim 35, wherein the solid oral agent type is a compressed tablets.
CNA2005800524449A 2005-12-28 2005-12-28 Fenofibrate medicinal preparation with improved bioavailability Pending CN101351191A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2005/047346 WO2007075171A1 (en) 2005-12-28 2005-12-28 Pharmaceutical formulations of fenofibrate having improved bioavailability

Publications (1)

Publication Number Publication Date
CN101351191A true CN101351191A (en) 2009-01-21

Family

ID=36499668

Family Applications (1)

Application Number Title Priority Date Filing Date
CNA2005800524449A Pending CN101351191A (en) 2005-12-28 2005-12-28 Fenofibrate medicinal preparation with improved bioavailability

Country Status (7)

Country Link
JP (1) JP2009522258A (en)
CN (1) CN101351191A (en)
BR (1) BRPI0520821A2 (en)
CA (1) CA2634094A1 (en)
IL (1) IL192230A0 (en)
MX (1) MX2008008589A (en)
WO (1) WO2007075171A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112618511A (en) * 2020-12-31 2021-04-09 辰欣药业股份有限公司 Prescription composition of fenofibrate capsule and preparation process thereof

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011029181A1 (en) * 2009-09-09 2011-03-17 Bernard Charles Sherman Choline fenofibrate delayed release compositions
FI3482771T3 (en) * 2013-03-14 2023-04-03 Nestle Sa Manufacture of peanut formulations for oral desensitization
KR101850119B1 (en) 2015-11-11 2018-04-20 제이투에이치바이오텍 (주) Novel Fenofibric Acid Prodrugs with Improved Bioavailability
US11229673B2 (en) 2019-05-10 2022-01-25 Société des Produits Nestlé S.A. Methods for improving the quality of life of a patient with a peanut allergy

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2627696B1 (en) * 1988-02-26 1991-09-13 Fournier Innovation Synergie NEW GALENIC FORM OF FENOFIBRATE
FR2758459B1 (en) * 1997-01-17 1999-05-07 Pharma Pass FENOFIBRATE PHARMACEUTICAL COMPOSITION HAVING HIGH BIODAVAILABILITY AND PROCESS FOR PREPARING THE SAME
US6368622B2 (en) * 1999-01-29 2002-04-09 Abbott Laboratories Process for preparing solid formulations of lipid regulating agents with enhanced dissolution and absorption
EP1322289B1 (en) * 2000-09-20 2007-07-25 Jagotec AG Spray drying process of compositions containing fenofibrate
DK1487416T3 (en) * 2002-03-26 2010-03-29 Teva Pharma Drug Microparticles
EP1680091B1 (en) * 2003-10-10 2017-05-31 Veloxis Pharmaceuticals A/S A solid dosage form comprising a fibrate
JP2007508249A (en) * 2003-10-10 2007-04-05 ライフサイクル ファーマ アクティーゼルスカブ Solid dosage form containing fibrates and statins

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112618511A (en) * 2020-12-31 2021-04-09 辰欣药业股份有限公司 Prescription composition of fenofibrate capsule and preparation process thereof

Also Published As

Publication number Publication date
WO2007075171A1 (en) 2007-07-05
CA2634094A1 (en) 2007-07-05
BRPI0520821A2 (en) 2009-06-30
MX2008008589A (en) 2009-02-25
IL192230A0 (en) 2008-12-29
JP2009522258A (en) 2009-06-11

Similar Documents

Publication Publication Date Title
CN109078006B (en) Medicinal preparation of palbociclib and preparation method thereof
US7923026B2 (en) Embedded micellar nanoparticles
TW202332423A (en) Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US20090263479A1 (en) Formulations for poorly permeable active pharmaceutical ingredients
KR101267782B1 (en) Stabilized amorphous forms of imatinib mesylate
CN101516344A (en) Pharmaceutical compositions comprising nilotinib or its salt
US8663697B2 (en) Solid dispersion preparation
US20070248682A1 (en) Solid preparation comprising enteric solid dispersion
KR100962447B1 (en) Composition for self-emulsifying of insoluble dutasteride and the tablet containing thereof
CN101351191A (en) Fenofibrate medicinal preparation with improved bioavailability
CN102793706B (en) The preparation method of Tolvaptan solid dispersion
CN103393617B (en) Febustat tablet and preparation method thereof
CN102292075A (en) Pharmaceutical compositions with superior product performance and patient compliance
US20070148233A1 (en) Pharmaceutical formulations of fenofibrate having improved bioavailability
CN1899277B (en) Composition of rheinic acid or rheinic acid compounds, its preparing method and its use in preparing medicine for treating diabetic nephrosis
CN102188417A (en) Dronedarone medicinal composition
WO2014167579A2 (en) Stable pharmaceutical compositions of tadalafil
CN103655470A (en) Dutasteride self-microemulsion composition and preparation method thereof
CN102423485B (en) Oral composition containing desmopressin acetate and preparation method for oral composition
CN101721351A (en) Solid dispersion of bystolic or pharmaceutical salt of bystolic, preparation method thereof and use thereof
CN104248769B (en) A kind of lurasidone medicine composition and preparation method thereof
CN105287412A (en) Aripiprazole dispersible tablet and preparation method thereof
CN102349889A (en) Composition containing dronedarone
CN107375225B (en) Level release formulation of a kind of succinic acid furan Luo Qu and preparation method thereof
JPH0776516A (en) Production of slightly soluble medicine-containing preparation

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Open date: 20090121