CN102188398A - Solid preparation containing highly dispersed fenofibrate - Google Patents
Solid preparation containing highly dispersed fenofibrate Download PDFInfo
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- CN102188398A CN102188398A CN2010101235275A CN201010123527A CN102188398A CN 102188398 A CN102188398 A CN 102188398A CN 2010101235275 A CN2010101235275 A CN 2010101235275A CN 201010123527 A CN201010123527 A CN 201010123527A CN 102188398 A CN102188398 A CN 102188398A
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- fenofibrate
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Abstract
The invention provides a solid preparation containing highly dispersed fenofibrate, wherein the fenofibrate stably exists in carrier materials in a highly dispersed form. The carrier materials are water-soluble carrier materials and are selected from polyethylene glycol, povidone, a surfactant containing a polyoxyethylene group, a water-soluble cellulose derivative, organic acid, organic sugar and organic alcohol. The carriers can be used separately or in a combination manner. The solid preparation containing the highly dispersed fenofibrate can be in a form of capsules or tablets. The bioavailability of the fenofibrate can be improved. The dosage of the single preparation of the fenofibrate can be reduced.
Description
Technical field
The invention belongs to field of biological pharmacy, be specifically related to a kind of solid preparation that contains the fenofibrate of high degree of dispersion, for example tablet or capsule the invention still further relates to the preparation method of the solid preparation of the described fenofibrate that contains high degree of dispersion.
Background technology
Fenofibrate (Fenofibrate), chemical name are 2-(4-(4-chlorobenzene formacyl) phenoxy group)-2 Methylpropionic acid isopropyl ester, are a kind of fibrates, and the preparation pattern of clinical practice at present is mainly capsule and tablet.The fenofibrate tablet dose of FDA approval is 48,54,145,160mg.Most of pro-systems of oral fenofibrate and the first site of crossing just have been metabolized to the glucosiduronic acid conjugate, and no prototype exists in blood plasma.Fenofibrate is a kind of prodrug, and the effect through esterase is metabolized to fenofibrate acid rapidly and plays effect for reducing blood fat in vivo, has tangible reduction serum cholesterol, the effect of triglyceride and high density lipoprotein increasing.
Fenofibrate is white or off-white color crystalline powder, and odorless is tasteless, and fusing point is 78～82 ℃, very easily is dissolved in chloroform, is soluble in acetone or ether, is dissolved in ethanol, and is water-soluble hardly, is a kind of medicine of very indissoluble.Although it is poorly soluble, it is reported that it also can be absorbed well during administration under the state on the feed, and relatively poor in the next absorption of fasting state.When taking with food as 54mg and 160mg fenofibrate tablet, the degree of absorption of fenofibrate has improved about 35% (PDR2004; Martidale the 33rd edition, the 889th page).
In disclosed 54mg of FDA and 160mg fenofibrate tablet (trade name Tricor) prescription, comprise colloidal silica, crospovidone, lactose monohydrate, lecithin, microcrystalline Cellulose, polyvinyl alcohol, polyvidone, sodium laurylsulfate, sodium stearyl fumarate, Pulvis Talci, titanium dioxide and xanthan gum.And at FDA in the 48mg and the tablet of 145mg of approval in 2004, comprise hypromellose (3cps), docusate sodium, sucrose, sodium laurylsulfate, lactose, silicified microcrystalline cellulose, crospovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, Pulvis Talci, soybean phospholipid and xanthan gum.
In open source literature, many improvement that relate to fenofibrate stripping or absorption are arranged.Disclose fenofibrate and the common micronization of surfactant as U.S. Pat 4895726 and US5880148, U.S. Pat 6074670 and US6277405 disclose micronized fenofibrate, and it has been coated on the water-solubility carrier that contains optional surfactant.U.S. Pat 6814977 discloses fenofibrate has been dissolved in the medium chain triglycerides of fatty acid, U.S. Pat 6719999 discloses fenofibrate has been dissolved in different third sorbitol anhydride of glycerol, propylene glycol or dimethyl, and U.S. Pat 5827536 discloses fenofibrate is dissolved in the TC.
In open source literature, mention particular formulations and the Emulsion and the suspensoid of micronized fenofibrate and particular polymers or surfactant additive.U.S. Patent Application Publication 20040087656 discloses particle diameter less than 2000nm, fenofibrate with bioavailability of improvement.The medicine that U.S. Patent Application Publication 20030224059 discloses the microgranule of active pharmaceutical ingredient and comprised same substance go forward one by one carrier and preparation method.U.S. Patent Application Publication 20040198646 discloses the compositions of the menthol solutions that comprises medicine, especially for the relatively poor medicine of dissolubility in water, and the method for preparing said composition.
The micronization of medicine and adding surfactant have moderately improved the bioavailability of fenofibrate, make the dosage of medicine be reduced to every dosage 67mg and 54mg from every dosage 100mg, wherein on the feed under the state bioavailability of all these all be identical.The nanoparticle formulations of medicine further makes every dosage be reduced to 48mg, it is reported that its bioavailability under fasting state and feed state class are seemingly.By inference, the real bioavailability of fenofibrate is also relatively low, and the space therefore still has greatly improved.
Summary of the invention
The object of the invention provides a kind of solid preparation that contains the fenofibrate of high degree of dispersion.
Another object of the present invention provides the preparation method of the solid preparation of the described fenofibrate that contains high degree of dispersion.
The solid preparation that the present invention contains the fenofibrate of high degree of dispersion can be capsule or tablet form, can improve the bioavailability of fenofibrate, reduces single agent dose of fenofibrate.
The high degree of dispersion of fenofibrate reaches by certain preparation technique.The present invention preferably adopts suitable solubilization carrier, makes fenofibrate to reach the purpose same with micronized medicine, promptly obtain higher medicine dispersion with the form stable existence of high degree of dispersion in carrier material, increases the stripping of medicine.
Be applicable to that carrier material of the present invention can be divided into water solublity, slightly solubility and enteric solubility three major types, can separately or unite use.Preferentially select following a few class for use: polyethylene glycols, polyvidone class, surfactant-based, the water-soluble cellulose derivative that contains polyoxyethylene groups, organic acid and saccharide and alcohols, these a few class carriers can separately or be united use.
Several schemes that carrier is selected are specifically described below, but are not construed as limiting the invention, and as known to those skilled in the art, carry out simple prescription screening and optimization of preparation, and carrier material and preparation method can be replaced.
Polyethylene glycols (PEG) has good water-solubility, also can be dissolved in multiple organic solvent, medicine is existed with molecularity, and in preparation process, because solvent evaporation, and viscosity increases suddenly, can hinder medicine assembles, the molecular weight of PEG that is used for solid dispersion is generally between 1000-20000, using always has PEG2000, PEG4000, PEG6000, PEG10000, PEG12000, one or more combination among the PEG20000, polyoxyethylene (40) monostearate, stearic acid, or poloxamer class surfactant is normal and the PEG class is united use to regulate the dispersion and the release of medicine.
Polyvidone claims polyvinylpyrrolidone again, acyl (Polyvinylpyrrolidone in the poly-N-vinyl fourth; Povidone; Plasdone; Kollidone; Be called for short PVP).PVP has the stronger brilliant effect that presses down to many medicines, and according to the difference of its molecular weight and the viscosity that shows, specification has PVPk15, PVPk25, PVPk30, PVPk60, PVPk90 etc.With the solid dispersion of PVP as the preparing carriers of medicine, useable solvents method, solvent deposition method or spray drying method.
The water soluble dyes analog derivative also can be used as solubilization carrier.An embodiment is that hydroxypropyl emthylcellulose (HPMC) and polyoxyethylene polyoxypropylene glycol are used as carrier material, the weight ratio of medicine, HPMC, polyoxyethylene polyoxypropylene glycol is 1: 3-5: 0.2-0.5, arrive, HPMC and polyoxyethylene polyoxypropylene glycol are dissolved in the mixture of ethanol/acetone/water, medicine is added wherein, mix homogeneously is sprayed onto the solution that makes on the celphere in the fluid bed, thereby makes the granule of solid dispersion compositions.In this scheme, solvent for use is selected following one or more mixture: methanol, ethanol, isopropyl alcohol, acetone, dichloromethane, water and their mixture.
The saccharide and the alcohols that can be used for preparing solid dispersion have: dextrose, galactose, sucrose, mannitol, sorbitol, xylitol etc.A plurality of hydroxyls are arranged in the molecule of these materials, can generate solid dispersion with medicine with hydrogen bonded.At the medicine among the present invention, preferred mannitol is as main carrier.
Freeze-drying also is applicable to the preparation of described solubilizing composition.As select for use polyoxyethylene (40) stearate, poloxamer 188, HPMC, PVPk29/32, glucide as the solubilization carrier material, the weight ratio that feeds intake of medicine and carrier material is 1: 5-1: 20, medicine and carrier material are dissolved in the organic solvent (dehydrated alcohol, dichloromethane, 70% ethanol), stir, make dissolving, carry out lyophilization, freeze-drying time is 24-48 hour, take out, cross 80 mesh sieves, promptly get solid dispersion.
As known to those skilled in the art, the preparation solid dispersion carrier be not limited to above-mentioned carrier, as gelatin hydrolysate, surfactant-based also be to be applicable to the present invention program.
Can be used as the intermediate of preparation as the above-mentioned prepared carrier that contains the fenofibrate of high degree of dispersion, add pharmaceutically acceptable carrier and make other solid preparations, as powder, granule, pellet, tablet, capsule, lozenge etc.These pharmaceutically acceptable carriers comprise aforementioned excipient, as can be used as starch and derivant, cellulose derivative, sucrose, mannitol, silicic acid and the calcium hydrogen phosphate of filler; As MC, HPC, gelatin, the PVP of binding agent, the optional self-crosslinking CMC-Na of disintegrating agent, PVPP, L-HPC, lubricant can be selected from magnesium stearate and Pulvis Talci; Correctives can be selected from the stevioside, A Siba is sweet and other essence, but is not limited thereto.
Another technical scheme comprises, the carrier that contains the fenofibrate of high degree of dispersion can be adsorbed in water solublity or water-soluble solid carrier.Water miscible as sucrose, lactose, Sorbitol, water-insoluble such as starch, cellulose, microcrystalline Cellulose or calcium phosphate.The powder of Xing Chenging can be chosen wantonly with the medicated premix of standard and mix like this, flows or other character helping, and can be filled in hard gelatin capsule or its equivalent.In another preferred embodiment, these powder can randomly mix with the drug excipient of standard and prepare and are used for being pressed into tablet or forming the fusing tablet at tablet machine.
The present invention also is adapted to other fibrates, comprises any salt or ester, bezafibrate, binifibrate, clinofibrate, ciprofibrate, chlorine Bei Te, etofibrate, etofylline clofibrate, gemfibrozil, pirifibrate, Ronifibrate and the simfibrate of fenofibric acid, fenofibric acid.
In the present invention, when representing quantitative values with percentage ratio, during " pact " word of its front, expression comprises the scope of this value ± 5%.
Below the invention will be further described by the specific embodiment.The specific embodiment does not constitute any limitation of the invention.
The specific embodiment
The preparation of the fenofibrate carrier of embodiment 1 high degree of dispersion
Press following prescription:
Fenofibrate 54g
Poloxamer 188 54g
PEG6000 54g
Preparation: take by weighing fenofibrate, poloxamer and PEG6000 by recipe quantity, it is standby that fenofibrate was pulverized 80 mesh sieves; Poloxamer and PEG6000 were pulverized 40 sieves, 80-90 ℃ of heating in water bath melting, fenofibrate is slowly added, be stirred to the drug powder complete obiteration, place fridge to place 24 hours for 4 ℃ fused pastille liquid, pulverize and promptly get the fenofibrate carrier that contains high degree of dispersion.
Embodiment 2 contains the preparation of tablet of the fenofibrate of high degree of dispersion
Add following excipient:
Microcrystalline Cellulose 80g
Hypromellose 23g
Polyvinylpolypyrrolidone XL 18g
Magnesium stearate 8g
Preparation: above-mentioned excipient pulverize separately is crossed 80 mesh sieves, and the fenofibrate carrier of the high degree of dispersion of preparation among the embodiment 1 was pulverized 60 mesh sieves, mix homogeneously, tabletting.
Claims (9)
1. contain the solid preparation of the fenofibrate of high degree of dispersion, it is characterized in that, fenofibrate with the form stable existence of high degree of dispersion in carrier material.
2. the solid preparation that contains the fenofibrate of high degree of dispersion as claimed in claim 1 is characterized in that, described carrier material is the water-solubility carrier material.
3. the solid preparation that contains the fenofibrate of high degree of dispersion as claimed in claim 1, it is characterized in that, described carrier material is selected from polyethylene glycols, polyvidone class, contain surfactant-based, water-soluble cellulose derivative, organic acid and the saccharide and the alcohols of polyoxyethylene groups, and these a few class carriers can separately or be united use.
4. the solid preparation that contains the fenofibrate of high degree of dispersion as claimed in claim 1 is characterized in that, described carrier material is selected among PEG2000, PEG4000, PEG6000, PEG10000, PEG12000, the PEG20000 one or more combination.
5. the solid preparation that contains the fenofibrate of high degree of dispersion as claimed in claim 1 is characterized in that, described carrier material is selected from one or more the combination among PVPk15, PVPk25, PVPk30, PVPk60, the PVPk90.
6. the solid preparation that contains the fenofibrate of high degree of dispersion as claimed in claim 1 is characterized in that described carrier material is selected from dextrose, galactose, sucrose, mannitol, sorbitol, xylitol etc.
7. the solid preparation that contains the fenofibrate of high degree of dispersion as claimed in claim 1 is characterized in that, further contains to have the excipient that improves liquidity with compressibility.
8. the solid preparation that contains the fenofibrate of high degree of dispersion as claimed in claim 7 is characterized in that, described can further contain to have improve liquidity and the excipient of compressibility comprises filler, disintegrating agent, lubricant, binding agent, fluidizer.
9. the solid preparation that contains the fenofibrate of high degree of dispersion as claimed in claim 1 is characterized in that, dosage form is tablet or hard capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101235275A CN102188398A (en) | 2010-03-12 | 2010-03-12 | Solid preparation containing highly dispersed fenofibrate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010101235275A CN102188398A (en) | 2010-03-12 | 2010-03-12 | Solid preparation containing highly dispersed fenofibrate |
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| CN102188398A true CN102188398A (en) | 2011-09-21 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104523574A (en) * | 2015-02-08 | 2015-04-22 | 长沙佰顺生物科技有限公司 | Apremilast solid dispersoid and preparation method thereof |
-
2010
- 2010-03-12 CN CN2010101235275A patent/CN102188398A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104523574A (en) * | 2015-02-08 | 2015-04-22 | 长沙佰顺生物科技有限公司 | Apremilast solid dispersoid and preparation method thereof |
| CN104523574B (en) * | 2015-02-08 | 2017-11-24 | 长沙佰顺生物科技有限公司 | A kind of Apremilast solid dispersions |
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Application publication date: 20110921 |