CN102309476B - Fenofibrate composition - Google Patents
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- CN102309476B CN102309476B CN201010219622.5A CN201010219622A CN102309476B CN 102309476 B CN102309476 B CN 102309476B CN 201010219622 A CN201010219622 A CN 201010219622A CN 102309476 B CN102309476 B CN 102309476B
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Abstract
The present invention relates to a kind of Fenofibrate composition of novelty.Particularly, the present invention relates to a kind of Fenofibrate composition, it comprises fenofibrate, the ii of i) effective dose) oily, iii) PVP and iv) solid adjuvant material, and described compositions is solid form.The invention still further relates to the preparation method of described compositions, comprise the pharmaceutical preparation of described compositions and described compositions for the preparation of the purposes treated and/or prevented in the medicine of the disease relevant with dyslipidemia or disease.The present composition surfactant use, produce in handling, bin stability, taking convenience, thermodynamic stability etc. there is useful advantage.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of Fenofibrate composition of novelty, and prepare the method for described compositions and the pharmaceutical preparation such as hard capsule containing this Fenofibrate composition.
Background technology
The shortcoming of many medicines is that dissolubility is low, dissolution is not enough in water-bearing media, causes the bioavailability in oral organism afterwards low.Like this, the therapeutic dose taken is needed must to increase, to overcome this shortcoming.For many Effective Fractions Depressing Blood-lipids, the effective ingredient as belonged to the special class (fibrate) of shellfish is all the more so.
Fenofibrate, English name: fenofibrate, chemical name: 2-methyl-2-[4-(4-chlorobenzene formacyl) phenoxy group] propanoic acid isopropyl ester, molecular formula C
20h
21clO
4, molecular weight is: 360.84.Structural formula is as follows:
Fenofibrate is a kind of white or off-white color crystalline powder; Odorless, tasteless.Very easily dissolve in chloroform, easily molten in acetone or ether, slightly molten in ethanol, almost insoluble in water.The model of action of fenofibrate activates peroxisome proliferator thing activated receptor (PeroxisomeProliferator actuvated receptor a, PPARa) adjustment to lipid metabolism is participated in by several approach, comprise the synthesis suppressing ApoC3, activate PPARa and reduce triglyceride synthesis and secretion, accelerate the counter transport of cholesterol, accelerate the catabolism being rich in the lipoprotein of triglyceride.Existing fenofibrate clinical trial medication report in 1975, applies very wide so far.Fenofibrate is the one hypolipidemic safely and effectively a few days ago commonly used.Except adjusting blood lipid, the still balance of scalable leukocyte lipid metabolism, regulates the generation of inflammatory cytokine.
Fenofibrate is the blood lipid-lowering medicine known of clofibrate, and its effect for reducing fat is clear and definite, and medication is without cumulative action repeatedly, is one hypolipidemic safely and effectively.But fenofibrate belongs to insoluble drug, dissolution is poor, and there is the first pass effect of liver, thus causes bioavailability low.In order to the problem overcoming existing issue particularly incomplete absorption comprises oral cavity disintegration tablet, solid dispersion controlled release preparation, cyclodextrin clathrate, micronized tablet and capsule for the preparation research of fenofibrate; in order to obtain optimal absorption effect, fenofibrate formulations in the past must with food with taking.Fenofibrate self-micro emulsion formulation effectively improves bioavailability, but there is medicine stability, produces, the problems such as storage, and a large amount of surfactants has GI irritation effect simultaneously.Although the various dose form of this medicine (100 and 300mg, such as
) have commercially available, but these forms often cause the bioavailability of effective ingredient low.In fact, because fenofibrate is almost insoluble in water, so the rate-limiting step being dissolved as its absorption of medicine.The oral dose of current ordinary preparation is large, and bioavailability is low, and comparatively large by food effect, and often varies with each individual.
In order to improve the dissolution characteristic of fenofibrate and its bioavailability, thus the dosage taken required by reducing, increasing the level that its dissolution can reach close to 100% and being highly profitable.EP-A-0330532 discloses a kind of method of the bioavailability for improving fenofibrate.That patent describes and fenofibrate and surfactant are total to micronize as sodium lauryl sulphate, to improve the dissolubility of fenofibrate, increase its bioavailability thus.This patent description: fenofibrate and solid surfactant altogether micronize improve the degree of fenofibrate bioavailability, than by add surfactant or by only Lipantil or by the micronized fenofibrate of fully mixing difference and surfactant much bigger.Although disclosed in above-mentioned EP-A-0330532, method instruction people obtain the preparation of higher bioavailability, but the surfactant wherein used will bring the problem of such as GI irritation.
(the Chinese journal of Practical Pharmacy such as high snowy peak, 2007, Vol.5, No.6, p.288) a kind of liquid fenofibrate formulations being called self emulsifying is disclosed, it consists of fenofibrate, ethyl oleate, Tween 80, PEG 400 (3.5: 35: 55: 10, w/w), but point out further in the document " non-ionic surface active agent toxicity is low; oral administration safety is good; but life-time service may cause the change of mucosa penetration and the chronic toxicity to whole body to the stimulation of gastrointestinal tract mucosa, and the alcohol as co-emulsifier also has certain zest and pharmacologically active ".Chinese patent application 200810167197.2 discloses a kind of liquid fenofibrate formulations being called self-microemulsion, it consists of fenofibrate, MCT, oleic acid, EL-35,1,2-propylene glycol (5: 20: 20: 40: 20, w/w), the surfactant that same employing is a large amount of, also also exists GI irritation and toxicity problem.It should be noted that in addition, the preparation being called self emulsifying and self-microemulsion prepared by above-mentioned document, is liquid preparation, preparing, store, take, in thermodynamic phase that liquid preparation is intrinsic etc. all not as solid preparation.
Therefore, a kind of Fenofibrate composition of solid is provided, it has the following advantage of at least one item: use no or little surfactant, there is the feature more excellent in such as bioavailability than existing product, ratio in liquid preparation, there is the better advantage of at least one item (such as producing handling, bin stability, taking convenience, thermodynamic stability), the novel Fenofibrate composition with at least one aspect advantage above-mentioned is that those skilled in the art expect.
Summary of the invention
The object of this invention is to provide a kind of novelty in the Fenofibrate composition of solid, it has the following advantage of at least one item: use no or little surfactant, there is the feature more excellent in such as bioavailability than existing product, ratio in liquid preparation, there is the better advantage of at least one item (such as producing handling, bin stability, taking convenience, thermodynamic stability).The present inventor finds, use the solid-state Fenofibrate composition that oil, PVP and other auxiliary material combinations are prepared into, said composition has above-mentioned at least one advantage astoundingly.The present invention is based on above-mentioned discovery and be accomplished.
Summary of the invention
For this reason, first aspect present invention provides a kind of Fenofibrate composition, and it comprises fenofibrate, the ii of i) effective dose) oily, iii) PVP and iv) solid adjuvant material, and described compositions is solid form.
The Fenofibrate composition of any one according to a first aspect of the present invention, it comprises
Fenofibrate 1 weight portion,
Oil 1-100 weight portion,
PVP 0.1-30 weight portion,
Solid adjuvant material 1-150 weight portion.
The Fenofibrate composition of any one according to a first aspect of the present invention, it comprises
Fenofibrate 1 weight portion,
Oil 1-80 weight portion,
PVP 0.2-20 weight portion,
Solid adjuvant material 1-125 weight portion.
The Fenofibrate composition of any one according to a first aspect of the present invention, it comprises
Fenofibrate 1 weight portion,
Oil 1-75 weight portion,
PVP 0.2-10 weight portion,
Solid adjuvant material 1.5-120 weight portion.
The Fenofibrate composition of any one according to a first aspect of the present invention, wherein said oil is selected from following at least one: ethyl oleate, soybean oil, olive oil, medium chain acid glyceride and oleic acid.In one embodiment, described oil is selected from following at least one: ethyl oleate, medium chain acid glyceride (such as: MCT Oil (MCT)) and oleic acid (in this article, can referred to as OA).In one embodiment, described oil is oleic acid and/or medium chain acid glyceride.In one embodiment, described oil is the mixture of oleic acid and medium chain acid glyceride.In one embodiment, described oil is oleic acid.In one embodiment, described oil is medium chain acid glyceride.In one embodiment, described oil be medium chain acid glyceride and oleic acid with (0 ~ 10): the mixture of 1 weight ratio.In one embodiment, described oil be medium chain acid glyceride and oleic acid with (0.1 ~ 10): the mixture of 1 [such as (0.15 ~ 10): 1, (0.15 ~ 8): 1, (0.15 ~ 5): 1, (0.15 ~ 4): 1 or (0.2 ~ 4): 1] weight ratio.
The Fenofibrate composition of any one according to a first aspect of the present invention, wherein said PVP is selected from following at least one: PVP 12pf, PVP C-15, PVP K-25, PVPK-30, PVP K-90.In one embodiment, at least one that described PVP is preferably following: PVP K-25, PVP K-30, PVP K-90, more preferably: PVP K-25, PVPK-30.
The Fenofibrate composition of any one according to a first aspect of the present invention, wherein said solid adjuvant material is selected from following at least one: micropowder silica gel, amylum pregelatinisatum, lactose, microcrystalline Cellulose, chitosan, dextran, mannitol, PEG class (PEG (such as molecular weight is the PEG of 1000 ~ 35000) in solid under such as room temperature, such as PEG1000, PEG1500, PEG2000, PEG4000, PEG6000, PEG8000).In one embodiment, described solid adjuvant material is selected from following at least one: micropowder silica gel, amylum pregelatinisatum, lactose, microcrystalline Cellulose, chitosan, dextran, mannitol, PEG class (PEG in solid under such as room temperature, such as PEG2000, PEG4000).In one embodiment, described solid adjuvant material is micropowder silica gel and the mixture being selected from following at least one material: amylum pregelatinisatum, lactose, microcrystalline Cellulose, chitosan, dextran, mannitol, PEG class (PEG in solid under such as room temperature, such as PEG2000, PEG4000).In one embodiment, described solid adjuvant material is micropowder silica gel and is selected from following at least one material with weight ratio 1: the mixture of (1 ~ 35) [such as 1: (2 ~ 30), 1: (2 ~ 15) or 1: (2 ~ 11)]: amylum pregelatinisatum, lactose, microcrystalline Cellulose, chitosan, dextran, mannitol, PEG class (PEG in solid under such as room temperature, such as PEG2000, PEG4000).
The Fenofibrate composition of any one according to a first aspect of the present invention, it carries out dissolution determination according to Pharmacopoeia of the People's Republic of China version in 2005 two annex XC " dissolution method first method ", with the 1%SDS solution of 500mL as dissolution medium, with the detecting rotational speed of 100rpm at 37 DEG C, be greater than 70% containing the dissolution of the said composition being equivalent to 50mg fenofibrate when 45min.Preferably, under these conditions, 80% is greater than containing the dissolution of the pharmaceutical composition of the present invention being equivalent to 50mg fenofibrate when 45min.Preferably, under these conditions, 85% is greater than containing the dissolution of the pharmaceutical composition of the present invention being equivalent to 50mg fenofibrate when 45min.
The Fenofibrate composition of any one according to a first aspect of the present invention, according to particles size and distribution under Pharmacopoeia of the People's Republic of China version in 2005 two annex XIXE " microcapsule, microsphere and Liposomal formulation guideline " item, with 1g said composition in 100ml water, under 37 DEG C of constant temperatures, after stirring 10min with the rotating speed of 50rmp, leave standstill 1min, get the diameter of supernatant liquid at the lower observation of microscope 400 times 600 emulsion droplet particles, arithmetic average diameter.Display emulsion droplet diameter is less than 50 μm, and preferable particle size is less than 25 μm, and preferable particle size is less than 10 μm, and preferable particle size is less than 5 μm
Second aspect present invention provides the method preparing Fenofibrate composition described in any one of first aspect present invention, and it comprises the following steps:
A () makes PVP anhydrous alcohol solution (such as, the weight ratio of PVP and dehydrated alcohol is 1: (0.5 ~ 2), 1: (0.75 ~ 1.5) or about 1: 1; Such as at the temperature of 30 ~ 80 DEG C, 40 ~ 60 DEG C, 45 ~ 55 DEG C or about 50 DEG C);
B () adds oil in step (a) gained solution, be stirred to homogeneous system;
C () adds fenofibrate in step (b) gained mixture, stir (such as, at the temperature of 30 ~ 80 DEG C, 40 ~ 60 DEG C, 45 ~ 55 DEG C or about 50 DEG C) to dissolving completely;
D step (c) gained solution drops in solid adjuvant material by (), stir, prepare soft material, and sieve (such as 10 ~ 20 mesh sieves), dries, to obtain final product.
The method of any one according to a second aspect of the present invention, it comprises the following steps:
A () makes PVP anhydrous alcohol solution (such as, the weight ratio of PVP and dehydrated alcohol is about 1: 1; Such as at the temperature of 45 ~ 55 DEG C or about 50 DEG C);
B () adds oil in step (a) gained solution, be stirred to homogeneous system;
C () adds fenofibrate in step (b) gained mixture, stir (such as, at the temperature of 45 ~ 55 DEG C or about 50 DEG C) to dissolving completely;
D step (c) gained solution drops in solid adjuvant material by (), stir, prepare soft material, sieve (such as using 10 mesh sieves), dries, and removing ethanol, obtains powder or granular compositions.
In the method for second aspect present invention, described ethanol is removed after particle drying process, and the present composition therefore obtained is solid form, the powder namely in solid or granular substance.
Third aspect present invention provides a kind of pharmaceutical preparation, and it comprises compositions described in any one of first aspect present invention and optional pharmaceutically acceptable carrier.
Pharmaceutical preparation described in any one of third aspect present invention of base area, it is granule, tablet or hard capsule.
Pharmaceutical preparation described in any one of third aspect present invention of base area, it is hard capsule, wherein comprises compositions described in any one of first aspect present invention and optional pharmaceutically acceptable carrier in capsule shells.
Fourth aspect present invention provides compositions described in any one of first aspect present invention for the preparation of the purposes treated and/or prevented in the medicine of the disease relevant with dyslipidemia or disease.In one embodiment, the described disease relevant with dyslipidemia or disease are the known treatable disease of fenofibrate or disease.In one embodiment, the described disease relevant with dyslipidemia or disease are hyperlipemias.
Fifth aspect present invention is provided in experimenter in need and treats and/or prevents the disease relevant with dyslipidemia or the method for disease, the method comprise use effective dose to described experimenter any one of first aspect present invention described in compositions.In one embodiment, the described disease relevant with dyslipidemia or disease are the known treatable disease of fenofibrate or disease.In one embodiment, the described disease relevant with dyslipidemia or disease are hyperlipemias.
The feature that any one of either side of the present invention or this either side has is equally applicable to any one of other either side or this other either side, as long as they can not be conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.In the present invention, such as, when mentioning " any one of first aspect present invention ", the arbitrary sub-aspect that " any one " refers to first aspect present invention is somebody's turn to do; When other side is mentioned in a similar manner, also there is identical meanings.
Detailed Description Of The Invention:
Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
As described herein, term " oil " refers to and can be used as that pharmaceutic adjuvant uses, or pharmaceutically acceptable oil.Its example as described above in the present invention.
As described herein, term " PVP " refers to the abbreviation of polyvinylpyrrolidone.In this article, PVP comprises its various models, such as but not limited to PVP 12pf, PVP C-15, PVP K-25, PVP K-30, PVP K-90, and their mixture.
As described herein, term " solid adjuvant material " refers in solid form, pharmaceutically acceptable adjuvant.Its example as described above in the present invention.
As described herein, term " EL-35 " refers to the abbreviation of CREMOPHORE EL.
As described herein, phrase " described compositions is solid form " refers to that compositions of the present invention is solid-state form, includes but not limited to powder, granule, tablet, block, cake etc.The present composition is applicable to especially because it is solid form and prepares solid pharmaceutical preparation such as tablet, capsule, granule etc. especially.
As described herein, term " effective dose " refers to the dosage that can realize treating, prevent, alleviate and/or alleviating disease of the present invention or disease in experimenter.
As described herein, term " compositions ", it can also refer to pharmaceutical composition, is used in experimenter and realizes treating, prevent, alleviate and/or alleviate disease of the present invention or disease.
As described herein, term " experimenter " can refer to patient or other accept the present composition to treat, to prevent, to alleviate and/or to alleviate the animal of disease of the present invention or disease, particularly mammal, such as people, Canis familiaris L., monkey, cattle, horse etc.
As described herein, term " disease and/or disease " refers to a kind of condition of described experimenter, and this condition is relevant with disease of the present invention and/or disease.
As described herein, percent symbol " % ", it has as the definition in the version Pharmacopoeia of the People's Republic of China note on the use in 2005.In some cases, as do not specialized, when being solid for total material, generally referring to the percentage ratio of w/w, when being liquid for total material, generally referring to the percentage ratio of weight/volume.
As described herein, term " medium chain acid glyceride " also refers to " medium chain length fatty acid triglyceride ", and it typically refers to has C
6~ C
14the fatty glyceride of chain length, more preferably refers to C
8~ C
12fatty glyceride; As to have C
8~ C
12fatty glyceride prepared by satisfied fatty acid, as one or more the mixture in medium chain fatty acid one ester, medium chain fatty acid diester, MCT Oil, wherein the former two is referred to as medium chain fatty acid part ester, English Medium Chain Partial Glycerides by name.MCT Oil more preferably can be used (to be called for short MCT, GTCC; European Pharmacopoeia name medium ChainTriglycerides; Japanese Pharmacopoeia name Caprylic/Capric Triglyceride).Medium chain fatty acid part ester can select the product of German SASOL company
742.MCT Oil can with the product purchased from German CONDEA chemical company (CONDEAChemie GmbH)
812 or
810 etc.; Or purchased from the product LABRAFAC CC etc. of French GATTEFOSSE company; Or the product of purchased from American LONZA company
mCT etc.The product of these different brands is at sad (C
8) and capric acid (C
10) ratio aspect slightly difference, as
812 containing sad 50 ~ 65%, capric acid 30 ~ 45%;
810 containing sad 65 ~ 80%, capric acid 20 ~ 35%; LABRAFAC CC is containing sad 50 ~ 80%, capric acid 20 ~ 50%;
mCT is containing sad 65 ~ 80%, capric acid 20 ~ 35%.But they are substantially identical in the physicochemical properties such as acid number, saponification number, iodine number, hydroxyl value, viscosity, freezing point, moisture, and the difference of two kinds of fatty acid proportions can not produce significantly impact to preparation nature.Certainly, be allow to exist with other a small amount of fatty acids of the conceptual understanding of " impurity " in pharmaceutical field, this is conceptually and without prejudice to spirit of the present invention.
In one embodiment of the invention, described " medium chain acid glyceride " is MCT Oil (can referred to as MCT), such as caprylic/capric glyceride etc., particularly such as caprylic/capric triglyceride.
In one embodiment of the invention, can also containing the additive being selected from correctives class, antiseptic kind, antioxidant class on a small quantity in described compositions.Described correctives class, can improve product taste, as menthol, Oleum menthae, milk chocolate essence (as BFL1227 type, International Flavors & Fragrances Products), sorbitol etc.Described antioxidant class, can improve product chemical stability, as BHA (BHA), toluene di-tert-butyl phenol (BHT) etc.Those of skill in the art can determine the consumption of these additives easily.
Liquid self-emulsified drug delivery system (Liquid Self-Emulsifying Drug DeliverySystem) is made up of medicine, oil phase, surfactant etc., slightly wriggling through gastrointestinal after it is oral can spontaneous formation oil in water emulsion, thus rely on the increase of fine oil droplets specific surface area significantly to improve water-insoluble drug dissolution in the gastrointestinal tract, greatly improve the bioavailability of medicine, the emulsion droplet simultaneously formed can also reduce the stimulation of medicine to gastrointestinal.Surprisingly, a kind of solid composite provided by the invention, although wherein do not add surfactant, after water mild or moderate stirs, also can be similar to known liquid self-emulsified drug delivery system, form the tiny emulsion droplet of dropping liquid in water voluntarily.Therefore, compared with the liquid self-emulsifiable preparation of routine, solid composite of the present invention can not use surfactant, prolong drug action time, improve medicine stability, effectively overcome liquid preparation producing, store, to take etc. in deficiency.The present inventor finds, the fenofibrate solid compositions of novelty of the present invention, does not use surfactant.Inventor has investigated the dissolubility of fenofibrate in ethyl oleate, soybean oil, olive oil, medium chain acid glyceride and oleic acid, finds that medium chain acid glyceride Chinese medicine dissolubility is maximum.In one embodiment, oil phase is selected from one or more in ethyl oleate, soybean oil, olive oil, medium chain acid glyceride and oleic acid.Be more preferably one or more in ethyl oleate, medium chain acid glyceride and oleic acid.
In one embodiment, solid adjuvant material of the present invention is selected from one or more in micropowder silica gel, PEG4000, lactose, amylum pregelatinisatum, microcrystalline Cellulose, dextran, mannitol, chitosan.Be more preferably the mixture of one or more in micropowder silica gel, PEG4000, mannitol, dextran, sucrose and amylum pregelatinisatum.In one embodiment, solid adjuvant material of the present invention can be any solid adsorption material being applicable to fluid to adsorb.
Fenofibrate solid compositions of the present invention can be mixed with the pharmaceutical preparation of granule, Tablet and Capsula agent.The preparation of the present composition can adopt following methods: after anhydrous alcohol solution PVP, add oil wherein, and be constantly stirred to homogeneous, transparent, obtain oil phase, fenofibrate is joined in oil phase, form homogeneous, transparent solution water bath with thermostatic control 50 DEG C down to complete drug dissolution; At above solution as binding agent, add a certain amount of solid adsorption material, by uniform Agitation and mixing, prepare soft material.Soft material prepared by the present invention by crushed sieve series grain, or can add pharmaceutic adjuvant and makes tablet, capsule, granule and powder etc.; Also after extrusion spheronization legal system can be adopted in centrifugal granulator to obtain the low micropill of the good friability of roundness, then tablet, capsule or powder is made.Prepared tablet and micropill can adopt coating material conventional in medicament to carry out sugar coating, film coating, or employing Sustained release coating materials, as ethyl cellulose, acrylic resin, cellulose acetate etc. carry out coating, make the Tablet and Capsula agent with slow releasing function.
According to the present invention, in the present composition, the content of active component can be fed intake by prescription and determine, but with regard to dosage when using with regard to patient, it embodies by the pharmaceutical preparation prepared by the present invention, under normal conditions, containing unit dose or the active ingredient lower than unit dose (such as 1/5,1/4,1/3,1/2 unit dose) in pharmaceutical preparation of the present invention, to realize medication easily.Such as the pharmaceutical preparation of the present invention in hard capsule, when every capsules contains 1/3 of the dosage expecting each medication, each dosage can be 3 capsules.Therefore, in Examples below, when preparing compositions of the present invention, unit dose need not be indicated.
Solid composite active constituents of medicine content prepared by the present invention is even, stable.Obtained compositions, through encapsulated, can meet the prescription of routine encapsulation.
Fenofibrate solid compositions prepared by the present invention can reach more than 70% at the 1%SDS accumulation dissolution of 45 minutes, such as, be greater than 75%, such as, be greater than 80%.Substantially increase dissolution rate and the degree of medicine.Effectiveness and the practicality of fenofibrate solid compositions is further illustrated hereafter by bioavailability study.
According to pharmaceutical composition of the present invention, it is compared with commercially available prod, not only has unexpected high-dissolution within a short period of time, and also has obviously higher bioavailability in animal body.
Accompanying drawing explanation
Fig. 1 is that fenofibrate soft capsule is (see a kind of liquid fenofibrate formulations being called self-microemulsion disclosed in Chinese patent application 200810167197.2, it consists of fenofibrate, MCT, oleic acid, EL-35,1,2-propylene glycol (5: 20: 20: 40: 20, w/w)) and the blood drug level of commercially available micronized capsule after beasle dog oral administration through time curve.In figure, black box represents the Drug-time curve of soft capsule, and black triangle represents the Drug-time curve of commercially available micronization capsule.
Fig. 2 is that Fenofibrate composition of the present invention and fenofibrate soft capsule are (see a kind of liquid fenofibrate formulations being called self-microemulsion disclosed in Chinese patent application 200810167197.2, it consists of fenofibrate, MCT, oleic acid, EL-35,1,2-propylene glycol (5: 20: 20: 40: 20, w/w)) blood drug level after beasle dog oral administration through time curve.In figure, black box represents the Drug-time curve of the present composition, and black triangle represents the Drug-time curve of soft capsule.
Detailed description of the invention
Can be conducted further description the present invention by example below, but scope of the present invention is not limited to following example.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.
The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and operational approach is well known in the art, the present invention still describes in detail as far as possible at this.
In the examples below, MCT used is the product of German CONDEA chemical company (CONDEA Chemie GmbH)
812.
In the examples below, the compositions of preparation can be encapsulated, and become capsule, in every capsules, the explosive payload of active component can be 5mg, 10mg, 15mg, 17mg, 20mg, 25mg, 40mg, 50mg, 75mg, 100mg, 125mg, 150mg or 200mg etc.)
the preparation of embodiment 1, the present composition
Fenofibrate 1g
Oil phase (OA) 75g
PVP 10g
Dehydrated alcohol 10g
Micropowder silica gel 10g
Amylum pregelatinisatum 90g
PVP is dissolved in dehydrated alcohol under 50 DEG C of waters bath with thermostatic control also continuous stirring condition.Until add oil phase after dissolving completely to be stirred well to the homogeneous system of formation.Take fenofibrate to join in oil phase and keep constant temperature to continue to be stirred to and dissolve completely, continue constant temperature and stir 30min.Be added dropwise in micropowder silica gel and solid adjuvant material mixture, stir evenly soft material processed, cross 12 mesh sieves, dry, to obtain final product.Above resulting composition is sub-packed in hard capsule further, or the pharmaceutical preparation of the present invention of the unit dose of direct packaging in bead dosage form in packaging bag.
the preparation of embodiment 2, the present composition
Fenofibrate 1g
Oil phase (MCT: OA=1: 1) 60g
PVP 10g
Dehydrated alcohol 10g
Micropowder silica gel 10g
Lactose 100g
PVP is dissolved in dehydrated alcohol under 50 DEG C of waters bath with thermostatic control also continuous stirring condition.Until add oil phase after dissolving completely to be stirred well to the homogeneous system of formation.Take fenofibrate to join in oil phase and keep constant temperature to continue to be stirred to and dissolve completely, continue constant temperature and stir 30min.Be added dropwise in micropowder silica gel and solid adjuvant material mixture, stir evenly soft material processed, cross 12 mesh sieves, dry, to obtain final product.Above resulting composition is sub-packed in hard capsule further, or the pharmaceutical preparation of the present invention of the unit dose of direct packaging in bead dosage form in packaging bag.
the preparation of embodiment 3, the present composition
Fenofibrate 1g
Oil phase (MCT: OA=1: 4) 6g
PVP 1g
Dehydrated alcohol 1g
Micropowder silica gel 1g
Microcrystalline Cellulose 10g
PVP is dissolved in dehydrated alcohol under 50 DEG C of waters bath with thermostatic control also continuous stirring condition.Until add oil phase after dissolving completely to be stirred well to the homogeneous system of formation.Take fenofibrate to join in oil phase and keep constant temperature to continue to be stirred to and dissolve completely, continue constant temperature and stir 30min.Be added dropwise in micropowder silica gel and solid adjuvant material mixture, stir evenly soft material processed, cross 12 mesh sieves, dry, to obtain final product.Above resulting composition is sub-packed in hard capsule further, or the pharmaceutical preparation of the present invention of the unit dose of direct packaging in bead dosage form in packaging bag.
the preparation of embodiment 4, the present composition
Fenofibrate 1g
Oil phase (MCT: OA=1: 0.25) 20g
PVP 2.5g
Dehydrated alcohol 2.5g
Micropowder silica gel 2.5g
Chitosan 23g
PVP is dissolved in dehydrated alcohol under 50 DEG C of waters bath with thermostatic control also continuous stirring condition.Until add oil phase after dissolving completely to be stirred well to the homogeneous system of formation.Take fenofibrate to join in oil phase and keep constant temperature to continue to be stirred to and dissolve completely, continue constant temperature and stir 30min.Be added dropwise in micropowder silica gel and solid adjuvant material mixture, stir evenly soft material processed, cross 12 mesh sieves, dry, to obtain final product.Above resulting composition is sub-packed in hard capsule further, or the pharmaceutical preparation of the present invention of the unit dose of direct packaging in bead dosage form in packaging bag.
the preparation of embodiment 5, the present composition
Fenofibrate 1g
Oil phase (MCT: OA=1: 0.5) 1g
PVP 0.5g
Dehydrated alcohol 0.5g
Micropowder silica gel 0.5g
Dextran 14g
PVP is dissolved in dehydrated alcohol under 50 DEG C of waters bath with thermostatic control also continuous stirring condition.Until add oil phase after dissolving completely to be stirred well to the homogeneous system of formation.Take fenofibrate to join in oil phase and keep constant temperature to continue to be stirred to and dissolve completely, continue constant temperature and stir 30min.Be added dropwise in micropowder silica gel and solid adjuvant material mixture, stir evenly soft material processed, cross 12 mesh sieves, dry, to obtain final product.Above resulting composition is sub-packed in hard capsule further, or the pharmaceutical preparation of the present invention of the unit dose of direct packaging in bead dosage form in packaging bag.
the preparation of embodiment 6, the present composition
Fenofibrate 1g
Oil phase (MCT: OA=1: 7) 1.5g
PVP 2g
Dehydrated alcohol 2g
Micropowder silica gel 2.5g
Dextran 80g
PVP is dissolved in dehydrated alcohol under 50 DEG C of waters bath with thermostatic control also continuous stirring condition.Until add oil phase after dissolving completely to be stirred well to the homogeneous system of formation.Take fenofibrate to join in oil phase and keep constant temperature to continue to be stirred to and dissolve completely, continue constant temperature and stir 30min.Be added dropwise in micropowder silica gel and solid adjuvant material mixture, stir evenly soft material processed, cross 12 mesh sieves, dry, to obtain final product.Above resulting composition is sub-packed in hard capsule further, or the pharmaceutical preparation of the present invention of the unit dose of direct packaging in bead dosage form in packaging bag.
the preparation of embodiment 7, the present composition
Fenofibrate 1g
Oil phase (MCT: OA=1: 0.1) 15g
PVP 1.5g
Dehydrated alcohol 1.5g
Micropowder silica gel 3g
Dextran 7g
PVP is dissolved in dehydrated alcohol under 50 DEG C of waters bath with thermostatic control also continuous stirring condition.Until add oil phase after dissolving completely to be stirred well to the homogeneous system of formation.Take fenofibrate to join in oil phase and keep constant temperature to continue to be stirred to and dissolve completely, continue constant temperature and stir 30min.Be added dropwise in micropowder silica gel and solid adjuvant material mixture, stir evenly soft material processed, cross 12 mesh sieves, dry, to obtain final product.Above resulting composition is sub-packed in hard capsule further, or the pharmaceutical preparation of the present invention of the unit dose of direct packaging in bead dosage form in packaging bag.
the preparation of embodiment 8, the present composition
Fenofibrate 1g
Oil phase (MCT: OA=1: 0.3) 20g
PVP 2.5g
Dehydrated alcohol 2.5g
Micropowder silica gel 4g
PEG4000 5g
Dextran 16g
PVP is dissolved in dehydrated alcohol under 50 DEG C of waters bath with thermostatic control also continuous stirring condition.Until add oil phase after dissolving completely to be stirred well to the homogeneous system of formation.Take fenofibrate to join in oil phase and keep constant temperature to continue to be stirred to and dissolve completely, continue constant temperature and stir 30min.Be added dropwise in micropowder silica gel, PEG4000 and solid adjuvant material mixture, stir evenly soft material processed, cross 12 mesh sieves, dry, to obtain final product.Above resulting composition is sub-packed in hard capsule further, or the pharmaceutical preparation of the present invention of the unit dose of direct packaging in bead dosage form in packaging bag.
the preparation of embodiment 9, the present composition
Fenofibrate 1g
Oil phase (MCT) 20g
PVP 2.5g
Dehydrated alcohol 2.5g
Micropowder silica gel 4g
PEG4000 5g
Dextran 16g
PVP is dissolved in dehydrated alcohol under 50 DEG C of waters bath with thermostatic control also continuous stirring condition.Until add oil phase after dissolving completely to be stirred well to the homogeneous system of formation.Take fenofibrate to join in oil phase and keep constant temperature to continue to be stirred to and dissolve completely, continue constant temperature and stir 30min.Be added dropwise in micropowder silica gel, PEG4000 and solid adjuvant material mixture, stir evenly soft material processed, cross 12 mesh sieves, dry, to obtain final product.Above resulting composition is sub-packed in hard capsule further, or the pharmaceutical preparation of the present invention of the unit dose of direct packaging in bead dosage form in packaging bag.
the preparation of embodiment 10, the present composition
Fenofibrate 1g
Miscella (MCT: OA=1: 1) 10g
PVP 2g
Dehydrated alcohol 2g
Micropowder silica gel 1.5g
PEG4000 3g
Dextran 7g
PVP is dissolved in dehydrated alcohol under 50 DEG C of waters bath with thermostatic control also continuous stirring condition.Until add oil phase after dissolving completely to be stirred well to the homogeneous system of formation.Take fenofibrate to join in oil phase and keep constant temperature to continue to be stirred to and dissolve completely, continue constant temperature and stir 30min.Be added dropwise in micropowder silica gel, PEG4000 and solid adjuvant material mixture, stir evenly soft material processed, cross 12 mesh sieves, dry, to obtain final product.Above resulting composition is sub-packed in hard capsule further, or the pharmaceutical preparation of the present invention of the unit dose of direct packaging in bead dosage form in packaging bag.
the preparation of embodiment 11, the present composition
Fenofibrate 1g
Oil phase (MCT: OA=1: 0.3) 8g
PVP 5g
Dehydrated alcohol 5g
Micropowder silica gel 1.5g
PEG4000 3g
Mannitol 7g
PVP is dissolved in dehydrated alcohol under 50 DEG C of waters bath with thermostatic control also continuous stirring condition.Until add oil phase after dissolving completely to be stirred well to the homogeneous system of formation.Take fenofibrate to join in oil phase and keep constant temperature to continue to be stirred to and dissolve completely, continue constant temperature and stir 30min.Be added dropwise in micropowder silica gel, PEG4000 and solid adjuvant material mixture, stir evenly soft material processed, cross 12 mesh sieves, dry, to obtain final product.Above resulting composition is sub-packed in hard capsule further, or the pharmaceutical preparation of the present invention of the unit dose of direct packaging in bead dosage form in packaging bag.
the preparation of embodiment 12, the present composition
Fenofibrate 0.1g
Miscella (MCT: OA=5: 4) 1.2g
PVP 0.2g
Dehydrated alcohol 0.2g
Micropowder silica gel 0.2g
Microcrystalline Cellulose 2.1g
Preparation method reference example 1.
the preparation of embodiment 13, the present composition
Fenofibrate 0.08g
Miscella (MCT: OA=6: 7) 1.5g
PVP 0.2g
Dehydrated alcohol 0.2g
Micropowder silica gel 0.2g
Chitosan 1.82g
Preparation method reference example 1.
the preparation of embodiment 14, the present composition
Fenofibrate 1.0g
Miscella (MCT: OA=4: 1) 1.0g
PVP 0.2g
Dehydrated alcohol 0.2g
Micropowder silica gel 0.2g
Dextran 1.4g
Preparation method reference example 1.
the preparation of embodiment 15, the present composition
Fenofibrate 0.2g
Miscella (MCT: OA=6: 7) 1.5g
PVP 0.2g
Dehydrated alcohol 0.2g
Micropowder silica gel 0.3g
Dextran 1.6g
Preparation method reference example 1.
the preparation of embodiment 16, the present composition
Fenofibrate 3g
Miscella (MCT: OA=8: 3) 15g
PVP 2g
Dehydrated alcohol 2g
Micropowder silica gel 4g
Dextran 14g
Preparation method reference example 1.
the preparation of embodiment 17, the present composition
Fenofibrate 0.25g
Miscella (MCT: OA=1: 0) 1g
PVP 0.2g
Dehydrated alcohol 0.2g
Micropowder silica gel 0.3g
PEG4000 0.8g
Dextran 1.25g
Preparation method reference example 1.
the preparation of embodiment 18, the present composition
Fenofibrate 0.2g
Miscella (MCT: OA=1: 1) 1g
PVP 0.2g
Dehydrated alcohol 0.2g
Micropowder silica gel 0.3g
PEG4000 0.6g
Dextran 1.4g
Preparation method reference example 1.
the preparation of embodiment 19, the present composition
Fenofibrate 0.2g
Miscella (MCT: OA=5: 4) 1g
PVP 0.2g
Dehydrated alcohol 0.2g
Micropowder silica gel 0.3g
PEG4000 0.6g
Mannitol 1.4g
Preparation method reference example 1.
the dissolution determination of test example 1, the present composition
1) sample:
A) compositions (being respectively every capsule containing 17mg active component) of embodiment 1-19;
B) soft capsule, with reference to the liquid fenofibrate formulations being called self-microemulsion a kind of disclosed in Chinese patent application 200810167197.2, (it consists of fenofibrate, MCT, oleic acid, EL-35,1,2-propylene glycol (5: 20: 20: 40: 20, w/w)) soft capsule (every containing 50mg active component) prepared;
2) dissolution determination condition and method:
Dissolution determination is carried out according to Pharmacopoeia of the People's Republic of China version in 2005 two annex XC " dissolution method first method ", with the 1%SDS solution of 500mL as dissolution medium, with the detecting rotational speed of 100rpm at 37 DEG C, containing the said composition being equivalent to 50mg fenofibrate, under these conditions, liquid 5ml (and the 5ml of fluid infusion simultaneously) is got in time starting 10min, 20min, 30min, 45min after measuring, with 0.45 μm of water system membrane filtration, discard just filtrate, get subsequent filtrate and carry out UV scanning, test dissolution.
3) dissolution determination result
The dissolution determination result of the present composition and soft capsule is as table 1.From table 1 result, present composition dissolution results and liquid self emulsifying dissolution are quite or close.
Table 1, the present composition and reference sample dissolution determination result
| Sample | Dissolution (%, 45min) | Sample | Dissolution (%, 45min) |
| Embodiment 1 | ＞75％ | Embodiment 12 | ＞80％ |
| Embodiment 2 | ＞75％ | Embodiment 14 | ＞80％ |
| Embodiment 3 | ＞75％ | Embodiment 15 | ＞75％ |
| Embodiment 4 | ＞80％ | Embodiment 16 | ＞80％ |
| Embodiment 6 | ＞80％ | Embodiment 17 | ＞80％ |
| Embodiment 7 | ＞80％ | Embodiment 18 | ＞80％ |
| Embodiment 8 | ＞80％ | Embodiment 19 | ＞80％ |
| Embodiment 10 | ＞80％ | Soft capsule | ＞75％ |
feature after stirring in test example 2, microexamination water
1) sample:
A) fraction compositions of embodiment 1-19;
B) soft capsule, with soft capsule used in test example 1;
2) observation of characteristics method:
condition determination and method:according to particles size and distribution under Pharmacopoeia of the People's Republic of China version in 2005 two annex XIXE " microcapsule, microsphere and Liposomal formulation guideline " item, with 1g said composition in 100ml water, under 37 DEG C of constant temperatures, after stirring 10min with the rotating speed of 50rmp, leave standstill 1min, get the diameter of supernatant liquid at the lower observation of microscope 400 times 600 emulsion droplet particles, arithmetic average diameter.
3) microscopic findings
Microscopic findings after fraction compositions of the present invention and soft capsule stir in water is as table 2.From table 2 result, the present composition, after water mild or moderate stirs, form the tiny emulsion droplet of drop voluntarily, and emulsion droplet diameter is less.
Table 2, the present composition and reference sample microscopic findings
| Sample | Droplet diameter (μm) | Sample | Droplet diameter (μm) |
| Embodiment 2 | ＜5 | Embodiment 12 | 2.8 |
| Embodiment 7 | ＜5 | Embodiment 13 | ＜5 |
| Embodiment 8 | 1.1 | Embodiment 16 | 2.0 |
| Embodiment 9 | ＜5 | Embodiment 17 | 1.2 |
| Embodiment 10 | 2.3 | Soft capsule | ＜5 |
in the body of test example 3, the present composition, behavior is investigated: bioavailability examination in dog body
test
1) test specimen:
A) compositions (every capsule containing 17mg active component) of embodiment 8;
B) soft capsule, with soft capsule used in test example 1;
C) commercially available micronization capsule (200mg/ grain, French Li Bofuni drugmaker)
2) the HPLC method of testing of plasma drug level:the assay method list of references (Zhao Yonghong, fenofibrate micronized capsules (micronize) human bioavailability is studied, China Dispensary, 17 volume 14 phase 1082-1083 in 2006) of blood plasma fenofibrate acid concentration carries out.Namely adopting high performance liquid chromatography, is interior mark with butoben, and mobile phase is 70% methanol: 30% water (phosphoric acid is adjusted to pH 2.6), and flow velocity is 1ml/min, and determined wavelength is 280nm.
3) test method and result:
(3-1) the comparing of soft capsule and commercially available micronized capsule preparations:
medication:adopt the administration of binary cycle intersection, beasle dog 6 (8-12kg), male and female half and half, are divided into two groups at random, and A group is soft capsule preparation, and B group is that commercially available fenofibrate micro powder capsules is as reference preparation.Dosage is 200mg/, and the cleaning frequency is 7 days.Fasting 12 hours before administration, respectively at after early morning oral drugs 0.5,1,1.5,2,2.5,3,4,5,6,8,12,24h gets blood 4mL at hind leg vein, be placed in the plastic test tube scribbling heparin, the centrifugal 10min of 3000r/min, separated plasma sample, be placed in-20 DEG C of refrigerator-freezers to preserve, to be measured.
(3-2) comparative result of soft capsule and commercially available micronized capsule preparations:
The AUC of the fenofibrate soft capsule obtained with the process of two-compartment model method and commercially available micronized capsule
0-24hbe respectively 44.66 ± 13.66 (μ g/ml) min and 6.00 ± 2.65 (μ g/ml) min.Result shows, soft capsule is compared with commercial preparation, can significantly improve the bioavailability of medicine.Bioavailability improves nearly 7 times.Drug-time curve is shown in Fig. 1.Pharmacokinetic parameters is in table 3.The soft capsule of liquid state and commercial preparation are carried out statistical test simultaneously.Result shows, under identical dosage, fenofibrate soft capsule and commercial preparation exist significant difference.
The commercially available micronization capsule of table 3 fenofibrate and soft capsule (200mg/ only)
Pharmacokinetic parameters after beasle dog oral administration
| Pharmacokinetic parameters | Commercially available capsule | Soft capsule |
| C max(μg/ml) | 1.26±0.8 | 11.79±2.47 |
| T max(h) | 2.5 | 2.00 |
| AUC 0-24h(μg/ml)mmin | 6.00±2.65 | 44.66±13.66 |
(3-3) the comparing of the present composition and soft capsule:
medication:adopt the administration of binary cycle intersection, beasle dog 6 (8-12kggl, male and female half and half, be divided into two groups at random, A group be soft capsule preparation as reference preparation, B group is fenofibrate solid compositions of the present invention (compositions of embodiment 8, every capsule containing 17mg active component).Dosage is 50mg/, and the cleaning frequency is 7 days.Fasting 12 hours before administration, respectively at after early morning oral drugs 0.5,1,1.5,2,2.5,3,4,6,8,12,24h gets blood 4mL at hind leg vein, is placed in the plastic test tube scribbling heparin, the centrifugal 10min of 3000r/min, separated plasma sample, is placed in-20 DEG C of refrigerator-freezers and preserves, to be measured.
The Fenofibrate composition of the present invention obtained with the process of two-compartment model method and the AUC of soft capsule
0-24hbe respectively 10.35 ± 2.54 (μ g/ml) min and 9.62 ± 0.96 (μ g/ml) min.Result shows, Fenofibrate composition of the present invention is compared with soft capsule, and bioavailability is close.Drug-time curve figure is shown in Fig. 2.Pharmacokinetic parameters is in table 4.Fenofibrate composition of the present invention and soft capsule are carried out statistical test simultaneously.Result shows, under identical dosage, Fenofibrate composition of the present invention and soft capsule do not have significant difference.
Table 4 Fenofibrate composition of the present invention and soft capsule (50mg/ only)
Pharmacokinetic parameters after beasle dog oral administration
| Pharmacokinetic parameters | A group (liquid self-emulsifiable preparation) | B group (present composition) |
| Cmax(μg/ml) | 2.59±0.64 | 3.31±0.97 |
| Tmax(h) | 1.75 | 1.875 |
| AUC 0-24h(μg/ml)min | 9.62±0.96 | 10.35±2.54 |
Can find out, the soft capsule preparation of the self emulsifying of liquid can significantly improve bioavailability compared with commercially available micronized capsule.Fenofibrate solid compositions prepared by the present invention is compared with liquid self-emulsifying soft capsule preparation, and bioavailability is slightly good, although do not have significant difference.But whether using surfactant, produce handling, bin stability, taking convenience, thermodynamic stability etc. one or more in, fenofibrate solid compositions prepared by obvious the present invention is better than liquid self-emulsifying soft capsule preparation.
Claims (20)
1. a Fenofibrate composition, it comprises the fenofibrate of i) effective dose, ii) oil, iii) PVP, and iv) solid adjuvant material, and described compositions is solid form, and do not conform in described compositions and have surfactant, wherein said oil is selected from following at least one: ethyl oleate, soybean oil, olive oil, medium chain acid glyceride and oleic acid, wherein said PVP is selected from following at least one: PVP 12pf, PVP C-15, PVP K-25, PVP K-30, PVP K-90, wherein said solid adjuvant material is selected from following at least one: micropowder silica gel, amylum pregelatinisatum, lactose, microcrystalline Cellulose, chitosan, dextran, mannitol, PEG class,
Wherein the content of each component is:
2. the Fenofibrate composition of claim 1, it comprises
3. the Fenofibrate composition of claim 1, wherein said PEG class is the PEG in solid under room temperature.
4. the Fenofibrate composition of claim 1, wherein said PEG class to be molecular weight be 1000 ~ 35000 PEG.
5. the Fenofibrate composition of claim 1, wherein said PEG class is PEG2000, PEG4000, PEG6000 or PEG8000.
6. the Fenofibrate composition of any one of claim 1 to 5, is characterized in that:
Dissolution determination is carried out according to Pharmacopoeia of the People's Republic of China version in 2005 two annex X C " dissolution method first method ", with the 1%SDS solution of 500mL as dissolution medium, with the detecting rotational speed of 100rpm at 37 DEG C, be greater than 70% containing the dissolution of the said composition being equivalent to 50mg fenofibrate when 45min; And/or
According to particles size and distribution under Pharmacopoeia of the People's Republic of China version in 2005 two annex XIX E " microcapsule, microsphere and Liposomal formulation guideline " item, with 1g said composition in 100ml water, under 37 DEG C of constant temperatures, after stirring 10min with the rotating speed of 50rmp, leave standstill 1min, get supernatant liquid under the microscope 400 times observe the diameter of 600 emulsion droplet particles, average diameter < 50 μm.
7. prepare the method for Fenofibrate composition described in any one of claim 1 to 6, it comprises the following steps:
A () makes PVP anhydrous alcohol solution;
B () adds oil in step (a) gained solution, be stirred to homogeneous system;
C () adds fenofibrate in step (b) gained mixture, be stirred to and dissolve completely;
D step (c) gained solution drops in solid adjuvant material by (), stir, prepare soft material, sieve, and dries, to obtain final product.
8. the method for claim 7, wherein the weight ratio of PVP and dehydrated alcohol is 1: (0.5 ~ 2), 1: (0.75 ~ 1.5) or 1: 1.
9. the method for claim 7, wherein makes PVP anhydrous alcohol solution be at the temperature of 30 ~ 80 DEG C.
10. the method for claim 7, wherein makes PVP anhydrous alcohol solution be at the temperature of 40 ~ 60 DEG C.
The method of 11. claim 7, wherein makes PVP anhydrous alcohol solution be at the temperature of 45 ~ 55 DEG C.
The method of 12. claim 7, wherein makes PVP anhydrous alcohol solution be at the temperature of 50 DEG C.
The method of 13. claim 7, the dissolving completely that is stirred to wherein described in step (c) refers at the temperature of 30 ~ 80 DEG C.
The method of 14. claim 7, the dissolving completely that is stirred to wherein described in step (c) refers at the temperature of 40 ~ 60 DEG C.
The method of 15. claim 7, the dissolving completely that is stirred to wherein described in step (c) refers at the temperature of 45 ~ 55 DEG C.
The method of 16. claim 7, the dissolving completely that is stirred to wherein described in step (c) refers at the temperature of 50 DEG C.
The method of 17. claim 7, wherein said sieving referred to 10 ~ 20 mesh sieves.
18. 1 kinds of pharmaceutical preparatioies, it comprises Fenofibrate composition described in any one of claim 1 to 6 and optional pharmaceutically acceptable carrier.
Fenofibrate composition described in 19. any one of claim 1 to 6 is for the preparation of the purposes treated and/or prevented in the medicine of the disease relevant with dyslipidemia or disease.
The purposes of 20. claim 19, the wherein said disease relevant with dyslipidemia or disease are hyperlipemias.
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