Background technology
At present, the lipid-regulation medicine can for selecting clinically falls into 5 types: Statins, the special class of shellfish, nicotinic acid class, resinae, cholesterol absorption inhibitor and other.Various kinds of drug due to chemical constitution different with the mechanism of action, it adjusts fat curative effect also to distinguish to some extent.
Fenofibrate (fenofibrate) is third generation phenoxy acetic acid class (i.e. the special class of shellfish) lipid regulating agent, and chemical name is 2-[4-(4-chlorobenzene formacyl) phenoxy group]-2 Methylpropionic acid isopropyl ester.There are some researches show, it can make total triglyceride (TG) reduce by 25 ~ 59%, and make HDL-C (HDL-C) raise 1 ~ 34%, T-CHOL (TC) declines 6% ~ 27%.Its effect in reduction TG is remarkable, is the choice drug reducing TG at present.In addition, fenofibrate also has enhancing insulin sensitivity, increases bone density, improves microalbuminuria and improve the Nonlipid-lowering Effects such as hyperuricemia, these effects can improve patient and the exception of depositing simultaneously, and the dyslipidemia being applicable to type Ⅱdiabetes mellitus or metabolic syndrome patients regulates.
Statins significantly can reduce the level of TC, low-density lipoprotein cholesterol (LDL-C), is the important drugs for the treatment of hypercholesterolemia; It is remarkable that the special class of shellfish reduces TG, fenofibrate is as the representative of the special class of shellfish, if with statins coupling, curative effect complementation can be formed, therefore visible fenofibrate and the coupling of the statins such as atorvastatin, simvastatin clinically, many R & D Enterprises are also just being devoted to the research of fenofibrate and statins compound pharmaceutical, significantly to improve the plasma lipid profile of combined hyperlipidemia familial patient.This kind of drug combination is applicable to the treatment of atherogenicity dyslipidemia, especially when diabetes and metabolic syndrome with dyslipidemia.
As mentioned above, although fenofibrate and statins coupling have irreplaceable advantage clinically, the safety of this kind of coupling must attract great attention.Because the special class of shellfish and statins all have the possibility of latent lesion liver function, and there is the danger that myositis and myopathy occur, the chance of generation untoward reaction during coupling, can be made to increase.Therefore, according to " Blood Lipid Abnormality in Chinese Adults guideline of prevention and treatment " that NCCD is formulated, should not take during both couplings simultaneously, fibrate and statins morning and evening should be taked to stagger the time the mode taken, to avoid the remarkable rising of blood drug level.But this mode taken of staggering the time brings very big inconvenience to patient especially gerontal patient, often causes problems such as missing, do not reach the regulating lipid that expection is desirable.Therefore fenofibrate is made delayed release formulation, utilize the dosage form feature of medicine delayed release, as made fenofibrate delayed release more than 6 hours, can reach that both to take statins (shorter when most statins reaches peak simultaneously, as be 1 ~ 2 hour for atorvastatin peak time, simvastatin is 4 hours) effect of avoiding again both blood drug level simultaneously to raise, not only improve patient's compliance, not easily occur that situation about missing turn improves the safety with statins coupling.But have no the relevant report of fenofibrate delayed release formulation.
Fenofibrate is II class medicine in typical Biopharmaceutics Classification system (BCS), and namely dissolubility is low, permeability is high, and dissolution rate is the rate-limiting step of its body absorption.Its ordinary preparation standard dose is 100mg/ time, every day three times, poor compliance, and because of dissolubility and dissolution rate low, absorb not exclusively, bioavailability is low, affects the curative effect of medicine.Therefore, the bioavailability how improving fenofibrate formulations is also researcheres problem demanding prompt solution.
A series of research and development courses such as the exploitation of fenofibrate novel form also experienced by from conventional tablet to slow releasing capsule, micronization and nanocrystal tablet, often walk research and development course and are all intended to the bioavailability improving fenofibrate further.The fenofibrate slow releasing capsule commodity that Aidifa Pharmaceutical Co., Ltd., Shanghai produces are called
(
), specification is 250mg, and dosage is 1 tablet/time, every day 1 time, without the need to taking after the meal, decreasing medicining times, improve compliance, be conducive to patient's long-term prescription.But still there is the low problem of bioavailability in this slow releasing capsule.Laboratories Fournier company of France (
) adopt micronization technology, mix by fenofibrate and surfactant, pulverized by air-flow disintegrating machine, obtain the material that mean diameter is 6 ~ 7 μm, prepare microparticle fenofibrate capsule
effectively improve the bioavailability of medicine.Abbott company and Skyepharma company adopt respectively
patented technology and Dissocubes
patented technology prepares fenofibrate nanometer crystallization tablet, by reducing diameter of aspirin particle further, significantly improves the dissolution rate of fenofibrate, thus improves the bioavailability of fenofibrate formulations.
Except above-mentioned micronization and nanocrystal technology, in open source literature, also there are many methods relating to raising fenofibrate bioavailability: the suspension of micronised fenofibrate is sprayed on inert hydrosoluble carrier by patent CN1243438A; Fenofibrate and surfactant and hydrophilic polymer are made homogenization solution and are sprayed onto on inert carrier by patent CN200780047730.5.Fenofibrate is made nanometer formulation by patent CN200810123751.7 and CN200710126366.3.Fenofibrate is made the solid preparation of high degree of dispersion by patent CN201010123527.5.These documents are all that fenofibrate is made quick releasing formulation, are reached the object improving its bioavailability by the dissolution rate improving fenofibrate.
But object of the present invention is but the rate of release will postponing fenofibrate, postpone being released in of medicine and will be an impediment to the raising of fenofibrate bioavailability to a great extent, therefore prepare the fenofibrate delayed release formulation with high bioavailability and there is great difficulty.In open source literature, there is no the relevant report of fenofibrate delayed release formulation.
Summary of the invention
The present invention completes in view of above-mentioned problem, and object is to provide a kind of fenofibrate delayed release formulation, and said preparation, while the release of delay fenofibrate, takes into account the bioavailability improving fenofibrate.
Another object of the present invention is to provide the method for the fenofibrate slowbreak pellet preparations preparing high bioavailability.The micropill release favorable reproducibility that the method obtains, prescription are simple, process equipment requirement is low, productive rate is high, be applicable to suitability for industrialized production.
3rd object of the present invention is to provide a kind of method improving fenofibrate bioavailability, by adopting, there is the controlled release coating layer of good Water permeability, the micronization of crude drug, powder medicine-feeding and micropill dosage form, the bioavailability of fenofibrate can be significantly improved.
Object of the present invention is achieved through the following technical solutions:
A kind of fenofibrate slowbreak micropill, described micropill only forms by carrying pill core and being wrapped in outer monolayer controlled release coating layer, and described coatings accounts for carries 6% ~ 10% of pill core gross weight; To carry pill core for weight basis, described year pill core comprises the percentage by weight of following composition: fenofibrate 60% ~ 85%, celphere 5% ~ 35%, adhesive 1% ~ 5% and fluidizer 1% ~ 5%; Take coatings as weight basis, described coatings comprises the percentage by weight of following composition: acroleic acid resin
45% ~ 50%, acroleic acid resin
9% ~ 12.5%, plasticizer 5% ~ 20% and antiplastering aid 20% ~ 35%.
Celphere particle diameter is 0.4 ~ 0.9mm, multiple for a kind of or arbitrary proportion in sucrose, starch, microcrystalline Cellulose, dextrin, inorganic salt, mannitol, lactose.
Adhesive is the multiple of a kind of or arbitrary proportion in hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone, sodium carboxymethyl cellulose.
Fluidizer is the multiple of a kind of or arbitrary proportion in micropowder silica gel, Pulvis Talci, microcrystalline Cellulose, lactose, mannitol.
Plasticizer is a kind of or arbitrary proportion multiple of triethyl citrate, Polyethylene Glycol, dibutyl sebacate;
Antiplastering aid is the multiple of a kind of or arbitrary proportion in Pulvis Talci, glyceryl monostearate, micropowder silica gel.
A preparation method for fenofibrate delayed release formulation, is characterized in that, comprises the steps:
(1) pill core preparation is carried:
Fluidized bed powder medicine carrying legal system is adopted to carry pill core for fenofibrate.Be parent nucleus with celphere, add micronised fenofibrate powder and fluidizer and spray adhesive on celphere.After medicine-feeding terminates, screen out 40 orders with the piller of lower part, to obtain final product.
(2) slowbreak micropill preparation:
Take copolymer, plasticizer and antiplastering aid that copolymer, butyl methacrylate, Dimethylaminoethyl Methacrylate and methyl methacrylate mol ratio that ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester mol ratio are 1:2:0.1 are 1:2:1, be dissolved or dispersed in ethanol-water solution, obtained coating solution, coating is carried out to the pill core that carries obtained in step (1), coating terminates rear drying, obtains fenofibrate slowbreak micropill.
In above-mentioned preparation method, the particle size range of micronised fenofibrate powder is less than 10 μm.
Compared with prior art, advantage of the present invention and good effect are:
The present invention have developed fenofibrate delayed release formulation first, fenofibrate slowbreak micropill provided by the invention not only has high bioavailability, and fenofibrate can be made to postpone to discharge after 6 hours, fenofibrate can be taken with statins simultaneously, improve the safety of medication, effectiveness and compliance, thus provide a kind of better selection newly for patient.
The fenofibrate delayed release formulation that the present invention obtains has high bioavailability, is the fenofibrate slow releasing preparation that gone on the market
149%, and reach quick releasing formulation
level.
In addition, fenofibrate delayed release formulation of the present invention also tool have the following advantages:
(1) formulation and technology is simple, does not use multilamellar release-controlled film, and the hybrid polymer film that only monolayer has a good Water permeability can reach the object of slowbreak;
(2) process equipment requires low, and drug powder micronization processes only by size controlling below 10 μm, need meet the requirement of powder bed area method medicine carrying;
(3) productive rate is high, and obtained micropill only need screen out 40 orders with the piller of lower part, without the need to strictly controlling the particle diameter of micropill, substantially increases productive rate;
(4) release favorable reproducibility, drug release behavior due to this drug-supplying system be unit piller drug release behavior adding and, and to the particle diameter of crude drug self and the Particle size requirements of micropill wider, the defect therefore in indivedual piller preparation technology can not produce serious influence to the drug release behavior of whole preparation.
Detailed description of the invention
(1) about coatings
Fenofibrate slowbreak micropill of the present invention adopts single coats layer, is namely only made up of year pill core and monolayer controlled release coating layer.
Containing polymeric coating material, plasticizer and antiplastering aid in monolayer controlled release coating layer.
Polymeric coating material is the mixture (both are about 5:1 ~ 4:1 by mass ratio) of Eugragit RS and Eugragit E.Eugragit RS is methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester (mol ratio 1:2:0.1) copolymer, and Eugragit E is butyl methacrylate, Dimethylaminoethyl Methacrylate and methyl methacrylate (mol ratio 1:2:1) copolymer.Eugragit E dissolves very soon in pH less than 5 medium, oral rear Eugragit E dissolves rapidly formation hole, body fluid cannot be delayed and enter medicated layer, prior art all shows, if by combined for Eugragit RS and Eugragit E, the mixture film obtained dissolves very soon in gastric juice, is applicable to the preparation of fast dissolving dosage form.If when Eugragit E is used for slow controlled release coat, often need outside bag one deck enteric coating again, so that medicine slow releasing in digestive tract, this mixing release-controlled film with good Water permeability of the equal no-trump of prior art document is separately for the report of delayed release formulation.
By this, the coating membrane seemed without any blocking medicine release action is used for fenofibrate to the present invention's trial, but achieves beyond thought slowbreak effect.Supposition may be because controlled release coating layer has good Water permeability, in addition fenofibrate autolysis speed is slow, although do not have fenofibrate Drug to be dissolved release in the slowbreak stage reaching 6 hours, but the low-density medicated layer caused by powder drug layering is already by abundant moistening, be conducive to the dissolving release of follow-up fenofibrate.
The present invention has fully utilized controlled release coating layer, the micronization of crude drug fenofibrate, powder medicine-feeding and the micropill dosage form with good Water permeability just and itself has been conducive to improving the feature of bioavailability, effectively improves the bioavailability of this delayed release formulation.
(2) about the content of coating material
With coatings gross weight for benchmark, ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester are content 45% ~ 50% with the copolymer of mol ratio 1:2:0.1, preferably 46% ~ 48%.Butyl methacrylate, Dimethylaminoethyl Methacrylate and methyl methacrylate with the content of the copolymer of mol ratio 1:2:1 for 9% ~ 12.5%, preferably 10% ~ 12%.
Embodiment
Below exemplify embodiment and comparative example is described in detail to of the present invention, but the present invention not limit by these embodiments, under the prerequisite not changing present inventive concept, those skilled in the art reasonably can change each key element of the present invention.
If without specifically indicating, the percent in embodiment and contrast test all refers to percetage by weight.
The preparation of embodiment 1 year pill core
A prescription
Table 1:
*, in table, q.s. represents appropriate.
B preparation technology
Fluidized bed powder medicine carrying legal system is adopted to carry pill core for fenofibrate:
Fenofibrate crude drug powder (Jiangsu En Hua pharmaceutcal corporation, Ltd) is carried out micronization processes by jet mill (Shanghai Hualy Superfines Science and Technology Co., Ltd., model: JGM-H100).Charging rate is 3kg/h, and operating pressure is 8Mpa, and after pulverizing twice continuously, gained fine powder measures granularity through laser particle analyzer.Result shows, and diameter of aspirin particle is 7.7 μm.Micronised fenofibrate powder is mixed homogeneously with fluidizer and is added in feeder; Be parent nucleus with celphere, and be placed in the material trough of tangent line spray apparatus; Adjustment Fluidization wind rate is 100m
3/ h, rotary speed are 518rpm, make ball core helically formula fluidisation kinestate; Adjustable spraying pressure 0.25MPa, sprays into binding agent to the moistening of ball wicking surface, opens the mixture adding above-mentioned micronised fenofibrate powder and fluidizer for powder groove of feeder.Regulate hydrojet speed and add powder speed, medicine-feeding being operated and carries out smoothly, avoiding micropill to cross wet or overdrying phenomenon (when stablizing, best hydrojet speed is 15g/min, and adding powder speed is 25 ~ 30g/min).After medicine-feeding terminates, screen out 40 orders with the piller of lower part, to obtain final product.
The preparation of embodiment 2 slowbreak micropill
A prescription
Table 2:
*:
pO: the powder (purchased from Evonic company) of ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester (mol ratio 1:2:0.1) copolymer
100: the granule (purchased from Evonic company) of ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester (mol ratio 1:2:0.1) copolymer
100: the granule (purchased from Evonic company) of butyl methacrylate, Dimethylaminoethyl Methacrylate and methyl methacrylate (mol ratio 1:2:1) copolymer
pO: the powder (purchased from Evonic company) of butyl methacrylate, Dimethylaminoethyl Methacrylate and methyl methacrylate (mol ratio 1:2:1) copolymer
B preparation technology
A. the preparation of coating solution: the plasticizer taking recipe quantity shown in table 2 is respectively placed in beaker, adds ethanol, adds recipe quantity shown in table 2 under stirring
and
continue stirring more than 2 hours, guarantee
be uniformly dispersed and fully dissolve; Separately take the antiplastering aid of recipe quantity shown in table 2, add water, under agitation added in ethanol by antiplastering aid aqueous suspension, and stir, the solvent being adjusted to final coating solution is 80% ethanol of the amount of Table 2, copolymer
and
total concentration be 5%.
B. the preparation technology of slowbreak micropill: take 50g fenofibrate and carry pill core and put in mini-glatt fluid bed, adjustment aspiration pressure is 0.2bar, atomisation pressure is 1.5bar, and temperature of charge is 22 ~ 25 DEG C, is that 1.5g/min carries out coating to carrying spray coating solution at the bottom of pill core with spray velocity.Finally in gained coated micropill, be sprinkled into a small amount of micropowder silica gel again, dry 2h in 40 DEG C of baking ovens, take out, obtain fenofibrate slowbreak micropill.
Embodiment 3
Drug accumulation release is tested
(i) drug release determination method:
Get fenofibrate slowbreak micropill appropriate (being equivalent to fenofibrate 250mg), according to drug release determination method (Chinese Pharmacopoeia version annex Ⅹ D in 2010), with the pH 4.0 aqueous solution 1000mL containing sodium lauryl sulphate (SLS) for solvent, rotating speed is 60 turns per minute, operate in accordance with the law, respectively at Isosorbide-5-Nitrae, 7,10, within 18 hours, get solution 2mL, centrifugal 1min (10000rpm), gets supernatant as need testing solution.
It is appropriate that another precision takes fenofibrate reference substance, adds methanol 1mL, ultrasonic dissolution, is diluted to the solution of 0.125mg/mL, product solution in contrast with pH 4.0 aqueous solution containing sodium lauryl sulphate (SLS).
Get need testing solution and each 10 μ L injection liquid chromatographies of reference substance solution respectively, calculate drug accumulation release by peak area external standard method.
Chromatographic condition is as follows:
Chromatographic column: Shim-pack VP-ODS (4.6mm × 250mm, 5 μm, purchased from Shimadzu Seisakusho Ltd.)
Mobile phase: methanol-water (80:20, v/v)
Flow velocity: 1.0mL/min
Column temperature: 35 DEG C
Detector: UV-vis detector
Determined wavelength: 286nm
Sample size: 20 μ L
(ii) drug release determination result
The Accumulation dissolution of 4 batches prepared by embodiment 2 different prescription fenofibrate slowbreak micropills is in table 3, Fig. 1.
Table 3
As can be seen from table 3, Fig. 1, all have obvious delayed release feature according to the different prescription micropill of 4 batches prepared by embodiment 2, it is complete that the release in 7h to be all less than in 15%, 12h release substantially, and release reaches more than 90%.
(iii) technique repeatability is investigated
Prepare three batches of fenofibrate slowbreak micropills respectively to investigate the repeatability of this this technique according to the prescription 2-1 of embodiment 2, the Accumulation dissolution of three batches of prepared fenofibrate slowbreak micropills in table 4, Fig. 2.
Table 4
As can be seen from table 4, Fig. 2, preparation technology's repeatability of the fenofibrate pellet of embodiment 2 is good.
Comparative example 1
The present invention wraps up controlled release layer after being surprised to find that in development process, at same year, pill core first wrapping up one deck contagion gown again, and its drug release behavior has very big-difference with the micropill not containing contagion gown.
Being prepared as follows of fenofibrate pellet containing contagion gown layer:
A carries the preparation of pill core: with embodiment 1;
B bag contagion gown layer: contagion gown layer consist of hydroxypropyl emthylcellulose (HPMC E5), the sealing coat coating solution of 5% is mixed with water, add medicine to the pill core that carries of sealing coat coating solution to steps A gained in fluid bed, coating weight gain is carry pill core weight 4%;
C bag slowbreak clothing layer: carry pill core with the fenofibrate carried in pill core alternate embodiment 2 containing contagion gown layer of step B gained, other formulation and technologies are all with embodiment 2.
Containing any coatings carry pill core (fenofibrate namely prepared by embodiment 1 carries pill core), not containing contagion gown layer fenofibrate pellet (the fenofibrate slowbreak micropill namely prepared by the present invention) and contain contagion gown layer the Accumulation dissolution of fenofibrate pellet in table 5, Fig. 3.
Table 5
As can be seen from table 5, Fig. 3, year pill core drug release not containing any coatings is rapid, discharges substantially completely after 4 hours; And the present invention namely carry pill core basis adopts mixed polymer (
with
) single coats is carried out to it after micropill there is obvious delayed release feature; If but this delayed release feature is destroyed again after year pill core and monolayer controlled release coat interlayer add one deck contagion gown layer (HPMC, weightening finish 4%) again, the release in 1h reaches more than 70%, without slowbreak effect.Though below all illustrate that slowbreak layer of the present invention only has single coats to form, beyond thought effect is played to the delayed release of fenofibrate, increase the effect that contagion gown layer does not reach delayed release on the contrary.
Comparative example 2
In delayed release coat layer of the present invention
with
the drug release behavior of proportioning to micropill there is considerable influence.
Different ratio is prepared according to table 6 Suo Shi
with
other are with embodiment 1 and embodiment 2, and their Accumulation dissolution compares in table 7.
Table 6
Table 7
Controlled release coating layer of the present invention is by mixed polymer
with
composition, wherein
for water-insoluble and high osmosis material.As can be seen from Table 7, when this mixed polymer completely by
during composition, or work as
ratio be greater than 50% and
content when being less than 9%, release <70% in micropill 12h, cannot release complete, in body, bioavailability is low; And work as
content is 47.3% still
content up to 15.9% time, in microsphere 4h, release to have reached in 22%, 7h release more than 50%, although bioavailability is good, cannot reach good slowbreak effect.
Comparative example 3
In controlled release coating layer of the present invention, mixed polymer is
with
combination.Once used in development process
with
or the combination of polyethylene glycol 6000 or succinic acid and different coating weight gain thereof, all do not reach desirable release result, representational prescription and Accumulation dissolution are in table 8 and table 9.
Table 8
pO: ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester (mol ratio 1:2:0.2) copolymer
Table 9
As can be seen from the above table, adopt
with
the combination of polyethylene glycol 6000 or succinic acid, does not all reach the effect having slowbreak and high bioavailability concurrently of the present invention.
Comparative example 4
Fenofibrate delayed release formulation (embodiment 2) prepared by the present invention, with commercially available fenofibrate slow releasing preparation
and micronize preparation
animal body in blood drug level contrast experiment
A analysis in vivo
Accurate 0.8mL blood plasma of drawing is placed in 5mL centrifuge tube, add 25 μ g/mL inner mark solutions (the chloro-4'-dihydroxy benaophenonel of 4-) 20 μ L and 5mol/L hydrochloric acid 0.2mL, vortex 5min, add 3mL n-hexane-ethyl acetate (9:1, v/v), the centrifugal 5min of vortex 5min, 13000rpm; Accurate absorption upper organic layer 2.5mL, be transferred in 5mL centrifuge tube, 40 DEG C of nitrogen dry up, and 200 μ L mobile phases redissolve, sample introduction 100 μ L.
Chromatographic condition is as follows:
Chromatographic column: Shim-pack VP-ODS (4.6mm × 150mm, 5 μm, purchased from Shimadzu Seisakusho Ltd.) pre-column Shim-pack Column Holder (4.6mm × 10mm, 5 μm, purchased from Shimadzu Seisakusho Ltd.)
Mobile phase: acetonitrile-phosphate aqueous solution (pH=2.5) (40:60, v/v)
Flow velocity: 1.2mL/min
Column temperature: 35 DEG C
Detector: UV-vis detector
Determined wavelength: 295nm
Sample size: 100 μ L
B Internal pharmacokinetics is tested
Medication:
Beagle dog 4, ♂ (male), (15 scholar 1) kg, regular grade.
Adopt own control trial design, the clean phase is 10 days.4 dogs, more than overnight fasting 12h, m seq is administration (being equivalent to fenofibrate 250mg) on an empty stomach, and after administration, 4h unifies fed standard meal.
Blood specimen collection:
Respectively at after (0h) before administration and administration 1,2,3,4,5,6,8,10,12,24,36,48 and 72h get foreleg vein blood 4mL, put in heparin sodium glass tubing, the centrifugal 5min of 4000rpm, gets supernatant blood plasma in-18 DEG C of freezen protective, to be analyzed.
Pharmacokinetic study experimental result:
Measure blood drug level (the results are shown in Table 10 ~ table 11, Fig. 4) by the assay method of above-mentioned plasma sample, fenofibrate pellet prepared by the present invention has obvious time lag, and can sustained release gently after 6h.Bioavailability be improved significantly, be commercially available fenofibrate slow releasing capsule
149% ~ 182%, and reach commercially available quick releasing formulation
level, illustrate that slowbreak micropill of the present invention has good slowbreak effect and has high bioavailability.
Table 10: fenofibrate slowbreak micropill prepared by the prescription (2-1 and 2-2) of embodiment 2 and commercially available fenofibrate slow releasing capsule
and micronize preparation
pharmacokinetic parameters
*, in table, AUC represents zeroth order square area under curve;
AUMC represents first moment area under curve;
MRT represents average residence time;
T
1/2zrepresent the half-life;
T
maxrepresent time to peak;
Cmax represents peak concentration.
Table 11: fenofibrate slow-release micro-pill prepared by the prescription (2-1 and 2-2) of embodiment 2 and commercially available fenofibrate slow releasing capsule
and micronize preparation
relative bioavailability