CN1867321A - A solid dosage form comprising a fibrate - Google Patents

Abstract

The invention provides stable, solid dosage forms and pharmaceutical compositions in particulate form comprising a fibrate, for example fenofibrate, dissolved in an non-aqueous vehicle in order to ensure improved bioavailability of the active ingredient upon oral administration relative to known fibrate formulations.

Description

The solid dosage forms that comprises Bei Te

The present invention relates to comprise Bei Te (fibrate) the particularly new solid dosage forms and the pharmaceutical composition of fenofibrate.Particularly the invention discloses the solid dosage forms of bioavailability with increase.Solid dosage forms of the present invention comprises the Bei Te that is dissolved in suitable vehicle or the vehicle mixture.Described dosage form is specially adapted to Orally administered and shows good storing stability, promptly is stable.Invention also relates to method and its purposes that is used to prepare described solid dosage forms and pharmaceutical composition.

Background of invention

Bei Te is the fat regulator.The example of Bei Te comprises gemfibrozil, fenofibrate, bezafibrate, clofibrate and ciprofibrate.Described chemical compound is considered to prodrug, produces its active metabolite by metabolism in vivo.Only for the purpose of illustration, below based on specific shellfish special case, i.e. fenofibrate.The fenofibrate chemical name be 2-[4-(the 4-chlorobenzoyl]-2-methyl-propanoic acid 1-Methylethyl ester, have following chemical formula:

Fenofibrate is a white solid.Described chemical compound is water insoluble.Fusing point is 79-82 ℃.Fenofibrate produces the active substance fenofibric acid through metabolism.Fenofibric acid has about 20 hours elimination half-life.The measurement result of detectable fenofibric acid amount can reflect the efficient that fenofibrate absorbs in the blood samples of patients.Fenofibric acid cause the patient that receives treatment T-CHOL (total-C), LDL-C, apolipoprotein B, total triglyceride and the lipoprotein (VLDL) that is rich in triglyceride reduce.In addition, use fenofibrate treatment to cause high density lipoprotein (HDL) and apolipoprotein apoA1 and apoAII to increase.Fenofibrate is brought into play the effect of effective fat regulator, and it provides unique clinical favourable aspect with respect to already present product in the Bei Te family of drug substance.Fenofibrate causes hypertriglyceridemia patient's plasma triglyceride significantly to reduce, and causes the remarkable minimizing of plasma cholesterol and LDL-C in the patient of hypercholesterolemia and mixing dyslipidemia.

Fenofibrate also can reduce the level of serum uric acid by the homaluria that increases uric acid in experimenter who suffers from hyperuricemia and normal subjects.

Clinical research has proved that the T-CHOL of raising, low-density lipoprotein cholesterol (LDL-C) are atherosis relevant with the human artery with apolipoprotein B (apo B) level.The HDL-C (HDL-C) that reduces with and transferring composite, ApoA (apo AI and apoAII) level relevant with development of atherosclerosis.

Fenofibrate also is effective on treatment type ii diabetes and metabolism syndrome.

Fenofibrate also suffers from the patient's of hypertriglyceridemia (Fredrickson IV type and V-type hyperlipemia) meals auxiliary treatment as treatment.In the diabetics that shows the fasting chylomicronemia, improve glycemic control and reduce the triglyceride under the fasting state usually and eliminate chylomicronemia, thereby do not need to carry out pharmacological intervention.

Bei Te is the known unsettled drug substance that is difficult to after Orally administered absorb and absorb.Generally speaking, it is enjoined with food edible to increase bioavailability.

To the existing many improvement of dosage form that the most widely used present Bei Te is a fenofibrate, also carried out many effort with the increase bioavailability of medicament, thereby improved its effectiveness.Yet,, still need improved dosage form with respect to present obtainable compositions and the dosage form that the crystal fenofibrate of micronization form is provided.Particularly still exist the compositions that shows suitable bioavailability and the needs of dosage form, described compositions and dosage form can reduce or overcome the difference between patient's the drug bioavailability of patient's the drug bioavailability of fasting and feed basically, and/or reduce basically or overcome in the current treatment of the product that uses commercially available acquisition in the observed individuality and/or change between individuality.In addition, also exist the new dosage form that can reduce observed side effect and/or the needs of compositions.

Especially exist the unsatisfied needs of development with the solid composite of granule (particulate) form existence, in the solid composite of described particle form, Bei Te exists with dissolved state, and said composition shows as other form of powder, microgranule, granule (granule), granule (granulate), pearl, pellet or granular materials rather than to contain the soft dosage form of liquid medium.

Summary of the invention

The inventor has now found that by being dissolved in shellfish special case such as fenofibrate in the suitable vehicle and using the preparation of compositions solid dosage forms of gained promptly to get rid of the dosage form of liquid form material, can increase the bioavailability of fenofibrate significantly.Known Bei Te particularly fenofibrate is water-fast, shows the feature that discharges rapidly, pharmaceutical composition and the preparation that is expected at bioavailability in the body that has remarkable increase among the patient who needs it but the invention provides.Particularly the present invention has successfully prepared solid dosage forms, tablet for example, and it comprises the Bei Te that dissolved form exists.The favourable aspect that is used for Orally administered solid and stable dosage form is well-known.

Therefore, a first aspect of the present invention relates to and comprises the solid oral dosage form that is dissolved in vectorial Bei Te, and described vehicle is hydrophobic, hydrophilic or can be miscible with water.Useful solid dosage forms exists with tablet, pearl, capsule, crystal grain, pill, granule, granule, powder, pellet, sachet or tablet form, useful Bei Te is fenofibrate, bezafibrate, clofibrate, ciprofibrate and its active metabolite and analog, comprises for example fenofibric acid of any relevant fibric acid (fibric acid).

Second aspect the present invention relates to comprise the pharmaceutical composition that is dissolved in vectorial Bei Te, and described vehicle is hydrophobic, hydrophilic or can be miscible with water; In others, the present invention relates to the solid composite medicament that exists with particle form, it comprises Bei Te, hydrophobicity or hydrophilic or vehicle and oil absorption material that can be miscible with water, the oil suction threshold value (oil threshold value) of said composition performance at least 10%.

In yet another aspect, the present invention relates to produce the method for solid oral dosage form of the present invention or pharmaceutical composition.

Others of the present invention will come into plain view by following description.The body build-in test that carries out in Canis familiaris L. shows (referring to embodiments herein) more: compare with the commercially available solid dosage forms that contains identical active component, promptly compare with Lipanthyl  capsule with Tricor  tablet, solid dosage forms of the present invention and compositions table reveal remarkable enhanced fenofibrate bioavailability.

In addition, believe firmly the solid dosage forms and/or the compositions that the invention provides Bei Te, it can significantly reduce usually in the observed individuality in Orally administered back and/or interindividual variation.In addition, compositions of the present invention and/or dosage form provide significantly reduced food effect, promptly absorb relatively not rely on the patient whether with compositions or dosage form with or do not take together with any food.Expection discharges the quantity that can reduce the side effect of the intestines and stomach dependency through the Bei Te of improvement.In addition, can absorb obvious more substantial Bei Te, thereby have only more a spot of Bei Te to be drained by feces without changing according to expection.

Describe in detail

Definition

As used herein, term " active component " or " active pharmaceutical ingredient " be meant any be used to provide pharmacologically active or other on diagnosis, treatment, alleviation, treatment or prevent disease direct effect or influence the people or the component of the structure of other animal health or any function.Described term comprises and can stand chemical change and be present in composition in the medicine with modified form in the production of drug products, is used to provide specific effect or activity.

In this manual, term " hydrophilic " is meant that material ' likes water ', and promptly the part of hydrophilic molecule or molecule is normally electropolar and can form hydrogen bond with hydrone, make its in water than easier dissolving in oil or other " nonpolar " solvent.

In this manual, term " amphipathic " is meant the molecule (as surfactant) with the polarity water soluble group that is attached on the water-fast hydrocarbon chain.Therefore, an end of described molecule is hydrophilic (polar) and the other end is hydrophobic (nonpolar).

In this manual, term " hydrophobicity " is meant and tends to be electric neutrality and nonpolar molecule, therefore has a preference for other neutral and non-polar solven or branch subenvironment.

As used herein, term " can be miscible with water " is meant completely or partially and the blended chemical compound of water.For example, some polarity fat is that part can be miscible with water.

As used herein, term " vehicle " is meant and does not have any solvent or a carrier of pharmacotoxicological effect in drug products.For example, water is the vehicle of xilocaine, and propylene glycol is many antibiotic vehicles.

In this manual, term " solid dispersion " is meant that medicine or active component or material are distributed to particle level in inertia vehicle, carrier, diluent or the substrate of solid state, i.e. fine particle dispersion normally.

In this manual, term " solid solution " is meant that medicine or active component or material are dissolved in inertia vehicle, carrier, diluent or the substrate of solid state on molecular level.

As used herein, term " analog " is meant chemical compound similar to another kind of chemical compound on the structure.

Term " medicine " be meant be used to diagnose, treat, slow down, the chemical compound of the disease of medical treatment or prevention people or other animal.

In this manual, term " dosage form " is meant medicine is delivered to the used form of patient.This comprises forms such as parenteral, part, tablet, oral (liquid or dissolved powder), suppository, suction, transdermal.

As used herein, term " bioavailability " is meant that medicine or other material are in the degree of using back arrival target tissue.

As used herein, term " biological identity property " be meant with class name and trade (brand) name medicine compare mutually based on scientific basic.For example, if it enters blood circulation with identical speed when using similar dosage under similar condition, then medicine is that biology is equal to.The parameter that is generally used for biological identity property research is t _Max, C _Max, AUC _0-infinity, AUC _0-tOther relevant parameter can be W ₅₀, W ₇₅And/or MRT.Therefore, when whether definite biological identity property exists, can use at least one in these parameters.In addition, in this manual, if used parameter value is within the 80-125% scope of parameter value of Prograf  used in check or commercially available similar products that contain tacrolimus, two kinds of compositionss are considered to that biology is equal to so.

In this manual, " t _Max" be illustrated in and reach maximum plasma concentration (C after using _Max) time time of needing; AUC _0-infinityOr ACU be meant under plasma concentration-time graph from the time 0 to the area between the infinity; AUC _0-tBe meant under plasma concentration-time graph the area between the t from the time 0 to the time; W ₅₀Be meant that plasma concentration reaches C _Max50% or time more for a long time; W ₇₅Be meant that plasma concentration reaches C _Max75% or time more for a long time; MRT is meant the average residence time of shellfish special case such as fenofibrate (and/or its analog).

In this manual, term " medicine " is meant the chemical compound that is used for the treatment of disease, damage or pain.Reasonably medicine is divided into " preventative " field of promptly keeping fit and " curative ", promptly restorative field.

In this manual, term " controlled release " is identical term with " modified release ", and it comprises the release from any kind of the tacrolimus of the present composition, and it is adapted at using the back to the experimenter and obtains specific treatment or prophylactic response.Those skilled in the art will know that the difference of the release of controlled release and/or modified release and conventional tablet or capsule.Term " discharges in check mode " or " discharging in modified mode " has the meaning same as described above.Described term comprises that slow release (produces lower C _MaxSlower t _Max, but t _1/2Constant), prolong to discharge and (to produce lower C _MaxSlower t _Max, but apparent t _1/2Elongated); Slow release (C _MaxConstant but prolonged the time, thereby, t _MaxPostpone, but t _1/2Constant) and pulsation (pulsatile) discharges, rapidly (burst) discharge, continue to discharge, prolong release, time-optimized (chrono-optimized) release, rapid release (to obtain enhanced initiation) etc.Described term also comprises, for example, utilizes interior for example different enzyme or the pH of specified conditions of body to change the release of controlling drug substance.

In this manual, for example decompose on the surface of tablet or tablet coating gradually on term " corrosion " or " erosion " surface that is meant material or structure.

Active drug substance

The medicine of dosage form of the present invention and pharmaceutical composition or active substance are Bei Te.The example of useful Bei Te is bezafibrate, ciprofibrate, clinofibrate, clofibrate, etofylline, clofibrate, fenofibrate, gemfibrozil, pirifibrate, simfibrate and tocofibrate; Useful especially is gemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate and its active metabolite and analog, comprises for example fenofibric acid of any relevant fibric acid.In preferred embodiments, described Bei Te is fenofibrate or its analog.Yet dosage form of the present invention and compositions also can comprise two kinds, three kinds or even the mixture of four kinds of different Bei Te and/or fibric acid.

According to Bei Te and vectorial total weight, the concentration of Bei Te is 10%w/w at least in the vehicle; Preferably according to Bei Te and vectorial total weight, be 15%w/w or 16%w/w or 17%w/w or 20%w/w or 25%w/w or 30%w/w, particularly 35%w/w at least at least at least at least at least at least at least; According to Bei Te and vectorial total weight, the concentration of Bei Te is 90%w/w at the most in the vehicle, or according to Bei Te and vectorial total weight, 80%w/w or 75%w/w or 70%w/w or 60%w/w or 50%w/w or 40%w/w or be no more than 35%w/w at the most at the most at the most at the most at the most at the most.Preferably, Bei Te is dissolved in the non-aqueous vehicle fully.Yet, the bioavailability that crystal or little crystalline active medicine may not can influence the increase of solid dosage forms of the present invention and compositions appears on a small quantity.Therefore, at least the fenofibrate of 90%w/w is dissolved in the vehicle, preferably 93%w/w or 95%w/w or 97%w/w or 98%w/w or 99%w/w or 99.5%w/w or described dosage form or the fenofibrate in the pharmaceutical composition of 99.9%w/w are dissolved in vehicle or vehicle system fully at least at least at least at least at least at least at least.

Except Bei Te, dosage form of the present invention and pharmaceutical composition can comprise other active drug substance, preferred a kind of extra drug substance.Preferably, this extra medicine is a kind of material that is used for identical indication usually with Bei Te.Specific example is ezetimibe.Certainly, also relate to and be used for three kinds of identical indication or even the combination product of four kinds of drug substances and comprise two kinds, three kinds or four kinds of combination products that are used for the active component of different indications or treatment.

The example of extra drug substance is unusual agent of other antilipemic such as Shi Dating (statins); The fat regulator is as Acipimox, binifibrate, etofibrate, niceritrol, nicofibrate, pirozadil, Ronifibrate, tocoferil nicotinate; Combination such as ace inhibitor with cardiovascular drugs: alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, temocapril, teprotide, trandolapril, zofenopril; Calcium channel blocker, as: amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, bepridil, cilnidipine, diltiazem grass (diltiazem), efonidipine, felodipine, gallopamil, isradipine, lacidipine, lercanidipine, Manidipine, mibefradil, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, verapamil; The alpha block medicine,, terazosin new, thymoxamine, tolazoline, urapidil as: alfuzosin, bunazosin, doxazosin, indoramine, naftopidil, phenoxybenzamine, phentolamine, prazosin, smooth (rope) Lip river; β-blocking agent, as: acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucindolol, bunitrolol, bupranolol, carazolol, carteolol, carvedilol, celiprolol, esmolol, indenolol, labetalol, Landiolol, levobetaxolol, levobunolol, mepindolol, metipranolol, metoprolol, nadolol, nebivolol, nipradilol, oxprenolol, penbutolol, pindolol, Propranolol, sotalol, talinolol, tertatolol, timolol; Angiotensin ii blocking agent, as: Candesartan, Eprosartan, irbesartan, losartan, Olmesartan, Tasosartan (ref. telmisartan), valsartan; Vasodilation, as: cadralazine, diazoxide, dihydralazine, endralazine, hydralazine, minoxidil, todralazine, tolazoline, carbocromen, cinepazet, (ref. cloridarol), the dilazep grass, etafenone, fendiline, hexobendine, oxyfedrine, trapidil, trimetazidine, azapetine, bamethan, bencyclane, buflomedil, butalamine, calcitonin-gene-related peptide, cetiedil, cinepazide, cyclandelate, diisopropyl ammonium monoxone, fasudil, ifenprodil, inositol nicotinate, naftidrofuryl, nicotinyl alcohol, pentoxifylline, pentifylline, pipratecol, propentofylline, raubasine, xantinol nicotinate (xantinol icotinat); Central action hypertension agents: apraclonidine, brimonidine, clonidine, guanabenz, guanfacine, methyldopa (methyldopa), moxonidine, rilmenidine, tiamenidine; Antiarrhythmics, as: ajmaline, cibenzoline, disopyramide, hydroquinidine, pirmenol, procainamide, quinidine, aprindine, mexiletine, tocainide, diprafenone, encainide, flecainide, lorcainide, pilsicainide, Propafenone, bretylium tosylate, acecainide, amiodarone, azimilide, bretylium tosylate, cibenzoline, dofetilide, ibutilide, Nifekalant, sotalol, cibenzoline, verapamil; Antiplatelet drug, as: abciximab, aspirin, cilostazol, clopidogrel, cloricromen, dipyridamole, ditazole, eptifibatide, indobufen, lamifiban, orbofiban, G-137, Sarpogrelate, sibrafiban, ticlopidine, tirofiban, trapidil, triflusal, xemilofiban; Diuretic, as: acetazolamide, brinzolamide, diclofenamide (dichlorphenamide), dorzolamide, methazolamide, azosemide, bumetanide, etacrynic acid, etozolin, furosemide, piretanide, torasemide, isosorbide, mannitol, amiloride, canrenone, canrenoate potassium, spironolactone, triamterene, althiazide, bemetizide, bendroflumethiazide, benzthiazide, butizide, chlorothiazide, chlortalidone, clopamide, cyclopenthiazide, cyclothiazide, epitizide, hydrochlorothiazide, hydroflumethiazide, indapamide, mebutizide, mefruside, methyclothiazide, meticrane, metolazone, polythiazide, quinethazone (quinethazone), teclothiazide, trichlormethiazide, tripamide (tripamide), xipamide; Antidiabetic drug, as: acarbose, acetohexamide, biguanide, the antidiabetic drug buformin, carbutamide, chlorpropamide, epalrestat, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, Glisentide, glisolamide, glisoxepide, glybuzole, glyclopyramide, glycyclamide, glymidine sodium, metformin hydrochloride, midaglizole, miglitol, Nateglinide, phenformin hydrochloride, pimagedine, the pioglitazone hydrochlorate, Pramlintide, repaglinide, rosiglitazone, sorbinil, tolazamide, tolbutamide, troglitazone; The voigelibo sugar substance, as: q10, vitamin (nicotiamide, Benadon hc1, b12, vitamin E, ascorbic acid etc.), antioxidant is also included within the useful compositions usually.

Extra drug substance also can be included in the compositions that can cause undesired triglyceride and/or cholesterol levels or therewith use.Therefore, compositions of the present invention can comprise medicine for example isotretinoin or reverse transcriptase inhibitors (for example hiv protease inhibitor), psychosis such as olanzapine and other medicines or therewith use.

As mentioned, the combination product that contains Bei Te is not limited to the compositions of two kinds of materials, and triple or quadruple treatment also can be useful especially.

Vehicle

The vehicle that is used for the present invention be can be miscible, hydrophilic or hydrophobic with water vehicle.Useful vehicle is non-aqueous substance.

Being used for the vectorial example of hydrophobicity of the present invention is straight chain saturation alkane, paraffin; Fatty and oily, for example cupu oil, Adeps Bovis seu Bubali, leaf fat; Higher fatty acids, for example stearic acid, myristic acid, Palmic acid; Hydrogenated tallow, replacement and/or non-substituted glycerol three esters, yellow beeswax (yellowbeeswax), cera alba (white beeswax), Brazil wax, castor wax (castorwax), Japan wax and its mixture.

Be used for of the present invention can with the miscible vectorial example of water be can be miscible with water polarity fat, for example sorbitan ester, PTMEG ester; Higher alcohols, for example spermol, octadecanol; Glycerin mono-fatty acid ester, replacement and/or non-substituted glycerol monoesters, replacement and/or non-substituted glycerol diester and its mixture.In a more preferred embodiment, described vehicle is hydrophilic or can be miscible with water.Preferably, vehicle is selected from Polyethylene Glycol, polyoxyethylene oxide, poloxamer, Myrj 45, poly--ε caprolactone and its mixture.Yet, described vehicle also advantageously polyglycolyzed glyceride for example with registered trade mark Gelucire ^A kind of in many products of selling, for example Gelucire 44/14.

Useful hydrophilic or can be polyvinylpyrrolidone, polyethylene-polyvinyl acetate ester copolymer (PVP-PVA), polyvinyl alcohol (PVA), PVP polymer, acrylic polymer, polymethacrylic acid polymer (Eudragit RS with the miscible vectorial example of water; EudragitRL, Eudragit NE, Eudragit E), myristyl alcohol, cellulose derivative comprise hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, pectin, cyclodextrin, galactomannan, alginate, carragenate, Xanthan gum and its mixture.

Described vehicle is the mixture of two or more materials preferably.

Described vehicle also can be the oily matter as giving a definition and describing.

Preferably, vectorial fusing point is preferably within 10 ℃ to 250 ℃ scope, preferably within 30 ℃ to the 100 ℃ scopes, more preferably within 40 ℃ to 75 ℃ scopes, especially within 40 ℃ to 70 ℃ scopes.

In embodiment preferred of the present invention, vehicle is Polyethylene Glycol (PEG), preferably have at least 3000, at least 4000 mean molecule quantity more preferably, its randomly with poloxamer for example poloxamer 188 with between preferred 1: 3 and 10: 1, preferably between 1: 1 and 5: 1, more preferably between 3: 2 and 4: 1, especially between 2: 1 and 3: 1 particularly 7: 3 weight ratio mix.

Bioavailability

Usually, known after oral using, multiple factor can influence therapeutic absorption of active agents and bioavailability.These factors comprise the food that exists in the gastrointestinal tract, usually, medicine the residence time of stomach under the situation that food exists obviously than long under the fasting state.If surpass certain point owing to food causes bioavailability of medicament to be affected in the gastrointestinal existence, medicine is considered to show food effect so.Food effect is extremely important, because there is risk, described risk is with relevant to patient's drug administration of just having eaten meal.Described risk comes from following: drug absorption is gone into blood flow and may be affected adversely, and treats the disease that this medicine will be used for the treatment of to such an extent as to this patient may not obtain enough absorptions.Under the situation of for example fenofibrate, the situation difference is because food increases its absorption.Therefore, when using medicine not dietary intake can cause incomplete absorption.With compare under the fasting situation, under the state, the degree of absorption that contains the obtainable product Tricor  of being purchased of fenofibrate (from Abbott) has increased about 35% on the feed.

As mentioned above, still need to comprise the new pharmaceutical composition of one or more Bei Te, described compositions table reveals the suitable bioavailability of reactive compound and/or reduces or eliminates food effect.In this manual, term " suitable bioavailability " be meant with use conventional tablet in active substance after the bioavailability that obtains compare, compositions of the present invention use the bioavailability that generation has been improved; Or with compare using the bioavailability that obtains behind the commercially available product that contains identical active substance with same amount, described bioavailability is identical at least or be improved.Go for absorption of active agents more completely especially, thereby may reduce the dosage of using.In addition, comprise the pharmaceutical composition of Bei Te and dosage form also can reduce or eliminate to the needs of dosage form dietary intake together, thereby make the patient can be freer on the time of taking medicine.Equally, bioavailability raising or that increase can cause the treatment that improves, because may obtain identical therapeutic reaction and more stable blood plasma level and not have the food restriction with dosage that reduces and/or less application times.The another way of treatment that obtains the improvement of disease (its for example need fenofibrate treat) is to discharge to gastrointestinal by balance fenofibrate by this way to realize, described mode makes after using the plasma concentration of the fenofibrate that obtains the plasma concentration of the fenofibrate that increases at the very start or postpone to obtain to increase, promptly by using the release composition that comprises one or more Bei Te modified or that postpone to carry out balance.

In one embodiment, the present invention relates to comprise the pharmaceutical composition or the solid dosage forms of the particle form of one or more Bei Te, wherein oral give need its mammal after, the AUC/AUC of compositions performance about at least 1.0 _ControlValue uses the commercially available product that contains identical Bei Te to determine AUC _Control, under similar condition, determine the AUC value.

Can not obtain based on Injectable composition data of the absolute bioavailability of fenofibrate (being likely) for example because the solubility problem in the aqueous medium causes.The commercially available compositions that contains fenofibrate comprises surfactant and/or lipophilic medium for example.Surfactant can provide the bioavailability of raising, thereby the bioavailability of such compositions can be enough.Yet, still need to develop the preparation technique that can prepare various dosage forms flexibly.Therefore, to this raising and/or the requirement of compositions more flexibly may be to obtain with the identical bioavailability of from commercially available product, having seen or than its higher bioavailability.

Therefore, in other embodiments of the present invention, by using the AUC/AUC that solid dosage forms of the present invention or pharmaceutical composition obtain _ControlValue is about 1.1 at least, for example, at least about 1.2, about at least 1.3, about at least 1.4, about at least 1.5, about at least 1.75 or more, about 1.8 or more, about 1.9 or more, about 2.0 or more, about 2.5 or more, about 2.75 or more, about 3.0 or more, about 3.25 or more, about 3.5 or more, about 3.75 or more, about 4.0 or more, about 4.25 or more, about 4.5 or more, about 4.75 or more, about 5.0 or more, under similar condition, determine the AUC value.

Equally, with respect to the C of commercially available Tricor  tablet _MaxValue is by using the C that solid dosage forms of the present invention or pharmaceutical composition obtain _MaxValue is about at least 1.1 or about at least 1.2 or about at least 1.3 or about at least 1.4 or about at least 1.5 or about at least 1.6 or more or about at least 2.0 or about at least 2.5 or about at least 3.0, determines C under similar condition _MaxValue.

Another object of the present invention is to reduce or eliminate food effect.Therefore, on the other hand, the present invention relates to contain the pharmaceutical composition or the solid dosage forms that exist with particle form of one or more Bei Te, wherein oral give need its mammal after, compositions or solid dosage forms do not show the food effect of significant adverse, as by about at least 0.85 AUC _Fed/ AUC _FastedValue (being at least 0.75 under 90% lower confidence limit) is proved.In specific embodiment, pharmaceutical composition of the present invention or solid dosage forms have about 0.9 or higher for example about 0.95 or higher, about 0.97 or higher or about 1 or higher AUC _Fed/ AUC _FastedValue.

In other words, respectively on the feed and under the not feed situation oral give administration after, the difference between the biological identity property parameter that records is lower than 25%, for example is lower than 20%, is lower than 15%, is lower than 10% or be lower than 5%.

In yet another aspect, the present invention relates to comprise particle form pharmaceutical composition and the solid dosage forms of Bei Te, wherein when when using with the commercially available identical or lower dosage of the product that contains identical Bei Te, the oral present composition of giving the administration that needs it is that biology is equal to the commercially available product that contains identical Bei Te basically.In its specific embodiment, described dosage is approximately the 98%w/w of the special dosage of using with the form of the commercially available product that contains identical Bei Te of shellfish at the most, for example, approximately 95%w/w, approximately 90%w/w, approximately 85%w/w, approximately 80%w/w, approximately 75%w/w, approximately 70%w/w, approximately 65%w/w, approximately 60%w/w, approximately 55%w/w or about 50%w/w at the most at the most at the most at the most at the most at the most at the most at the most at the most at the most.

Usually, determine biological identity property: t by following at least a parameter _Max(reaching the time of maximal plasma concentration), c _Max(maximal plasma concentration), AUC _0-t(from the area under curve of time 0 to t), AUC _0-infinity(infinitely-great area under curve), W from the time 0 to the time ₅₀(plasma concentration is c _Max50% or the time span when higher), W ₇₅(plasma concentration is c _Max75% or the time span when higher) and/or MRT (average residence time).

Subject matter with the Bei Te treatment is huge individual interior or interindividual variation.Therefore, advancing on the one hand, the present invention relates to comprise the pharmaceutical composition of the particle form of one or more Bei Te, wherein under the same conditions and under with the dosage that the identical treatment effect is provided, with between the commercially available individuality that contains identical shellfish special product product or individual interpolation out-phase ratio, orally reduced between individuality for the described compositions of administration that needs it and/or difference in individual.

In above-mentioned comparison test, when described Bei Te is fenofibrate, commercially available product be tablet form Tricot  or, selectively, the Tricot  of Capsule form.When Bei Te was gemfibrozil, then suitable commercially available product was Lopid ; When Bei Te was bezafibrate, suitable commercially available product was Bezalip ; When Bei Te was clofibrate, then suitable commercially available product was Atromid ; When Bei Te was ciprofibrate, then suitable commercially available product was Lipanon .

Be used to determine whether to have absorbed appropriate amount Bei Te to make things convenient for method can be by determining through defecate but the content of the Bei Te that does not change carries out.Therefore, the present invention relates to solid composite medicament or solid dosage forms in one embodiment, wherein after Orally administered, at the most approximately 25%w/w for example at the most approximately 20%w/w, at the most approximately 15%w/w, at the most approximately 10%w/w, approximately the Bei Te in the described compositions of 5%w/w is drained at the most.

Production method

Can prepare particulate composition of the present invention by any method that is suitable for mixing the active substance that is insoluble in water.Can lead to pharmaceutical compositions such as any method is easily for example granulated, mixing, spray drying.Useful especially method is a disclosed method among the International Publication No. WO 03/004001, and the method for preparing granular materials by in check condensing method has been described in described application, the method that granule is grown in size controllably.Described method comprises and being injected on the solid carrier containing vectorial first compositions of active substance and liquid form.Generally speaking, vehicle has at least 5 ℃ fusing point, but described fusing point must be lower than the fusing point of active substance.In the present invention, vectorial fusing point should be no more than 250 ℃.

Use general knowledge and conventional experimental selection medicine acceptable, can disperse or fully or at least in part the lytic activity material and have want the fusing point in the scope vehicle within those skilled in the art's technical scope.

In this manual, suitable vehicle is for example to be mentioned as vehicle or oily matter (oily material) and disclosed material in WO 03/004001.The favourable aspect of using the controlled condensing method of describing among the WO03/004001 is possible use a large amount of relatively liquid systems and not have undesired particle size growth granular materials.Therefore, in one embodiment of the invention, how much weight mean diameter d that the granular materials of pharmaceutical composition has _Gw〉=10 μ m, μ m for example 〉=20, from about 20 to 2000, from about 30 to about 2000, from about 50 to about 2000, from about 60 to about 2000, from about 75 to about 2000, for example from about 100 to 1500 μ m, from about 100 to about 1000 μ m or from about 100 to about 700 μ m or about at the most 400 μ m or 300 μ m at the most, for example from about 50 to about 400 μ m, for example from about 50 to about 350 μ m, from about 50 to about 300 μ m, from about 50 to about 250 μ m or from about 100 to about 300 μ m.

Preferably by spray drying technology, controlled coacervation, lyophilizing or to the bag of carrier granular by or any other remove the method for desolvating and form compositions of the present invention and dosage form.The product of drying contains the active substance that preferably exists with dissolved form, and described active substance dissolves fully with the form of solid solution or is partly dissolved with the form of solid dispersion (comprising molecular dispersoid and solid solution).

Yet, preferably produce compositions of the present invention and dosage form by the method that comprises the following steps:

I) vehicle of generation liquid form, if promptly vehicle at room temperature is solid then it is dissolved,

The vehicle that ii) under the temperature that is lower than the special fusing point of shellfish, keeps liquid condition,

Bei Te that iii) will the amount of wanting is dissolved in the vehicle,

Iv) the solution with gained is injected on the solid carrier with the temperature that is lower than described vehicle fusing point,

The compositions of v) mechanically operating gained to be to obtain granule, promptly granular materials and

Vi) randomly granular materials is accepted conventional method with the preparation solid dosage forms.

In principle, use any appropriate method that is used for pharmaceutical compositions known in the art to prepare to comprise at least the pharmaceutical composition of the active substance that exists with part solid dispersion or solution form.Can diverse ways for example by with an organic solvent or by active substance being dispersed or dissolved in the another kind of suitable medium (for example at room temperature or the oily matter that under the temperature that improves, exists) obtaining solid dispersion with liquid form.Be dissolved in the ordinary organic solvents by physical mixture, prepare solid dispersion (solvent method) by solvent evaporation then active substance (for example, drug substance) and carrier.Carrier is hydrophilic polymer normally.Appropriate organic solvent comprises that medicine is acceptable, the solvent of solubilized active substance, for example methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetone or its mixture.

Suitable water-solubility carrier comprises polymer, and for example Polyethylene Glycol, poloxamer, Myrj 45, poly--6-caprolactone, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinyl acetate copolymer p VP-PVA (Kollidon VA64), polymethacrylic acid polymer (Eudragit RS, Eudragit RL, Eudragit NE, Eudragit E), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxypropyl emthylcellulose (HPMC), methylcellulose and poly-(oxirane) are (PEO).

The polymer that contains acidic functionality can be suitable for solid dispersion, and it is release of active agent in preferred pH scope, thereby provides acceptable absorption at enteral.These polymer can be to be selected from following one or more: hydroxypropylmethyl cellulose phthalate (HPMCP), Opaseal (PVAP), hydroxypropyl emthylcellulose acetate succinate (HPMCAS), alginate, carbomer, carboxymethyl cellulose, methacrylic acid copolymer (Eudragit L, Eudragit S), lac, cellulosic phthalic acetate (CAP), the starch glycolate, polacrilin, methylcellulose acetic acid phthalic acid ester, hydroxypropyl acetic acid phthalic acid ester, the cellulose acetate terephthalate, benzoate and cellulose acetate benzenetricarboxylic acid ester between cellulose acetate.

The weight ratio of active substance and polymer can be at about 3: 1 to about 1: 20 scope.Certainly, also can use narrower from about 3: 1 to about 1: 5 scope, for example from about 1: 1 to about 1: 3 scope etc.

Except using method based on organic solvent, also can be by active substance being disperseed and/or being dissolved in solid dispersion or the solid solution that obtains one or more Bei Te in the carrier compositions that in controlled condensing method, uses.Can add stabilizing agent etc. to guarantee the stability of solid dispersion/solution.

Drug excipient and additive

In this manual, term " medicine can be accepted excipient " is meant any material, and it is inert on the meaning that himself does not have any therapeutic and/or prophylactic effects basically.In order to obtain to have medicine, cosmetics and/or the food compositions that to accept technical characteristic, can add these excipient.

The example that is used for the suitable excipient of compositions of the present invention or solid dosage forms comprises filler, diluent, fluidizer, disintegrating agent, binding agent, lubricant etc. or its mixture.Because compositions of the present invention or solid dosage forms can be used for different purposes, therefore consider the purposes that these are different usually and select excipient.Other pharmaceutically-acceptable excipients of be fit to using is for example acidulant, basifier, antiseptic, antioxidant, buffer agent, chelating agen, coloring agent, complexant, emulsifying agent and/or solubilizing agent, correctives and spice, wetting agent, sweeting agent, wetting agent etc.

Appropriate filler, the example of diluent and/or binding agent comprises lactose (for example spray-dired lactose, alpha-lactose, beta lactose, Tabletose , Pharmatose  at different levels, Microtose  or Fast-Floc ), microcrystalline Cellulose (Avicel  at different levels, Elcema , Vivacel , Ming Tai  or Solka-Floc ), hydroxypropyl cellulose, L-hydroxypropyl cellulose (low replacement), hydroxypropyl emthylcellulose (HPMC) (the Methocel E of Shin-Etsu company for example, F and K, MetoloseSH, for example 4, the Methocel E of 000cps level and Metolose 60 SH, 4, the Methocel F of 000cps level and Metolose 65 SH, 4,000,15,000 and 100, the Methocel K of 000cps level; With 4,000,15,000,39,000 and 100,000 grade Metolose 90 SH), methylcellulose polymer (for example, Methocel A, Me thocel A4C, Methocel A15C, Methocel A4M), hydroxyethyl-cellulose, sodium carboxymethyl cellulose, the carboxylic methylene, carboxymethyl hydroxyethyl cellulose and other cellulose derivative, sucrose, agarose, sorbitol, mannitol, dextrin, maltodextrin, starch or modified starch (comprise potato starch, corn starch and rice fecula), calcium phosphate (basic calcium phosphate for example, calcium hydrogen phosphate, the dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen etc.

The specific examples of diluent is the starch, sucrose, sugar of for example calcium carbonate, secondary calcium phosphate, tertiary calcium phosphate, calcium sulfate, microcrystalline Cellulose, powdery cellulose, glucosan, dextrin, glucose, fructose, Kaolin, lactose, mannitol, sorbitol, starch, pre-gelatinizing etc.

The specific examples of disintegrating agent is the starch, carboxymethyl starch (for example Primogel  and Explotab ) of for example alginic acid or alginate, microcrystalline Cellulose, hydroxypropyl cellulose and other cellulose derivative, cross-linking sodium carboxymethyl cellulose, crospovidone, polacrilin potassium, Explotab, starch, pre-gelatinizing etc.The specific examples of binding agent is the starch of for example Radix Acaciae senegalis, alginic acid, agar, carrageenin calcium, sodium carboxymethyl cellulose, microcrystalline Cellulose, dextrin, ethyl cellulose, gelatin, liquid glucose, guar gums, hydroxypropyl emthylcellulose, methylcellulose, pectin, PEG, polyvinylpyrrolidone, pre-gelatinizing etc.

Second compositions also can contain fluidizer and lubricant.Example comprises stearic acid, magnesium stearate, calcium stearate or other Metallic stearates, Pulvis Talci, paraffin and glyceride, light mineral oil, PEG, glyceryl behenate, silica sol, hydrogenated vegetable oil, corn starch, sodium stearyl fumarate, Polyethylene Glycol, alkyl sulfate, sodium benzoate, sodium acetate etc.

Other excipient that compositions of the present invention or solid dosage forms can comprise be for example correctives, coloring agent, mask agent, pH regulator agent, buffer agent, antiseptic, stabilizing agent, antioxidant, wetting agent, moisture regulator, surfactant, suspending agent, absorption enhancer, be used for the reagent of modified release etc.

Other additive in compositions of the present invention or the solid dosage forms can be an antioxidant, for example ascorbic acid, ascorbyl palmitate, butylatedhydroxyanisole, Yoshinox BHT, hypophosphorous acid, single thioglycerol, inclined to one side Potassium acid sulfite, propyl gallate, sodium sulfoxylate formaldehyde, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, acetic acid tocopheronic acid, hemisuccinic acid tocopherol, TPGS or other Tocopheryl derivatives etc.Carrier compositions also can contain for example stabilizing agent.The antioxidant in the carrier compositions and/or the concentration of stabilizing agent are normally from the extremely about 5%w/w of about 0.1%w/w.

The material that compositions of the present invention or solid dosage forms also can comprise one or more surfactants or have the surface activity feature.These materials participate in the sl. sol. active substance of moistening, thereby the dissolubility that improves active substance is made contributions.The suitable surfactant that is used for compositions of the present invention or solid dosage forms is a surfactant, for example hydrophobicity and/or hydrophilic surfactant active, Lipocine for example, those disclosed among the WO 00/50007 of Inc..

The specific examples of suitable surfactant is the polyethoxylated fatty acid, the for example fatty-acid monoester of Polyethylene Glycol or diester or its mixture, for example, Polyethylene Glycol and lauric acid, oleic acid, stearic acid, myristic acid, the monoesters of castor oil acid or diester, Polyethylene Glycol can be selected from PEG 4, PEG 5, PEG 6, PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20, PEG 25, PEG 30, PEG 32, PEG 40, PEG 45, PEG 50, PEG 55, PEG 100, PEG 200, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 10,000, PEG 15,000, PEG 20,000, PEG 35,000, the polyethylene glycol glycerol fatty acid ester, promptly as mentioned above but ester that exist with the form of the glyceride of single fatty acid; With for example vegetable oil such as castor oil hydrogenated, almond oil, palm-kernel oil, Oleum Ricini, almond oil, olive oil, Oleum Arachidis hypogaeae semen, the glycerol that the hydrogenated palm kernel wet goods forms, propylene glycol, ethylene glycol, PEG or sorbitol ester, polyglycerol fatty acid glyceride is as poly-tristerin, poly-olein, poly-ricinoleic acid glyceride, poly-glyceryl linoleate, methyl glycol fatty acid ester is PGML for example, propylene glycol ricinoleate etc., list and two glyceride such as glyceryl monooleate, glyceryldioleae, glycerin mono-fatty acid ester and/or dioleate, glycerol caprylate, glycerol decanoin etc.; Sterin and steroid derivant; Polyethylene Glycol sorbitan fatty acid esters (PEG-sorbitan fatty acid esters) for example has ester and the various Tween  series of the PEG of the various molecular weight of pointing out above; Polyethylene glycol alkyl ether is PEG oleyl ether and PEG lauryl ether for example; Sugar ester such as sucrose palmitic acid ester and sucrose monolaurate; Polyalkylene glycol alkyl phenol is Triton  X or N series for example; Polyox-yethylene-polyoxypropylene block copolymer is Pluronic  series, Synperonic  series, Emkalyx , Lutrol , Supronic  etc. for example.The class name of these polymer is " poloxamers ", and example relevant in this description is a poloxamer 105,108,122,123,124,181,182,183,184,185,188,212,215,217,231,234,235,237,238,282,284,288,331,333,334,335,338,401,402,403 and 407; Sorbitan fatty acid esters such as Span  series or Ariacel  series is sorbitan monolaurate, sorbitan monopalmitate, dehydrated sorbitol mono-fatty acid ester, sorbitan monostearate etc. for example; Lower alcohol fatty acid esters such as oleate, isopropyl myristic acid ester, isopropyl cetylate etc.; Ionic surfactant comprises cation, anion and amphipathic ionic surface active agent for example soap, bile salts, phospholipid, phosphate ester, carboxylate, sulfuric ester and sulphonic acid ester etc.

When surfactant or surfactant mixtures are present in compositions of the present invention or the solid dosage forms, surfactant concentrations usually about 0.1 to 80%w/w, for example from about 0.1 to about 20%w/w, from about 0.1 to about 15%w/w, about 0.5 to about 10%w/w or selectively from about 0.10 to about 80%w/w, for example from about 10 to about 70%w/w, from about 20 to about 60%w/w or within about scope of 30 to 50%w/w.

In particular aspects of the present invention, one or more medicines can be accepted at least a silicic acid or derivatives thereof or the salt of being selected from the excipient, comprise silicate, silicon dioxide and its polymer; Magnesiumaluminumsilicate and/or positive Magnesiumaluminumsilicate (magnesium aluminometasilicate), bentonite, Kaolin, magnesium trisilicate, Montmorillonitum and/or saponite, Nuesellin ^TM

Absorbent material

Material, the material of just having mentioned above for example is specially adapted to the absorbent material as the oily matter in medicine, cosmetics and/or the food.In specific embodiment, described material is as the absorbent material of the oily matter in the medicine.Material with ability of the absorbent material that serves as oily matter is also referred to as " oil absorption material ".

In addition, in this manual, term " absorption " is used for expression " absorption " and " absorption ".Be to be understood that no matter use which term, it all comprises absorption and adsorption phenomena.Term " absorbent material " has the identical meaning with " oil absorption material ".

Being suitable for being used for absorbent material of the present invention is the acceptable solid material of medicine, when as described herein testing: 1) it has 10% or more oil suction threshold value (oilthreshold value), when testing according to threshold test method disclosed herein, with when this material is used for compositions of the present invention, further satisfy i) and ii) in one or two:

I) when testing according to the release method of inspection, the hydrophobicity of compositions release at least 30% or hydrophilic or vehicle that can be miscible with water;

Ii) the compositions that exists with tablet form contains at least approximately oil absorption material of 90%w/w, and when testing according to the Ph.Eur.Disintegration method of inspection, performance is 60 minutes disintegration time at the most.

Described material is particularly suitable for especially being used as at medicine, cosmetics and/or food the absorbent material of oily matter in medicine.

It is very important that oil absorption material satisfies at least two checks.One of them check is enforceable, promptly must satisfy threshold test (Threshold Test).These checking measurements oil absorption material can absorb how many oily matters, can keep simultaneously suitable mobile feature again.It is very important that the oil absorption material that is used for the present invention (absorbing or not absorbing under the oil condition) has suitable flowability, thus its can be easily with other mixed with excipients and/or further be processed into compositions and do not have and significantly relate to for example the adherent problem of equipment to using.In material and method part, describe described method of inspection below, and explanation how to carry out described check is provided.Threshold test comprises the flowability of the solid material of determining to be loaded with different oil masses.

From as seen last, the oil suction threshold value generally must surpass 10%, it is about at least 15% that oil absorption material has usually, for example about at least 20%, about at least 25%, about at least 30%, about at least oil suction threshold value of 35%, about at least 40% or about at least 45%.

Being particularly suitable for material of the present invention is Aeropearl 300, has very high about 60% oil suction threshold value.Therefore, in particular of the present invention, use and have at least 50% material of about at least 55% or about at least 60% oil suction threshold value for example.

In addition, be used for oil absorption material of the present invention and must satisfy at least one other check, promptly discharge check (Release Test) and/or disintegrate check.

Discharge checking measurements oil absorption material when contacting and discharge the ability that is absorbed into the oil in the described material with water.This ability is extremely important, especially comprises under the situation of active substance at oily matter.If oil absorption material can not discharge oil, the principal risk that so just exists active substance seldom to discharge to degree from material from material.Therefore, for example relating to, the problem of the bioavailability of relatively poor adsorptivity etc. will take place in these cases.

Discharging test requirements is when testing as method described herein, it is about at least 30% that the solid drugs acceptable material discharges, for example about at least 35%, about at least 40%, about at least 45%, about at least oil of 50%, about at least 55% or about at least 60%.In the example from here, suitable oil absorption material such as Aeroperl 300 have much higher release.Therefore, in the particular of the present invention, when testing as method described herein, the solid drugs acceptable material discharges about at least 65% for example about at least oil of 70%, about at least 75% or about at least 80%.

Not on the solid material of particle form but carry out the disintegrate check on the tablet of solid materials preparation.Requirement about disintegrate is very important, its objective is and guarantee when solid dosage forms comprises solid material, described solid material does not provide undesired characteristic to dosage form, for example makes active substance contained in the dosage form produce undesired disintegrate and bioavailability characteristics.Be suitable for material of the present invention for some, may suppress the tablet that himself contains the 100%w/w solid material.If in this case, on this tablet, test so.Yet, face and may have a situation about only being difficult to from the solid materials preparation tablet.In these cases, may add the pharmaceutically-acceptable excipients that is generally used for preparing compressed tablets, its concentration can reach 10%w/w or lower.The example that suitable medicine can be accepted excipient comprises filler, diluent, binding agent and lubricant.Yet, should avoid using the excipient that generally is classified as disintegrating agent.

Therefore, when testing as method described herein, the solid drugs acceptable material that is used for tablet form of the present invention should have 1 hour disintegration time at the most, when testing according to the Ph.Eur.Disintegration method of inspection, tablet contains the about 90%w/w or the medicine acceptable material of many cases such as about 92.5%w/w or more, about 95%w/w or more, about 97.5%w/w or more or about 100% more.

In other embodiments, the solid drugs acceptable material that exists with tablet form when as described herein testing has about at the most 50 minutes disintegration time, for example about at the most 40 minutes, about at the most 30 minutes, about at the most 20 minutes, about at the most 10 minutes or about at the most 5 minutes, when testing according to the Ph.Eur.Disintegration method of inspection, tablet contains about 90%w/w or more many cases such as about 92.5%w/w or more, about 95%w/w or more, approximately 97.5%w/w or more or about 100% medicine acceptable material.

In specific embodiment, the solid material that is used as absorbent material satisfies all three checks.Therefore, when testing as method described herein, the solid drugs acceptable material

I) have about at least 10%, for example about at least 15%, about at least 20%, about at least 25%, about at least 30%, about at least 35%, about at least 40%, about at least 45%, about at least oil suction threshold value of 50%, about at least 55% or at least 60%

Ii) discharge about at least 30%, for example about at least 35%, about at least 40%, about at least 45%, about at least 50%, about at least 55%, about at least 60%, about at least 65%, about at least oil of 70%, about at least 75% or about at least 80% and

Iii) tablet form has 1 hour for example about at the most 50 minutes at the most, about 40 minutes at the most, about 30 minutes at the most, about 20 minutes at the most, about 10 minutes or about at the most 5 minutes disintegration time at the most, when testing according to the Ph.Eur.Disintegration method of inspection, tablet contains about 90%w/w or more, the medicine acceptable material of for example about 92.5%w/w or more, about 95%w/w or more, about 97.5%w/w or more or about 100%.

Other particular of the present invention is such embodiment, wherein when as described herein testing, is used as the solid drugs material of absorbent material in compositions of the present invention

I) has about at least 55% oil suction threshold value;

When method as described herein is tested, the solid drugs material

Ii) discharge about at least 75 oil; And/or

When method as described herein is tested, the solid drugs material of tablet form

Iii) have about at the most 10 minutes disintegration time, when testing according to the Ph.Eur.Disintegration method of inspection, tablet contains the medicine acceptable material of about 97.5%w/w.

In compositions of the present invention, be used as the granular materials that the solid drugs acceptable material of absorbent material normally exists with for example forms such as powder, granule, granule, graininess.

These granular materialss that are suitable as oil absorption material generally have about 0.15g/cm ³Or more many cases as at least about 0.20g/cm ³Or about at least 0.25g/cm ³Bulk density.

In addition, oil absorption material generally has at least approximately 100g oil/100g, for example at least approximately 150g oil/100g, at least approximately 200g oil/100g, at least approximately 250g oil/100g, at least approximately 300g oil/100g or at least about oily absorption value of 400g oil/100g medicine acceptable material.Determine oily absorption value according to the described method of experimental section herein.

The common trait that it has been observed by the present inventors that the material that some are suitable as oil absorption material is to have relatively large surface area.Therefore, the medicine acceptable material as oil absorption material of the present invention can have 5m at least ²The for example about at least 25m of/g ²/ g, about at least 50m ²/ g, about at least 100m ²/ g, about at least 150m ²/ g, about at least 200m ²/ g, about at least 250m ²/ g or about at least 275m ²The BET surface area of/g.

As mentioned above, a feature that is used as the medicine acceptable material of oil absorption material of the present invention is that it keeps good flowability, even it has loaded oily matter.Therefore, loaded 25%w/w or more, for example the flowability of the medicine acceptable material of 30%w/w or more, 40%w/w or more, 45%w/w or more, 50%w/w or more, 55%w/w or more, 60%w/w or more, 65%w/w or more or about 70%w/w viscoleo generally satisfies the requirement of Ph.Eur..

Clearly, oil absorption material can comprise the silicic acid or derivatives thereof or salt (for example silicon dioxide or its polymer) can be accepted excipient as medicine.Yet, depending on used quality, silicon dioxide can be that lubricant or its can be oil absorption materials.The quality that satisfies latter's function is seemingly most important.

In specific embodiment, compositions of the present invention or solid dosage forms comprise pharmaceutically-acceptable excipients, and described excipient is the silica product that has corresponding to the characteristic of Aeroperl  300.

The purposes of the oil absorption material in compositions of the present invention or the dosage form is highly beneficial in the preparation of medicine, cosmetics, nutrient and/or food compositions, and wherein said compositions comprises oily matter.One of them favourable aspect is possible be integrated into a large amount of relatively oily matters but still material with solid form.Therefore, the oil absorption material of the application of the invention may prepare the solid composite with higher relatively oily matter heap(ed) capacity.At pharmaceutical field, it is favourable a large amount of relatively oily matters can being integrated in the solid composite, particularly (for example do not have suitable water solublity at active substance, relatively poor water solubility), under the situation of the stability (promptly in aqueous medium, degrading) in the aqueous medium, oral administration biaavailability characteristics such as (for example low bioavailability), or when the release of wanting the active substance in the modifying composition with controlled, that postpone, that continue and/or that pulse the is sent situation that obtains active substance under.Therefore, in specific embodiment, it is used for pharmaceutical compositions.

Be used for being manufactured into the general about 5%w/w or more of absorption of oil absorption material of solid composite, for example about 10%w/w or more, about 15%w/w or more, about 20%w/w or more, about 25%w/w or more, about 30%w/w or more, about 35%w/w or more, about 40%w/w or more, about 45%w/w or more, about 50%w/w or more, about 55%w/w or more, about 60%w/w or more, about 65%w/w or more, about 70%w/w or more, about 75%w/w or more, about 80%w/w or more, about 85%w/w or more, approximately 90%w/w or more or about 95%w/w or more oil or oily matter, and still be solid material.

Oily matter

Importance of the present invention is compositions or the solid dosage forms that comprises oily matter.

In this manual, term " oily matter " broadly comprise oil, paraffin, generally in pharmaceutical industries as the semisolid material and the material of solvent (for example organic solvent) or cosolvent, it is the therapeutic and/or the preventative active substance of liquid form that described term is also included within the ambient temperature; Described in addition term comprises Emulsion such as microemulsion and nano-emulsion (nanoemulsion) and suspending agent.Can absorbed oil and oil sample material (because the reason of practice, maximum temperature is about 250 ℃) under the temperature of environment or raising generally be liquid.It can be hydrophilic, lipophilic, hydrophobic and/or amphipathic nature material.

Be suitable for oily matter of the present invention and be having the material or the material of about at least 10 ℃ and about at the most 250 ℃ fusing point.

In particular of the present invention, oily matter has about 5 ℃ or higher, for example about 10 ℃ or higher, about 15 ℃ or higher, about 20 ℃ or higher or about 25 ℃ or higher fusing point.

In other embodiments of the present invention, oily matter has about at least 25 ℃ for example about at least 30 ℃, about at least 35 ℃ or about at least 40 ℃ fusing point.Because the reason of practice, fusing point is generally may not can too high, and therefore, oily matter has about at the most 300 ℃ usually, for example, and about at the most 250 ℃, about 200 ℃ at the most, about 150 ℃ or about at the most 100 ℃ fusing point at the most.If fusing point is higher, then when comprising therapeutic and/or preventative active substance, high relatively temperature just may promote for example oxidation of active substance or the degraded of other type.

In this manual, determine fusing point by DSC (difference formula scanning calorimetry).Fusing point is confirmed as the linear DSC curve that increases and temperature axis intersects the temperature that (further detailed content is referring to Fig. 1) locates.

Noticeable oily matter generally is the material that is used as so-called melt adhesive (melt binders) or solid solvent (with solid dosage form) or is used as cosolvent or composition in drug manufacture in the medicine that use the part.It can be hydrophilic, hydrophobic and/or have surface active characteristic alive.General hydrophilic and/or hydrophobic oily matter are suitable for containing the production of the pharmaceutical composition of therapeutic and/or preventative active substance, described active substance has low relatively water solublity, and/or the release of active substance from pharmaceutical composition is being designed to immediately or is being fit to use described oily matter during the release of non-modification.On the other hand, the hydrophobicity oily matter generally is used to modify the production of the pharmaceutical composition of release.The consideration that simplification provides above is illustrating General Principle, but in many cases, the combination of other oily matter and other purpose is relevant, thereby top example never should limit the present invention.

Usually, suitable hydrophilic oily matter is selected from: PTMEG, for example, Polyethylene Glycol, polypropylene glycol; Polyoxyethylene; Polyoxypropylene; Poloxamer and its mixture, or it can be selected from: xylitol, sorbitol, potassium sodium tartrate, three behenic acid sucrose, glucose, rhamnose, lactose, behenic acid, hydroquinone monomethyl ether, sodium acetate, fumaric acid ethyl ester, myristic acid, citric acid, Gelucire 50/13 or other Gelucire type, for example Glucire44/14 etc., Glucire 50/10, Glucire 62/05, Sucro-ester 7, Sucro-ester11, Sucro-ester 15, maltose, mannitol and its mixture.

Suitable hydrophobicity oily matter can be selected from straight chain saturation alkane, sorbitan ester, paraffin; Fat and oil is cupu oil, Adeps Bovis seu Bubali, leaf fat, PTMEG ester for example; Higher fatty acids for example stearic acid, myristic acid, Palmic acid, higher alcohol for example spermol, stearyl alcohol, low melt wax for example glyceryl monostearate, glyceryl monooleate, hydrogenated tallow, myristyl alcohol, octadecanol, monoglyceride replacement and/or non-replacement, replacement and/or non-substituted glycerol diester, triglyceride replacement and/or non-replacement, yellow beeswax, cera alba, Brazil wax, castor wax, Japan wax, acetylation monoglyceride; NVP polymer, PVP polymer, acrylic polymer, or its mixture.

In an interesting embodiment, oily matter is to have mean molecule quantity approximately from 400 to about 35,000, for example from about 800 to about 35,000, from about 1,000 Polyethylene Glycol to about 35,000 scopes, for example Polyethylene Glycol 1,000, Polyethylene Glycol 2,000, Polyethylene Glycol 3,000, Polyethylene Glycol 4,000, Polyethylene Glycol 5,000, polyethylene glycol 6000, Polyethylene Glycol 7,000, Polyethylene Glycol 8,000, Polyethylene Glycol 9,000, Polyethylene Glycol 10,000, Polyethylene Glycol 15,000, Polyethylene Glycol 20,000, or Polyethylene Glycol 35,000.In some cases, can use the poly-ethanol of molecular weight from about 35,000 to about 100,000.

In another interesting embodiment, oily matter is to have from about 2,000 to about 7,000,000, for example, from about 2,000 to about 100,000, from about 5,000 to about 75,000, from about 10,000 to about 60,000, from about 15,000 to about 50,000, from about 20,000 to about 40,000, from about 100,000 to about 7,000,000 for example, from about 100,000 to about 1,000,000, from about 100,000 to about 600,000, from about 100,000 to about 400, the poly(ethylene oxide) of 000 or from about 100,000 to about 300,000 molecular weight.

In another embodiment, oily matter is a poloxamer, for example for example Pluronic  and/or Tetronic  series of the block copolymer of poloxamer 188, poloxamer 237, poloxamer 338 or poloxamer 407 or other oxirane and expoxy propane.The suitable block copolymers of Pluronic  series comprises having about 3,000 or more, for example from about 4,000 to about 20,000 molecular weight and/or from about 200 to about 4,000cps be for example from about 250 to about 3, the polymer of the viscosity of 000cps (Brookfield).Suitable example comprises Pluronic  F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123, F127,10R8,17R8,25R5,25R8 etc.The block copolymer of suitable Tetronic  series comprises having about 8,000 or higher for example from about 9,000 to about 35,000 molecular weight and/or from about 500 to about 45,000cps is the polymer of from about 600 to about 40,000 viscosity (Brookfield) for example.Under 60 ℃, determine at outdoor relaxing the bowels with purgatives of warm nature it is the above-mentioned viscosity of the material of pasty state, determine it at room temperature is the above-mentioned viscosity of solid material down at 70 ℃.

Oily matter also can be sorbitan ester, for example sorbitan diisopstearate, the sorbitan dioleate, sorbitan monolaurate, sorbitan list isostearate, dehydrated sorbitol mono-fatty acid ester, the sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquialter isostearate, NOFABLE SO-992 NOFABLE SO-902, the sorbitan sesquistearate, sorbitan three isostearates, sorbitan trioleate, sorbitan tristearate or its mixture.

Certainly oily matter also can comprise the mixture of different oily matters, for example mixture of hydrophilic and/or hydrophobic material.Other suitable oily matter can be solvent or semisolid excipient, mixing-in fat material as propylene glycol, polyglycolyzed glyceride (comprising Gelucire 44/14), plant origin comprises cupu oil, Brazil wax, vegetable oil such as almond oil, Oleum Cocois, Semen Maydis oil, cotton seed oil, Oleum sesami, soybean oil, olive oil, Oleum Ricini, palm-kernel oil, Oleum Arachidis hypogaeae semen, vegetable oil, Semen Vitis viniferae wet goods, and hydrogenant vegetable oil is hydrogenated groundnut, hydrogenated palm kernel oil, hydrogenation cotton seed oil, oil with hydrogenated soybean, castor oil hydrogenated, hydrogenated coconut oil for example; The fat material of natural animal origin comprises Cera Flava, lanoline, aliphatic alcohol, comprises spermol, octadecanol, dodecanol, myristyl alcohol, palmityl alcohol, stearic acid fat alcohol; Ester, comprise tristerin, ethylene glycol stearate, ethyl oleate, isopropyl myristate; The semi-synthetic glyceride of liquid ester exchange comprises Miglycol 810/812; Amide or fatty alkanol amide comprise polyglycerin ester, the polyglycerol polyricinoleate of diglycollic amide, acetic acid esters of mono and acetic acid two glyceride, citric acid monoglyceride and citric acid two glyceride, lactic acid esters of mono and lactic acid two glyceride, monoglyceride and diglyceride, the fatty acid of stearmide ethanol, fatty coconut acid, propylene glycol ester, sorbitan monostearate, sorbitan tristearate, sodium stearoyl lactate, CSL, diacetyl tartaric acid monoglyceride and the diglyceride etc. of fatty acid.

Pharmaceutical composition of the present invention or solid dosage forms can have about 5%w/w or more in described compositions or dosage form, for example about 10%w/w or more, about 15%w/w or more, about 20%w/w or more, about 25%w/w or more, about 30%w/w or more, about 35%w/w or more, about 40%w/w or more, about 45%w/w or more, about 50%w/w or more, about 55%w/w or more, about 60%w/w or more, about 65%w/w or more, about 70%w/w or more, about 75%w/w or more, about 80%w/w or more, about 85%w/w or more, approximately 90%w/w or more or about 95%w/w or more oily matter concentration.

In specific embodiment, the concentration of the oily matter of compositions of the present invention or solid dosage forms about 20% to about 80%w/w, within for example about scope of 25% to about 75%w/w.

One of them favourable aspect is possible integrate a large amount of relatively oily matters but still the maintenance solid material.Therefore, the oil absorption material of possible the application of the invention prepares the solid composite with high relatively oily matter amount.In pharmaceutical field, it is favourable a large amount of relatively oily matters can being integrated in the solid composite, especially (for example do not have suitable water solublity at active substance, relatively poor water solubility), under the situation of the stability (promptly in aqueous medium, degrading) in the aqueous medium, Orally administered bioavailability characteristics such as (for example low bioavailability), or when the release of wanting the active substance in the modifying composition with controlled, that postpone, that continue and/or that pulse the is sent situation that obtains active substance under.

Other favourable aspect is that the granular materials that obtains is a form of free flowing powders, therefore is easy to be processed into for example solid dosage forms, for example tablet, capsule or sachet.Usually, granular materials has and is adapted to pass through direct compacting and need not to add the characteristic that a large amount of other additives are produced tablet.The method of inspection of suitable check granular materials flowability is the method that is described among the Ph.Eur., and its flow velocity of measuring the funnel of material by having 10.0mm diameter ozzle (hole) is checked flowability.

In embodiments of the invention, form that can solid dispersion to small part shellfish spy is present in the compositions, and described solid dispersion comprises molecular dispersoid and solid solution.Usually, wherein have 10% or more, for example 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more many cases as 95% or the active substance of more or about 100%w/w be present in the compositions with dissolved form.

Solid dosage forms

Pharmaceutical composition of the present invention exists with particulate form and can so use.Yet, in many cases, compositions is comprised that with the form of granule, pellet, microsphere, nano-particle etc. or with solid dosage forms there is more apparent convenience in the form of tablet, tablet, pearl, capsule, crystal grain, pill, granule, granule, powder, pellet, sachet, lozenge, tablet etc.

Solid dosage forms of the present invention can be the dosage form of single unit or its can contain multiple single unit for example many storehouses (polydepot) dosage form of pellet, pearl and/or granule exist.

Common pharmaceutical composition of the present invention or solid dosage forms are used by oral, oral cavity or sublingual administration approach.

The present invention also relates to the above-mentioned form of expression.Be used within the scope of the present invention with the compositions/solid dosage forms of rapid release, slow release or modified delivery mode release of active agent.

Solid dosage forms of the present invention comprises the pharmaceutical composition of above-mentioned particle form.Of the present invention this main aspect disclosed details and the details others that have been applied to invent with having done necessary correction.Therefore, describe and/or increase, the change of bioavailability parameter, the reduction of unfavorable food effect and the characteristics such as release of one or more Bei Te at the bioavailability of the pharmaceutical composition of particle form of claiming are equally applicable to solid dosage forms of the present invention herein.

Usually, the concentration of the pharmaceutical composition that exists with particle form is from about 5 to 100%w/w, for example within the scope of the dosage form from about 10% to about 90%w/w, from about 15% to about 85%w/w, from about 20% to about 80%w/w, from about 25% to about 80%w/w, from about 30% to about 80%w/w, from about 35% to about 80%w/w, from about 40% to about 75%w/w, from about 45% to about 75%w/w or from about 50% to about 70%.In embodiments of the invention, the concentration of the pharmaceutical composition that exists with particle form is the 50%w/w of dosage form or more.

Solid dosage forms of the present invention is very stable.For example, when measuring after storing three months under about 40 ℃ temperature and under about 75% the relative humidity, with respect to the amount before storing, Bei Te exists with at least 90% or 95% or 100% amount at least at least.Physical stability is also very high, as seeing from the following examples.

Process granular materials of the present invention by technology well known to those skilled in the art and can obtain solid dosage forms of the present invention.Usually, this comprises that one or more medicines of mentioning of further interpolation can accept excipient herein.

Compositions of the present invention or solid dosage forms can be designed to discharge in any suitable manner one or more Bei Te, as long as keep the increase of bioavailability.Therefore, release of active agent is to obtain the initiation of increase relatively apace, and its mode that can defer to zero or first order kinetics uses or it can in check or modified mode discharge to obtain predetermined release mode.Ordinary preparation also within the scope of the invention.

Compositions of the present invention or solid dosage forms also can be wrapped by film coating, enteric coating, modified release coating (release coating), protectiveness coating, antiseized coating etc.

Also can wrap by to obtain suitable characteristic the characteristic that for example relevant active substance discharges to solid dosage forms of the present invention.Can use coating or its to can be used for many storehouses dosage form or its single unit to the dosage form (for example, tablet, capsule) of single unit.

Suitable coating material is a methylcellulose for example, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, acrylate copolymer, ethyl cellulose, cellulosic phthalic acetate, Opaseal, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol, sodium carboxymethyl cellulose, cellulose ethanoate, cellulosic phthalic acetate, gelatin, methacrylic acid copolymer, Polyethylene Glycol, lac, sucrose, titanium dioxide, Brazil wax, microwax, zein.

Can in coating material, add plasticizer and other composition.Also identical or different active substance can be added coating material.

Pharmaceutical composition of the present invention or solid dosage forms are used for discharging Bei Te with suitable manner through design.Specific release mode is disclosed in the additional claim of quoting.Also provide specific dependent absorption pattern herein.

Other embodiment of the present invention

In yet another aspect, the present invention relates to the solid composite medicament that comprises one or more Bei Te and one or more oily matters that exists with particle form, described compositions has the proper flow of determining according to the method for describing among the Ph.Eur., determines described flowability by measuring compositions by the flow velocity of the funnel that has the 10.0mm pipe and chew.For fear of the adhesion to production and/or filler equipment, it is very important that granular materials flows swimmingly.This feature also is very important under the situation of the formulation example of wanting granular materials further is processed into other type such as solid dosage forms.

Another aspect of the present invention relates to the solid composite medicament that comprises one or more Bei Te, one or more oily matters and one or more oil absorption materials that exists with particle form, when testing according to threshold test method herein, its i) have 10% or more oil suction threshold value, and satisfy in following at least one:

Ii) when testing according to release method of inspection herein, discharge at least 30% oil and

Iii) tablet form has 1 hour disintegration time at the most, and when testing according to the Ph.Eur.Disintegration method of inspection, tablet contains about 90%w/w or more oil absorption material.In some cases, found absorbent material is integrated into that the oily matter of high concentration is favourable to enable for example to obtain in the compositions.Have at oily matter under the situation of about at the most 250 ℃ fusing point, it can be particularly suitable integrating absorbent material.Provide the suitable oily matter and the example of absorbent material herein.

In other particular, Bei Te is so that the form existence of small part solid dispersion (comprising solid solution).

In other embodiments, the present invention relates to the solid composite medicament or the solid dosage forms that exist with particle form, it comprises one or more and is dissolved in Bei Te in one or more oily matters.Aspect this, Bei Te is present in the particulate composition with the form of solid solution and can detects existing of solid solution by the DSC method of inspection of mentioning herein.Aspect this, randomly under the temperature that improves, mixture is sprayed on the carrier of describing herein prepare particulate composition by Bei Te being dissolved in oily matter neutralization (randomly add other active substance and/or one or more medicines can accept excipient after).Preferably, the concentration of oily matter is about 10%w/w at least.

Material and method

Material

Fenofibrate (providing) by Sigma

Lactose monohydrate 200 orders (from DMV)

Granulating silicon dioxide, Aeroperl ^300, (Degussa)

Polyethylene glycol 6000, Pluracol ^E6000 (from BASF)

Poloxamer 188, Pluronic ^, F-68 (from BASF)

Glyceryl monostearate, Rylo ^, MD 50, (from Danisco Cultor), Ph.Eur.

Avicel PH200 (microcrystalline Cellulose) (from FMC)

Magnesium stearate

Available dissimilar polymer for example hydroxypropyl emthylcellulose acetate succinate (Aqoat), cellulosic phthalic acetate CAP, hydroxypropyl methylcellulose phthalate HPMCP or methacrylic acid copolymer for example Eudragit L30D, Eudragit100/S, Eudragit100/L to tablet, capsule or granule bag by enteric coating.

The Tricor tablet formulation

TRICORN  tablet is to contain fenofibrate, can be used for Orally administered tablet, and every tablet contains 54mg or the micronized fenofibrate of 160mg.

Tablet contains following non-active ingredient: silica sol, crospovidone, lactose monohydrate, lecithin, microcrystalline Cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium lauryl sulphate, sodium stearyl fumarate, Talcum, titanium dioxide, Xanthan gum, colorant.Tricor  is as the fat regulator.The recommended dose of the Tricor  that takes in food is 54-160mg/ days.With 54 and the intensity of 160mg Tricor  is provided tablet, but with 67 and the intensity of 200mg Tricor  is provided capsule.Tablet has higher bioavailability than capsule.Other trade name is Lipanthyl , Lipantil  or Catalip .

The Lipanthyl preparation

By with fenofibrate and solid surface activity composition altogether micronize with produce two kinds of compositions closely and the mixture of fine dispersion, thereby generation Lipanthyl  67M.

Equipment

Laboratory scale fluid unit: Strea-1.

The melt insertion unit is the prototype that the unit that separates by the source of the gas that is used to add thermal foggers, head tank and feed pipe constitutes.Artificial screening granule and in the Turbula blender with super granule (extragranular) mixed with excipients.

On single punching punch press Diaf TM20, carry out tablet press.

Method

According to method of the present invention, with the fenofibrate medicine dissolution the fusing vehicle in and following being applied on the particulate vector:

Vehicle is melted at the beaker that places microwave oven.Beaker is transferred to is furnished with in heating plate magnetic stirring apparatus, that temperature is controlled.Slowly fenofibrate is being dissolved in the melt under the effect in magnetic agitation under 75 ℃ of temperature.The solution of heat is transferred in the head tank so that the carrier in the fluid bed is carried out melt spray.Release particles product and the sieve by 0.7mm or 1.0mm carry out artificial screening from fluid bed.The product of screening was mixed in the Turbula blender 0.5 minute with magnesium stearate.If must integrate super granule phase, will surpass the premixing 3 minutes in the Turbula blender of granule and granule.

On single punching punch press Diaf TM20, carry out tablet press.

Threshold test

Check comprises according to the method for describing among the Ph.Eur. determines flowability of the present invention by the flow velocity of measuring the funnel of material by having 10.0mm diameter ozzle.

With Viscoleo (medium chain triglyceride MCT; Miglyol 812N is from Condea) be added to the pedestrian worker that goes forward side by side in the solid drugs acceptable material of 100g and mix, described material is the material that accepts inspection with regard to purposes of the present invention.Sieve by 0.3mm screens the mixture of gained to guarantee the mixture of homogeneous.The logistics of the mixture of 100g adds oil step by step till can not flow through the mouth of pipe.Had high cumulative volume (for example as Aeroperl300) if try material, when these mixture of check, only use the 50g mixture.Can make material keep mobile maximum oil concentration to be called as threshold value (representing) with %w/w.

Discharge check

14.3mg is dissolved in the 50.0g viscoleo (fractionated medium chain triglyceride) from the fat-soluble colorant Sudan II (BDH Gur ) that BDH VWR International obtains.

10g oil is added in the 10.0g solid drugs acceptable material and mixes until oil be absorbed into solid material fully, described solid drugs acceptable material is the material that accepts inspection with regard to purposes of the present invention.Sieve by 0.3mm screens mixture to obtain the mixture of homogeneous then.

Be transferred to the 1.00g mixture in the centrifuge tube and add 3.00ml water.Mixing suspension is 1 hour in blood sample turner (blood sample turner), under 5000rpm centrifugal 10 minutes then.With oil be transferred to carefully mutually in the beaker with the top of water, under 80 ℃ in baking oven transpiring moisture until constant weight.Weight based on water evaporation back residue is calculated the oil mass that discharges from solid material.

The disintegrate check

Determine disintegration time according to the method for describing among the Ph.Eur..

The dissolubility check

Use agitating device (paddle apparatus) to test according to Ph.Eur 2.9.3.The HPLC that use has the UV detection carries out quantitatively.

Medium: 900ml contains the water of 0.75% sodium lauryl sulphate (SLS)

Rotary speed: 50rpm

Temperature: 37 ℃

Sample time: 10,20,30,45 and 60 minutes

Accept standard: at 45 minutes time＞75%

Determining of bulk density

By pouring the described powder of 100g in 250ml graduated cylinder measurement volumes density.Bulk density is decided to be the bulk density of representing with g/ml through patting.Determine according to .Ph.Eur. (apparent volume).

Determining of oil absorption value

Be added to being subjected to of clearly measuring by the viscoleo that will clearly measure (10g) and determine oily absorption value in the reagent thing acceptable material (100g).When further adding 10g oil caused producing the material with inappropriate mobile character, promptly material did not satisfy when (flowability is checked according to Ph.Eur.; Referring to top threshold test) need satisfy when testing require the time, reached oily absorption value (being expressed as g viscoleo/100g material).

Determining of BET surface area

Used equipment is Micromertics Gemini 2375.Used method is the USP cubage measuring method of determining according to based on multiple spot.

Mobile determines

Flow velocity according to the funnel of the method for describing among the Ph.Eur. by measuring the ozzle of material by having the 10.0mm diameter is determined flowability.

Determining of weight change

The tablet for preparing among the embodiment herein accepted the weight change check carried out according to Ph.Eur..

Determining of average tablet hardness

The tablet for preparing among the embodiment is herein accepted the tablet Hardness Surveillance, use Schleuniger Model 6D instrument and test according to the general remark of instrument.

Determining of solid solution

According to the present invention, Bei Te is dissolved in the vehicle.Particularly, relate to the check of differential scanning calorimetry.Mixture (forming the back at the supposition solid solution) to particulate composition, solid dosage forms or vehicle and Bei Te is tested.Use is connected to the standard DSC equipment on the PC.

Sample size: 10mg is in aluminum pot

The rate of heat addition: 5 ℃/minute, from 27 ℃ to 110 ℃

Assessment: if do not observe Bei Te endothermic peak (endoterm peak) and if compare with independent vehicle, fusion is not significantly skew at interval, thinks what Bei Teshi existed with dissolved state or non-crystal state so.

How much weight mean diameter dgw determine

By in air, using laser diffraction dispersion method to determine weight mean diameter how much to the granule (or parent material) that obtains.In Sympatec Helos equipment, under 1 crust dispersion pressure, measure the distribution of described equipment records same sphere diameter.This fitting of distribution becomes volume-big or small logarithm normal distribution." how much weight mean diameters " that herein uses is meant the average diameter of volume-big or small logarithm normal distribution.

Research in the body in the beagle (Beagle dog)

For determining with respect to commercially available fenofibrate tablet formulation is Tricorn , and the bioavailability of compositions of the present invention uses beagle to carry out research in the body.

Use the work that experimentizes of 4 male beagles, each bar Canis familiaris L. body weight 12-18kg (starting weight) in Denmark.Carry out described research with research mode that open, nonrandom, that intersect.Each animal is the contrast of himself.Use the oral dose of fenofibrate according to following data.Preceding in dispenser (arbitrarily obtaining water) with the Canis familiaris L. overnight fasting and at back 5 hours feedings of dispenser (arbitrarily obtaining water).Take for each Canis familiaris L. and do not consider the body weight of Canis familiaris L. with the fenofibrate of clear and definite dosage.

Collect blood sample on the time point below in the jugular vein outside: before the dispenser, after the dispenser 1,1.5,2,3,4,6,8,12 and 24 hour.Collect 4ml blood, mix with EDTA, sample freezing (80 ℃).Use is at line drawing LC/MS analyzing blood sample, and the result represents with mg/mL.Use pharmacokinetics software WinNonlin  (Pharsight, California; USA) handle the whole blood concentration feature of determined fenofibrate to calculate pharmacokinetic parameter.When needing, all data are carried out dose titration.

Being used to illustrate embodiments of the invention does not below limit the scope of the invention.In embodiment 1-7 illustration pharmaceutical composition of the present invention and dosage form.The extracorporeal dissolution-ability assay of dosage form of the present invention is shown among the embodiment 8.The stability test of dosage form of the present invention the results are shown among the embodiment 9.In embodiment 10-12, can find and compare result of study (plasma concentration) in the body in the beagle.

Embodiment 1

Release tablet immediately with bioavailability of raising

Fenofibrate is dissolved under 75 ℃ in polyethylene glycol 6000 and the poloxamer 188 (ratio of 70: 30 w/w) with 17% concentration.Under 75 ℃, the solution of 244g fusion is injected on the 200g lactose among the fluid bed Strea-1.Sieve screening granular product by 0.7mm was also mixed 0.5 minute with magnesium stearate in the Turbula blender.Mixture is pressed into the tablet (tablet that 540mg is cup-shaped has chemical compound (tabletwith compound cup shaped)) that 10mm has 50mg intensity.

Material	％	mg
			Fenofibrate	9.30	50.00
Lactose	44.78	240.64
			PEG 6000	31.80	170.88
Poloxamer 188	13.63	73.24
			Magnesium stearate	0.50	2.69
Amount to	100.00	537.45

Average disintegration time: 26 minutes, hardness: 45N

Embodiment 2

Release tablet immediately with bioavailability of raising

Described in embodiment 1, the 10mm tablet of preparation 50mg intensity (tablet that 540mg is cup-shaped has chemical compound) and following composition:

Material	％	mg
			Fenofibrate	9.30	50.00
Lactose	44.78	240.64
			PEG 6000	45.43	244.12
Magnesium stearate	0.50	2.69
			Amount to	100.00	537.45

Average disintegration time: 21 minutes, hardness: 55N

Embodiment 3

Release tablet immediately with bioavailability of raising

Described in embodiment 1, the 10mm tablet of preparation 50mg intensity (tablet that 540mg is cup-shaped has chemical compound) and following composition:

Material	％	mg
			Fenofibrate	9.30	50.00
Lactose	44.78	240.64
			PEG 4000	31.80	170.88
Poloxamer 188	13.63	73.24
			Magnesium stearate	0.50	2.69
Amount to	100.00	537.45

Average disintegration time: 22 minutes, hardness: 48N

Embodiment 4

Release tablet immediately with bioavailability of raising

Fenofibrate is dissolved in the Macrogol 4000 under 75 ℃ with 17% concentration.Under 75 ℃, the solution of 244g fusion is injected on the 200g lactose among the fluid bed Strea-1.Sieve screening granular product by 0.7mm was also mixed 0.5 minute with magnesium stearate in the Turbula blender.Mixture is pressed into 10mm tablet (tablet that 540mg is cup-shaped has chemical compound) with 50mg intensity.

Material	％	mg
			Fenofibrate	9.30	50.00
Lactose	44.78	240.64
			PEG 4000	45.43	244.12
Magnesium stearate	0.50	2.69
			Amount to	100.00	537.45

Average disintegration time: 21 minutes, hardness: 55N

Embodiment 5

Release tablet immediately with bioavailability of raising

Fenofibrate is dissolved in the Macrogol 4000 under 75 ℃ with 17% concentration.Under 75 ℃, the solution of 244g fusion is injected on the mixture of 190g lactose among the fluid bed Strea-1 and 10g sodium lauryl sulphate (SDS).Sieve screening granular product by 0.7mm was also mixed 0.5 minute with magnesium stearate in the Turbula blender.Mixture is pressed into 10mm tablet (tablet that 540mg is cup-shaped has chemical compound) with 50mg intensity.

Material	％	mg
			Fenofibrate	9.30	50.00
Lactose	42.54	228.61
			SDS	2.23	12.03
PEG 4000	45.43	244.12
			Magnesium stearate	0.50	2.69
Amount to	100.00	537.45

Average disintegration time: 18 minutes, hardness: 65N

Embodiment 6

Release tablet immediately with bioavailability of raising

Fenofibrate is dissolved under 75 ℃ in Macrogol 4000 and the poloxamer 188 (70: 30 w/w ratios) with 30% concentration.Under 75 ℃, the solution of 466g fusion is injected on the 200g Aeroperl 300 among the fluid bed Strea-1.Sieve screening granular product by 0.7mm was also mixed 0.5 minute with magnesium stearate in the Turbula blender.Mixture is pressed into 13.5mm tablet (tablet that 720mg is cup-shaped has chemical compound) with 150mg intensity.

Material	％	mg
			Fenofibrate	20.90	150.00
Aeroperl 300	29.85	214.29
			PEG 6000	34.13	245.00
Poloxamer 188	14.63	105.00
			Magnesium stearate	0.50	3.59
Amount to	100.00	717.88

Average disintegration time: 35 minutes, hardness: 35N

Embodiment 7

Preparation of the present invention

The tablet that has 50mg and 160mg intensity respectively and have following composition as the preparation described in embodiment 1,4 and 6:

Material	Composition	A mg	B mg	C mg	D mg	E mg
							Medicine	Fenofibrate	160.09	50.05	50.08	50.09	159.99
Vehicle 1	PEG6000 PEG4000 GMS(Rylo)	208.12 - -	171.09 - -	124.29 - -	- 244.57 -	- - 86.15
							Vehicle 2	Poloxamer 188	89.19	73.33	53.27	-	-
Carrier	Lactose Aeropearl 300	356.51 -	231.87 -	- 63.89	232.02 -	163.01 -
							Excipient	Magnesium stearate Avicel	4.09 -	2.65 -	1.47 -	5.32 -	8.35 417.50
Amount to		818.00	529.00	293.00	532.00	835.00
							Hardness	N	60	44	44	47	102
Disintegration time	Minute	25	14	30	48	＞55
							Diameter	Mm	Oblong	12	12	10	Oblong

Embodiment 8

The dissolubility check

Tablet formulation A of the present invention among the embodiment 7 is received in the dissolubility check that method is partly described, and the result is as follows:

Time (min)	The % dissolving
		0	0
10	28
		20	56
30	74
		45	88
60	97

Embodiment 9

Stability test

Under following condition, store the sample of the tablet formulation A of the present invention among the embodiment 7 respectively, and the dissolubility of after storing 1 month and 3 months, its receiving method partly being described (stability) experiment; The percentage ratio of " % dissolving " expression dissolved fenofibrate after 45 minutes:

Month	The % dissolving
				25 ℃ and 60%RH	30 ℃ and 65%RH	40 ℃ and 75%RH
	0	88	-				-
1				99	88	90
	3	90	97				90

Store the sample of the tablet formulation A of the present invention among the embodiment 7 respectively under following condition, and make it accept Bei Te mensuration, the result is as follows:

Month	The mg fenofibrate
				25 ℃ and 60%RH	30 ℃ and 65%RH	40 ℃ and 75%RH
	0	163.8	-				-
1				161.9	160.1	160.8
	3	162.6	164.9				164.4

Under following condition, store the sample of the tablet formulation A of the present invention among the embodiment 7 respectively, and (degradation products A, B, G and unknown product are accumulated as the total degradation product according to Ph.Eur. with its acceptance; The HPLC method) degradation products check, the result is as follows:

Month	The total degradation product, %w/w, impurity
				25 ℃ and 60%RH	30 ℃ and 65%RH	40 ℃ and 75%RH
	0	0.05	-				-
1				0.05	0.05	0.05
	3	0.05	0.05				0.05

Embodiment 10

Study in the body in Canis familiaris L.

Described as top method part, in beagle, use preparation A among the 160mg embodiment 7 carry out with respect to 160mg Tricot  (lot number: study the body of preparation A 098212E21) in, the result is as follows:

Haemoconcentration after the administered formulation (ml/mL) (4 meansigma methods of Canis familiaris L.):

Time (hr)	Preparation
			Tricor (160mg)	The present invention, A (160mg)
	0	n.a.			n.a.
0.5			367.5	995.8
	1.0	612.5			2209.3
1.5			722.0	2627.8
	2.0	725.8			2097.3
3.0			443.8	1219.5
	4.0	295.3			930.5
6.0			160.5	642.0
	8.0	250.3			869.5
12.0			211.8	615.3
	24.0	133.3			394.0
48.0			n.a.	164.5

Relative bioavailability (the present invention, A/Tricor ) based on AUC: 306%.

Relative c _Max(the present invention, A/Tricor ): 356%.

Embodiment 11

Study in the body in Canis familiaris L.

Described as top method part, in beagle, use preparation A among the 160mg embodiment 7 carry out with respect to 160mg Tricot  (lot number: study second body of preparation A 098212E21) in, the result is as follows:

Haemoconcentration after the administered formulation (mg/mL) (4 meansigma methods of Canis familiaris L.):

Time (hr)	Preparation
			Tricor (160mg)	The present invention, A (160mg)
	0	0			0
0.5			339.3	3616.0
	1.0	1318.8			3724.8
1.5			1313.3	2982.0
	2.0	1390.0			2355.8
3.0			1361.3	1359.5
	4.0	1019.3			1309.5
6.0			969.3	973.8
	8.0	667.0			1113.0
12.0			390.3	768.5
	24.0	183.3			295.0
48.0			85.0	302.0

Relative bioavailability (invention, A/Tricor ) based on AUC: 198%.

Relative c _Max(invention, A/Tricor ): 238%.

Embodiment 12

Study in the body in Canis familiaris L.

Described as top method part, in beagle, use preparation B, C among 2 * 50mg embodiment 7 and D carry out with respect to 2 * 67mg Lipanthyl  (lot number: research in the body 75641), the result is as follows:

Haemoconcentration after the administered formulation (mg/mL) (4 meansigma methods of Canis familiaris L.):

Time (hr)	Preparation
					Lipanthyl67M (2×67mg)	The present invention, B (2 * 50mg)	The present invention, C (2 * 50mg)	The present invention, D (2 * 50mg)
	0	0	0	0					0
0.5					187.3	2769.5	227.3	546.0
	1.0	669.5	3526.8	521.5					1381.5
1.5					960.3	3106.3	858.3	1615.5
	2.0	895.3	2938.0	989.3					1566.8
3.0					433.0	2465.5	902.5	1503.3
	4.0	240.0	1492.3	783.8					1719.0
6.0					77.8	809.5	655.8	1034.5
	8.0	79.3	1202.8	409.0					1056.0
12.0					291.3	848.0	269.8	597.3
	24.0	82.5	378.0	163.8					282.8
48.0					19.3	18.8	51.5	36.5
	72.0	0	0	0					0

Relative bioavailability (invention, B/Lipanthyl  67M) based on AUC: 532%.

Relative c _Max(invention, BA/Lipanthyl  67M): 548%.

Relative bioavailability (invention, C/Lipanthyl  67M) based on AUC: 228%.

Relative c _Max(invention, C/Lipanthyl  67M): 161%.

Relative bioavailability (invention, D/Lipanthyl  67M) based on AUC: 424%.

Relative c _Max(invention, D/Lipanthyl  67M): 329%.

Claims (62)

1. comprise the solid oral dosage form that is dissolved in the Bei Te in the vehicle, described vehicle is hydrophobic, hydrophilic or can be miscible with water.

2. the solid dosage forms of claim 1, it is tablet, pearl, capsule, crystal grain, pill, granule, granule, powder, pellet, sachet or tablet.

3. the solid dosage forms of claim 1, it is a tablet.

4. the solid dosage forms of claim 1, wherein said shellfish is elite from gemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate and its active metabolite and analog, comprises for example fenofibric acid of any relevant fibric acid.

5. the solid dosage forms of claim 1, wherein said Bei Te is fenofibrate or its analog.

6. the solid dosage forms of claim 1, wherein said vehicle has about at the most 250 ℃ fusing point.

7. the solid dosage forms of claim 1, wherein said vehicle is hydrophobic and can be selected from straight chain saturation alkane, paraffin; Fat and oil is cupu oil, Adeps Bovis seu Bubali, leaf fat for example; Higher fatty acids is stearic acid, myristic acid, Palmic acid for example; Hydrogenated tallow, replacement and/or non-substituted glycerol three esters, yellow beeswax, cera alba, Brazil wax, castor wax, Japan wax and its mixture.

8. the solid dosage forms of claim 7, wherein said vehicle be can be miscible with water polarity fat, preferably it is selected from sorbitan ester, PTMEG ester; Higher alcohol is spermol, octadecanol for example; Glycerin mono-fatty acid ester, replacement and/or non-substituted glycerol monoesters, replacement and/or non-substituted glycerol diester and its mixture.

9. the solid dosage forms of claim 1, wherein said vehicle is hydrophilic or can be miscible with water.

10. the solid dosage forms of claim 9, wherein said hydrophilic or can be selected from Polyethylene Glycol, polyoxyethylene oxide, poloxamer, Myrj 45, poly--ε caprolactone and its mixture with the miscible vehicle of water.

11. the solid dosage forms of claim 9, wherein said hydrophilic or can be selected from for example Gelucire of polyglycolyzed glyceride with the miscible vehicle of water ^

12. the solid dosage forms of claim 9, wherein said hydrophilic or can be selected from polyvinylpyrrolidone, polyethylene-polyvinyl acetate ester copolymer (PVP-PVA), polyvinyl alcohol (PVA), PVP polymer, acrylic polymer, polymethacrylic acid polymer (Eudragit RS with the miscible vehicle of water; Eudragit RL, Eudragit NE, Eudragit E), myristyl alcohol, cellulose derivative comprise hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, pectin, cyclodextrin, galactomannan, alginate, carragenate, Xanthan gum and its mixture.

13. the solid dosage forms of claim 10, wherein said vehicle are Polyethylene Glycol (PEG).

14. the solid dosage forms of claim 13, wherein said Polyethylene Glycol has at least 3000 mean molecule quantity.

15. the solid dosage forms of claim 9, it comprises two or more hydrophilic or vectorial mixture that can be miscible with water.

16. the solid dosage forms of claim 15, wherein said mixture comprises Polyethylene Glycol and poloxamer, and its part by weight is between 1: 3 and 10: 1, preferably between 1: 1 and 5: 1, more preferably between 3: 2 and 4: 1, especially between 2: 1 and 3: 1, especially about 7: 3.

17. the solid dosage forms of claim 16, wherein said poloxamer are poloxamers 188.

18. the solid dosage forms of claim 16, wherein said Polyethylene Glycol have about 6000 mean molecule quantity (PEG6000).

19. the solid dosage forms of claim 1, wherein said vehicle is non-aqueous.

20. the solid dosage forms of claim 1 is wherein pressed Bei Te and vectorial total weight, the concentration of Bei Te is 10%w/w at least in the vehicle.

21. the solid dosage forms of claim 1, wherein press Bei Te and vectorial total weight, the concentration of Bei Te is 15%w/w or 16%w/w or 17%w/w or 20%w/w, preferred 25%w/w at least at least at least at least at least in the vehicle, more preferably 30%w/w, particularly 35%w/w at least at least.

22. the solid dosage forms of claim 1 is wherein pressed Bei Te and vectorial total weight, the concentration of Bei Te is 90%w/w at the most in the vehicle.

23. the solid dosage forms of claim 1, wherein press Bei Te and vectorial total weight, the concentration of Bei Te is 80%w/w at the most or is 75%w/w at the most or is 70%w/w at the most or is 60%w/w at the most in the vehicle, preferably be 50%w/w at the most, more preferably be 40%w/w at the most, particularly 35%w/w at the most.

24. the solid dosage forms of claim 1, wherein the fenofibrate of 90%w/w is dissolved in the vehicle at least.

25. the solid dosage forms of claim 1, wherein at least 93%w/w or at least 95%w/w at least 97%w/w or at least 98%w/w at least 99%w/w or at least 99.5%w/w or at least the fenofibrate of 99.9%w/w be dissolved in the vehicle.

26. the solid dosage forms of claim 1, wherein when using 0.75% sodium lauryl sulphate to dissolve when checking external as dissolve medium under about 37 ℃ temperature and under the 50rpm according to Ph.Eur. dissolving method of inspection (stirrings), at least 75% Bei Te is released in about 45 minutes.

27. the solid dosage forms of claim 26 is wherein carried out described dissolving check after storing 3 months under about 40 ℃ temperature and under about 75% relative humidity.

28. the solid dosage forms of claim 1, it further comprises one or more medicines can accept excipient.

29. the solid dosage forms of claim 28, wherein said medicine can be accepted excipient and be selected from filler, diluent, disintegrating agent, binding agent, fluidizer and lubricant.

30. the solid dosage forms of claim 28, wherein at least a medicine can be accepted excipient and be selected from silicic acid or derivatives thereof or salt, comprises silicate, silicon dioxide and its polymer; Magnesiumaluminumsilicate and/or positive Magnesiumaluminumsilicate, bentonite, Kaolin, magnesium trisilicate, Montmorillonitum and/or saponite.

31. the solid dosage forms of claim 28, it is silicic acid or derivatives thereof or salt that wherein at least a medicine can be accepted excipient.

32. it is silicon dioxide or its polymer that the solid dosage forms of claim 28, wherein at least a medicine can be accepted excipient.

33. the solid dosage forms of claim 28, wherein said silica product has corresponding to Aeroperl ^The characteristic of 300 (can be, Frankfurt, Germany is commercially available) from Degussa.

34. the solid dosage forms of claim 1, it further comprises the medicine that is selected from correctives, coloring agent, mask agent, pH regulator agent, buffer agent, antiseptic, stabilizing agent, antioxidant, wetting agent, moisture regulator, surfactant, suspending agent and absorption enhancer can accept additive.

35. the solid dosage forms of claim 1, it further comprises medicine can accept oil absorption material.

36. the solid dosage forms of claim 1, it is a unit dosage forms.

37. the solid dosage forms of claim 1 is wherein wrapped by the individual unit of solid dosage forms with the coating that is selected from film coating, modified release coating, enteric coating, protectiveness coating and antiseized coating.

38. the solid dosage forms of claim 1, wherein said Bei Te is embedded in the substrate, and described substrate discharges described Bei Te by diffusion.

39. the solid dosage forms of claim 38, wherein during drug release, described substrate is kept perfectly basically.

40. the solid dosage forms of claim 1, wherein said Bei Te is embedded in the substrate, and described substrate discharges described Bei Te by corroding.

41. the solid dosage forms of claim 1 wherein discharges described Bei Te through water-fast coating basically from described dosage form by diffusion.

42. the solid dosage forms of claim 1, after being administered to the mammal that needs it, with respect to the existing special dosage form of shellfish that is purchased, it causes the special bioavailability of shellfish that increases.

43. the solid dosage forms of claim 42, the AUC value that it provides is about 1.1 or about at least 1.2 or about at least 1.3 or about at least 1.4 or about at least 1.5 or about at least 1.75 or more or about at least 2.0 or about at least 2.5 or about at least 3.0 with respect to the AUC value of commercially available Tricor  tablet at least, and described AUC value is determined under similar condition.

44. the solid dosage forms of claim 42, the AUC value that it provides is with respect to the c of commercially available Tricor  tablet _MaxValue is about 1.1 or about at least 1.2 or about at least 1.3 or about at least 1.4 or about at least 1.5 or about at least 1.6 or more or about at least 2.0 or about at least 2.5 or about at least 3.0 at least, described c _MaxValue is determined under similar condition.

45. the solid dosage forms of claim 1, wherein said Bei Te is stable.

46. the solid dosage forms of claim 45, when wherein after storing 3 months under about 40 ℃ temperature and under about 75% relative humidity, measuring, with respect to the amount before storing, described Bei Te exists with at least 90% or 95% or 100% amount at least at least.

47. comprise the pharmaceutical composition that is dissolved in the Bei Te in the vehicle, described vehicle is hydrophobic, hydrophilic or can be miscible with water.

48. the compositions of claim 47, wherein said vehicle has about at the most 250 ℃ fusing point.

49. the compositions of claim 47, wherein said vehicle is selected from straight chain saturation alkane, sorbitan ester, paraffin; Fat and oil is cupu oil, Adeps Bovis seu Bubali, leaf fat, PTMEG ester for example; Higher fatty acids is for example spermol, octadecanol of stearic acid, myristic acid, Palmic acid, higher alcohol for example; Low melt wax is glyceryl monostearate, glyceryl monooleate, hydrogenated tallow, myristyl alcohol, octadecanol, replacement and/or non-substituted glycerol monoesters, replacement and/or non-substituted glycerol diester, replacement and/or non-substituted glycerol three esters, yellow beeswax, cera alba, Brazil wax, castor wax, Japan wax, acetylated monoglyceride for example; PVP polymer, acrylate copolymer; Polyethylene Glycol, polyoxyethylene oxide, poloxamer, Myrj 45, poly--the ε caprolactone, polyglycolyzed glyceride be Gelucire for example ^, polyvinylpyrrolidone, polyethylene-polyvinyl acetate ester copolymer (PVP-PVA), polyvinyl alcohol (PVA), polymethacrylic acid polymer (Eudragit RS; Eudragit RL, Eudragit NE, Eudragit E), cellulose derivative comprises hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, pectin, cyclodextrin, galactomannan, alginate, carragenate, Xanthan gum and its mixture.

50. the compositions of claim 47, wherein said mixture comprises Polyethylene Glycol and poloxamer, and its weight ratio is between 1: 3 and 10: 1, preferably between 1: 1 and 5: 1, more preferably between 3: 2 and 4: 1, especially between 2: 1 and 3: 1, especially about 7: 3.

51. the compositions of claim 47, wherein based on described Bei Te and vectorial gross weight, the concentration of Bei Te is 10%w/w or 15%w/w or 16%w/w or 17%w/w or 20%w/w, preferred 25%w/w at least at least at least at least at least at least in the vehicle, more preferably 30%w/w, 35%w/w especially at least at least.

52. the compositions of claim 47, wherein at least 90%w/w, at least 93%w/w or at least 95%w/w at least 97%w/w or at least 98%w/w or at least the fenofibrate of 99%w/w be dissolved in the vehicle.

53. the compositions of claim 47, it further comprises one or more medicines that are selected from filler, diluent, disintegrating agent, binding agent, fluidizer and lubricant can accept excipient.

54. the compositions of claim 47, it further comprises medicine can accept oil absorption material.

55. the compositions of claim 47, the AUC value that it provides is about 1.1 or about at least 1.2 or about at least 1.3 or about at least 1.4 or about at least 1.5 or about at least 1.75 or more or about at least 2.0 or about at least 2.5 or about at least 3.0 with respect to the AUC value of commercially available Tricor  tablet at least, and described AUC value is determined under similar condition.

56. the solid dosage forms of claim 47, the AUC value that it provides is with respect to the c of commercially available Tricor  tablet _MaxValue is about 1.1 or about at least 1.2 or about at least 1.3 or about at least 1.4 or about at least 1.5 or about at least 1.6 or more or about at least 2.0 or about at least 2.5 or about at least 3.0 at least, described c _MaxValue is determined under similar condition.

57. the compositions of claim 47, it exists with particle form.

When 58. the compositions of claim 47, the method for describing in according to Ph.Eur. are measured by the flow velocity of measuring the funnel of described compositions by having 10.0mm diameter ozzle, the flowability that its performance is suitable.

59. the solid composite medicament that exists with particle form, it comprises Bei Te, hydrophobic or vehicle and oil absorption material hydrophilic or can be miscible with water, when testing according to the threshold test method, the oil suction threshold value of described compositions performance at least 10%, and described compositions further satisfies i) and ii) one or both:

I) when testing according to the release method of inspection, the hydrophobicity of compositions release at least 30% or hydrophilic or vehicle that can be miscible with water;

Ii) the compositions that exists with tablet form contains at least approximately oil absorption material of 90%w/w, and when testing according to Ph.Eur. disintegrate method of inspection, its performance is 60 minutes disintegration time at the most.

60. the method for the solid oral dosage form in the production claim 1, it comprises step:

I) if suitable, produce the vehicle of liquid form,

The temperature of ii) keeping liquid vehicle is lower than the special fusing point of shellfish,

Iii) the Bei Te with aequum is dissolved in the vehicle,

Iv) the solution with gained is sprayed on the solid carrier with the temperature that is lower than described vehicle fusing point,

The compositions of v) mechanically operating gained to be to obtain granule, promptly granular materials and

Vi) randomly handle granular materials with the conventional method of preparation solid dosage forms.

61. the compositions of claim 47 is increasing the particularly application in the oral administration biaavailability of fenofibrate of Bei Te.

62. the compositions of claim 47 is used to prepare the purposes of oral dosage form preferred tablet or sachet.