HK1096034B - A solid dosage form comprising a fibrate - Google Patents

Description

Solid dosage form comprising a fibrate

The present invention relates to novel solid dosage forms and pharmaceutical compositions comprising a fibrate, in particular fenofibrate. In particular, the present invention discloses solid dosage forms having increased bioavailability. The solid dosage forms of the present invention comprise a fibrate dissolved in a suitable vehicle or mixture of vehicles. The dosage forms are particularly suitable for oral administration and exhibit excellent storage stability, i.e. are stable. The invention also relates to methods for preparing said solid dosage forms and pharmaceutical compositions and uses thereof.

Background

Fibrates are lipid regulators. Examples of fibrates include gemfibrozil, fenofibrate, bezafibrate, clofibrate and ciprofibrate. The compounds are considered prodrugs and are metabolized in vivo to produce their active metabolites. For illustrative purposes only, the following is based on a specific example of fibrate, fenofibrate. Fenofibrate is known by the chemical name 2- [4- (4-chlorobenzoyl ] -2-methyl-propionic acid 1-methylethyl ester and has the following formula:

fenofibrate is a white solid. The compounds are insoluble in water. The melting point is 79-82 ℃. Fenofibrate is metabolized to produce fenofibric acid, the active substance. Fenofibric acid has an elimination half-life of about 20 hours. The measurement of the amount of fenofibric acid detectable in the blood of a patient may reflect the efficiency of fenofibrate absorption. Fenofibric acid causes a reduction in total cholesterol (total-C), LDL-C, apolipoprotein B, total triglycerides and triglyceride-rich lipoproteins (VLDL) in the treated patient. In addition, treatment with fenofibrate resulted in an increase in High Density Lipoprotein (HDL) and apolipoproteins apoA1 and apoAII. Fenofibrate acts as a potent lipid modulator, providing unique clinical advantages over existing products in the fibrate family of drug substances. Fenofibrate results in a significant reduction in plasma triglycerides in patients with hypertriglyceridemia and in significant reductions in plasma cholesterol and LDL-C in patients with hypercholesterolemia and mixed dyslipidemia.

Fenofibrate can also reduce serum uric acid levels by increasing urinary excretion of uric acid in subjects with hyperuricemia and normal subjects.

Clinical studies have demonstrated that elevated levels of total cholesterol, low density lipoprotein cholesterol (LDL-C) and apolipoprotein b (apo b) are associated with human atherosclerosis. Reduced high density lipoprotein cholesterol (HDL-C) and its transport complexes, apolipoprotein a (apo AI and apoAII) levels, are associated with the development of atherosclerosis.

Fenofibrate is also effective in the treatment of type II diabetes and metabolic syndrome.

Fenofibrate is also used as a dietary adjunct in the treatment of patients with hypertriglyceridemia (Fredrickson type IV and V hyperlipidemia). Improving glycemic control in diabetic patients who exhibit fasting chylomicronemia generally reduces triglycerides in the fasting state and eliminates chylomicronemia, thereby eliminating the need for pharmacological intervention.

Fibrates are drug substances known to be difficult and unstable to absorb after oral administration. Typically, they are ordered for consumption with food to increase bioavailability.

There have been many improvements to the dosage forms of the most widely used fibrate, fenofibrate, at present, and many efforts have been made to increase the bioavailability of the drug, thereby increasing its effectiveness. However, there remains a need for improved dosage forms relative to currently available compositions and dosage forms that provide crystalline fenofibrate in micronized form. In particular, there remains a need for compositions and dosage forms that exhibit suitable bioavailability that substantially reduce or overcome the difference between the bioavailability of drugs in fasted patients and fed patients, and/or that substantially reduce or overcome intra-and/or inter-individual variations observed in current treatments using commercially available products. Furthermore, there is also a need for new dosage forms and/or compositions that can reduce the side effects observed.

In particular, there is an unmet need to develop solid compositions in the form of granules (granules) in which the fibrate is present in dissolved form, in the form of powders, microgranules, granules (granules), beads, microtablets or other forms of granular material, rather than in the form of a soft dosage form containing a liquid medium.

Summary of The Invention

The inventors have now found that the bioavailability of fenofibrate can be significantly increased by dissolving a fibrate, e.g. fenofibrate, in a suitable vehicle and using the resulting composition to prepare a solid dosage form, i.e. a dosage form excluding materials in liquid form. Fibrates, and in particular fenofibrate, are known to be water insoluble, but the present invention provides pharmaceutical compositions and formulations exhibiting rapid release characteristics, expected to have significantly increased in vivo bioavailability in patients in need thereof. In particular, the present invention has succeeded in preparing solid dosage forms, such as tablets, comprising a fibrate in dissolved form. The advantageous aspects of solid and stable dosage forms for oral administration are well known.

Accordingly, a first aspect of the present invention relates to a solid oral dosage form comprising a fibrate dissolved in a vehicle, which is hydrophobic, hydrophilic or water-miscible. Useful solid dosage forms are in the form of tablets, beads, capsules, grains, pills, granules, powders, pellets, sachets, or troches, and useful fibrates are fenofibrate, bezafibrate, clofibrate, ciprofibrate and active metabolites and analogs thereof, including any related phenoxy acid (fibric acid) such as fenofibric acid.

In a second aspect, the present invention relates to a pharmaceutical composition comprising a fibrate dissolved in a vehicle, which is hydrophobic, hydrophilic or water-miscible; in other aspects, the invention relates to a solid pharmaceutical composition in particulate form comprising a fibrate, a hydrophobic or hydrophilic or water-miscible vehicle and an oil-absorbing material, the composition exhibiting an oil threshold value of at least 10%.

In another aspect, the invention relates to a method of producing a solid oral dosage form or pharmaceutical composition of the invention.

Other aspects of the invention will be apparent from the following description. Comparison of in vivo tests in dogs has been shown (see examples herein): compared with commercially available solid dosage forms containing the same active ingredient, i.e. withTablets andcapsules compared to capsules, the solid dosage forms and compositions of the present invention show significantly enhanced bioavailability of fenofibrate.

Furthermore, it is believed that the present invention provides solid dosage forms and/or compositions of a fibrate that are capable of significantly reducing the intra-and/or inter-individual variation typically observed after oral administration. In addition, the compositions and/or dosage forms of the present invention provide a significantly reduced food effect, i.e., absorption is relatively independent of whether the patient takes the composition or dosage form and or not with any food. Improved fibrate release is expected to reduce the number of gastrointestinal related side effects. Furthermore, it is expected that a significantly larger amount of fibrate may be absorbed, so that only a smaller amount of fibrate is excreted unchanged through the faeces.

Detailed description of the invention

Definition of

As used herein, the term "active ingredient" or "active pharmaceutical ingredient" refers to any component that is used to provide pharmacological activity or other direct effect in the diagnosis, treatment, alleviation, cure or prevention of disease, or to affect the structure or any function of the human or other animal body. The term includes ingredients that can undergo chemical changes in the manufacture of a pharmaceutical product and be present in the pharmaceutical product in a modified form for providing a particular effect or activity.

In this specification, the term "hydrophilic" means that the substance 'prefers water', i.e. the hydrophilic molecule or part of a molecule is generally electrically polar and capable of forming hydrogen bonds with water molecules, making it more soluble in water than in oil or other "non-polar" solvents.

In this specification, the term "amphiphilic" refers to molecules (such as surfactants) having a polar water-solubilizing group attached to a hydrocarbon chain that is insoluble in water. Thus, one end of the molecule is hydrophilic (polar) and the other end is hydrophobic (non-polar).

In this specification, the term "hydrophobic" refers to molecules that tend to be electrically neutral and non-polar, and therefore favor other neutral and non-polar solvent or molecular environments.

As used herein, the term "water-miscible" refers to a compound that is fully or partially mixed with water. For example, certain polar lipids are partially miscible with water.

As used herein, the term "vehicle" refers to any solvent or carrier that does not have a pharmacological effect in the drug product. For example, water is a vehicle for xilocaine and propylene glycol is a vehicle for many antibiotics.

In this specification, the term "solid dispersion" means that the drug or active ingredient or substance is dispersed at the particle level in an inert vehicle, carrier, diluent or matrix in the solid state, i.e. typically a dispersion of fine particles.

In the present specification, the term "solid solution" means that the drug or active ingredient or substance is dissolved at the molecular level in an inert vehicle, carrier, diluent or matrix in the solid state.

As used herein, the term "analog" refers to a compound that is structurally similar to another compound.

The term "drug" refers to a compound that is used to diagnose, treat, alleviate, treat, or prevent a disease in a human or other animal.

In this specification, the term "dosage form" refers to the form in which a drug is delivered to a patient. This includes parenteral, topical, tablet, oral (liquid or dissolved powder), suppository, inhalation, transdermal and the like forms.

As used herein, the term "bioavailability" refers to the degree to which a drug or other substance reaches a target tissue after administration.

As used herein, the term "bioequivalence" refers to the scientific basis on which class and brand name drugs are compared to one another. For example, a drug is bioequivalent if it enters the circulatory system at the same rate when administered at similar doses under similar conditions. The parameter commonly used for bioequivalence studies is t_max、C_max、AUC_0-infinity、AUC_0-t. Other relevant parameter may be W₅₀、W₇₅And/or MRT. Thus, at least one of these parameters may be used when determining whether biological equivalence exists. In addition, in the present specification, if the parameter value used is that used in the examinationOr a commercially available similar product containing tacrolimus, is within 80-125% of the parameter value, then the two compositions are considered bioequivalent.

In the present specification, "t" is_max"means that the highest plasma concentration (C) is reached after administration_max) The time required; AUC_0-infinityOr ACU refers to the area under the plasma concentration-time curve from time 0 to infinity; AUC_0-tRefers to the area under the plasma concentration-time curve from time 0 to time t; w₅₀Means that the plasma concentration reaches C_max50% or more of the time; w₇₅Means that the plasma concentration reaches C_max75% or more of time; MRT refers to a fibrate such asMean residence time of fenofibrate (and/or an analog thereof).

In this specification, the term "drug" refers to a compound used to treat a disease, injury or pain. Drugs are reasonably divided into the "prophylactic", i.e. health-preserving, field and the "therapeutic", i.e. health-restoring, field.

In the present specification, the terms "controlled release" and "modified release" are the same terms, which include any type of release of tacrolimus from the compositions of the present invention suitable for obtaining a specific therapeutic or prophylactic response upon administration to a subject. One skilled in the art is aware of the differences in controlled release and/or modified release from the release of a conventional tablet or capsule formulation. The term "release in a controlled manner" or "release in a modified manner" has the same meaning as described above. The term includes slow release (resulting in lower C)_maxAnd later t_maxBut t is_1/2Invariant), extended release (resulting in lower C)_maxAnd later t_maxBut apparent t_1/2Lengthening); sustained release (C)_maxUnchanged but extended time, thus, t_maxDelay, but t_1/2Invariant), as well as pulsatile (burst) release, burst (burst) release, sustained release, extended release, time-optimized (chrono-optimized) release, rapid release (to obtain enhanced onset of action), and the like. The term also includes, for example, the use of specific conditions in the body, such as different enzymes or pH changes, to control the release of a drug substance.

In this specification, the term "erode" or "erosion" refers to the gradual disintegration of the surface of a material or structure, such as a tablet or tablet coating.

Active drug substance

The drug or active substance of the dosage forms and pharmaceutical compositions of the present invention is a fibrate. Examples of useful fibrates are bezafibrate, ciprofibrate, clinofibrate, clofibrate, etoxytheophylline, clofibrate, fenofibrate, gemfibrozil, pirfibrate, bisfibrate and tocofibrate; particularly useful are gemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate and active metabolites and analogs thereof, including any related phenoxy acid such as fenofibric acid. In a preferred embodiment, the fibrate is fenofibrate or an analog thereof. However, the dosage forms and compositions of the present invention may also comprise a mixture of two, three or even four different fibrates and/or phenoxy acids.

The concentration of fibrate in the vehicle is at least 10% w/w, calculated on the total weight of fibrate and vehicle; preferably at least 15% w/w, or at least 16% w/w, or at least 17% w/w, or at least 20% w/w, or at least 25% w/w, or at least 30% w/w, in particular at least 35% w/w, calculated on the total weight of fibrate and vehicle; the concentration of fibrate in the vehicle is at most 90% w/w, calculated on the total weight of fibrate and vehicle, or at most 80% w/w, or at most 75% w/w, or at most 70% w/w, or at most 60% w/w, or at most 50% w/w, or at most 40% w/w, or not more than 35% w/w, calculated on the total weight of fibrate and vehicle. Preferably, the fibrate is completely dissolved in the non-aqueous vehicle. However, the small presence of crystalline or microcrystalline active drug may not affect the increased bioavailability of the solid dosage forms and compositions of the present invention. Thus, at least 90% w/w of the fenofibrate is dissolved in the vehicle, preferably at least 93% w/w, or at least 95% w/w, or at least 97% w/w, or at least 98% w/w, or at least 99% w/w, or at least 99.5% w/w, or at least 99.9% w/w of the fenofibrate in the dosage form or pharmaceutical composition is completely dissolved in the vehicle or vehicle system.

In addition to the fibrate, the dosage form and pharmaceutical composition of the present invention may comprise other active drug substances, preferably one additional drug substance. Preferably, this additional drug is one that is normally used for the same indication as the fibrate. A specific example is ezetimibe. Of course, combinations with three or even four drug substances for the same indication as well as combinations comprising two, three or four active ingredients for different indications or treatments are also contemplated.

Examples of additional pharmaceutical substances are other anti-dyslipidemic agents such as statins; lipid regulating agents such as: oxamethylpyrazine, binifibrate, etofibrate, pentaerythrite, nicofibrate, pirzadil, chlorofibrate, tocoferil nicotinate; combinations with cardiovascular drugs such as ace inhibitors: alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, temocapril, teprolide, trandolapril, zofenopril; calcium channel blockers, such as: amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, bepridil, cilnidipine, diltiazem, efonidipine, felodipine, gallopamil, isradipine, lacidipine, lercanidipine, manidipine, miberadil, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, verapamil; α -blockers, such as: alfuzosin, bunazosin, doxazosin, indoramine, naftopidil, phenoxybenzamine, phentolamine, prazosin, tamsulosin, terazosin, moxiflorin, tolazolin, urapidil; beta-blockers, such as: acebutolol, alprenolol, amosulalol, arotinolol, atenolol, bufuralol, betaxolol, bevantolol, bosanolol, bucindolol, bunranolol, bucindolol, carabronolol, carvedilol, celiprolol, esmolol, indonolol, labetalol, landiolol, levobetaxolol, levobunolol, mepindolol, metipranolol, metoprolol, nadolol, nebivolol, nipradilol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, tarlinolol, terbanolol, timolol; angiotensin ii blockers such as: candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan (ref. telmisartan), valsartan; vasodilators, such as: cadralazine, diazoxide, dihydralazine, endralazine, hydralazine, minoxidil, todralazine, tolazoline, carbopol, cinepazide, (ref. clodamycin), delavay, etaphenone, fendiline, hexobenedine, oxicfedrine, trapidil, trimeprazine, azapetine, bamethacin, bencyclane, buflomedil, butatamine, calcitonin gene-related peptide, cetidil, cinepazide, cyclanolate, diisopropylammonium chloroacetic acid, fasudil, ifenprodil, inositol nicotinate, naftid, nicotinol, pentoxifylline, pentaphylline, protamphetamine, norgestrel, nicotinol (ninol oticoat); centrally acting hypertensive agents: (ii) apraclonidine, brimonidine, clonidine, guanabenz, guanfacine, methyldopa (methydopa), moxonidine, rimenidine, thimetanidine; antiarrhythmic drugs, such as: ajmaline, sibenzazoline, propylpiramide, hydroquinidine, piremenol, procainamide, quinidine, aprepidine, mexiletine, tocainide, cumylketone, encarnib, flecainide, loracarb, piricamide, propafenone, bromobenzylamine, acetylcarnib, amiodarone, azimilide, bromobenzylamine, xylometazoline, dofetilide, nifekalant, sotalol, xylometazoline, verapamil; antiplatelet agents, such as: abciximab, aspirin, cilostazol, clopidogrel, clocrolimus, dipyridamole, ditrazol, eptifibatide, indobufen, lamifiban, orbofiban, picotamide, sarpogrelate, cilafliban, ticlopidine, tirofiban, trapidil, triflusal, timifloxacin; diuretics, such as: acetazolamide, brinzolamide, diclofenamide, dorzolamide, methazolamide, azosemide, bumetanide, ethacrynic acid, etozoline, furosemide, piretanide, torasemide, isosorbide, mannitol, amiloride, canrenone, potassium canrenoate, spironolactone, triamterene, aldiazide, bemethiazide, bendroflumethiazide, buprothiazide, chlorothiazide, chlorthalidone, chlorprotiamine, cyclopenthiazide, cyclothiazide, epipizide, hydrochlorothiazide, hydroflumethiazide, indapamide, mebuthiazide, mefosiltide, meclothiazide, metipram, metolazone, polythiazide, polythiazone, polythiazide, tripamide (tripamide), xipamide; antidiabetic agents, such as: acarbose, acetohexamide, biguanide, antidiabetic agent buformin, amisulbutamide, chlorpropamide, epalrestat, glyburide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glibenclamide, glisomide, glisoxepide, glibutrazole, glipiride, gliclazide, glipizide sodium, metformin hydrochloride, imiglizole, miglitol, nateglinide, phenformin hydrochloride, pimagedine, pioglitazone hydrochloride, pramlintide, repaglinide, rosiglitazone, sorbinil, tolazamide, tolbutamide, troglitazone; voglibose substances, such as: q10, vitamins (niacinamide, pyridoxine hc1, b12, vitamin E, ascorbic acid, etc.), antioxidants are also typically included in useful compositions.

Additional drug substances may also be included in or used with compositions that may result in undesirable triglyceride and/or cholesterol levels. Thus, the compositions of the present invention may comprise or be used with drugs such as isotretinoin or reverse transcriptase inhibitors (e.g., HIV protease inhibitors), antipsychotics such as olanzapine, and other drugs.

As mentioned, the combined product containing the fibrate is not limited to a two-substance combination, triple or quadruple therapy can also be particularly beneficial.

Media

The vehicle used in the present invention is a water-miscible, hydrophilic or hydrophobic vehicle. Useful vehicles are non-aqueous materials.

Examples of hydrophobic vehicles useful in the present invention are straight chain saturated hydrocarbons, paraffins; fats and oils, such as cocoa butter, beef tallow, lard; higher fatty acids such as stearic acid, myristic acid, palmitic acid; hydrogenated tallow, substituted and/or unsubstituted triglycerides, yellow beeswax (yellowbeesx), white beeswax (white beesx), carnauba wax, castor wax (castowax), Japan wax, and mixtures thereof.

Water mixable for use in the inventionExamples of soluble vehicles are water-miscible polar lipids such as sorbitan esters, polyether glycol esters; higher alcohols such as cetyl alcohol, stearyl alcohol; monoolein, substituted and/or unsubstituted monoglycerides, substituted and/or unsubstituted diglycerides and mixtures thereof. In a more preferred embodiment, the vehicle is hydrophilic or water-miscible. Preferably, the vehicle is selected from the group consisting of polyethylene glycol, polyoxyethylene oxide, poloxamer, polyoxyethylene stearate, poly-epsilon caprolactone and mixtures thereof. However, the vehicle may also advantageously be a polyglycolized glyceride, for example under the registered trademarkOne of many products sold, such as Gelucire 44/14.

Examples of useful hydrophilic or water-miscible vehicles are polyvinylpyrrolidone, polyethylene-polyvinyl acetate copolymer (PVP-PVA), polyvinyl alcohol (PVA), PVP polymers, acrylic polymers, polymethacrylic polymers (Eudragit RS; Eudragit RL, Eudragit NE, Eudragit E), myristyl alcohol, cellulose derivatives including hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, pectin, cyclodextrin, galactomannan, alginates, carragelates, xanthan gum and mixtures thereof.

The vehicle is preferably a mixture of two or more substances.

The vehicle may also be an oily substance as defined and described below.

Preferably, the melting point of the vehicle is preferably in the range of 10 ℃ to 250 ℃, preferably in the range of 30 ℃ to 100 ℃, more preferably in the range of 40 ℃ to 75 ℃, especially in the range of 40 ℃ to 70 ℃.

In a preferred embodiment of the invention, the vehicle is a polyethylene glycol (PEG), preferably having an average molecular weight of at least 3000, more preferably at least 4000, optionally mixed with a poloxamer, such as poloxamer 188, in a preferred weight ratio of 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 7: 3.

Bioavailability of

In general, it is known that various factors can affect the absorption and bioavailability of therapeutically active substances when administered orally. These factors include the presence of food in the gastrointestinal tract, and in general, the residence time of the drug in the stomach is significantly longer in the presence of food than in the fasted state. A drug is considered to exhibit a food effect if the bioavailability of the drug is affected beyond a certain point due to the presence of food in the gastrointestinal tract. The food effect is very important because of the risks associated with administering drugs to patients who have just eaten meals. The risk comes from the following: absorption of the drug into the bloodstream may be adversely affected such that the patient may not be able to obtain sufficient absorption to treat the condition for which the drug is intended. In the case of fenofibrate, for example, the situation is different, since the food increases its absorption. Therefore, not ingesting food while using a drug may result in insufficient absorption. Commercially available product containing fenofibrate (from Abbott) in the fed state compared to fasted stateThe degree of absorption of (a) is increased by about 35%.

As noted above, there remains a need for new pharmaceutical compositions comprising one or more fibrates that exhibit suitable bioavailability of the active compound and/or reduce or eliminate food effects. In the present specification, the term "suitable bioavailability" means that administration of the composition of the invention will result in an increased bioavailability compared to the bioavailability obtained after administration of the active substance in a conventional tablet; or at least the same or improved, compared to the bioavailability obtained after administration of the same commercially available product containing the same active substance in the same amount. It is particularly desirable to obtain a more complete absorption of the active substance, so that it is possible to reduce the dose administered. In addition, pharmaceutical compositions and dosage forms comprising a fibrate can also reduce or eliminate the need for food intake with dosage forms, thereby allowing the patient more freedom in the timing of taking the drug. Also, increased or increased bioavailability may lead to improved treatment, as it is possible to achieve the same therapeutic response and more stable plasma levels with reduced doses and/or fewer administrations and no food restriction. Another way of obtaining an improved treatment of a disease which requires, for example, the treatment of fenofibrate, is by balancing the release of fenofibrate to the gastrointestinal tract in such a way that an increased plasma concentration of fenofibrate is obtained from the beginning or delayed after administration, i.e. by using a modified or delayed release composition comprising one or more fibrates.

In one embodiment, the present invention relates to a pharmaceutical composition or solid dosage form comprising one or more fibrates in the form of particles, wherein the composition exhibits an AUC/AUC of at least about 1.0 following oral administration to a mammal in need thereof_controlValue, AUC determined using a commercially available product containing the same fibrate_controlAUC values were determined under similar conditions.

Data based on the absolute bioavailability of injectable compositions such as fenofibrate cannot be obtained (probably due to solubility problems in aqueous media). Commercially available compositions containing fenofibrate include surfactants and/or, for example, lipophilic media. Surfactants may provide improved bioavailability and thus the bioavailability of such compositions may be sufficient. However, there is still a need to develop flexible formulation techniques that enable the formulation of various dosage forms. Thus, a requirement for such enhanced and/or more flexible compositions may be to achieve the same or higher bioavailability than has been seen with commercially available products.

Thus, in other embodiments of the invention, the AUC/AUC obtained by administration of a solid dosage form or pharmaceutical composition of the invention_controlValues are at least about 1.1, e.g., at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 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 conditions, AUC values are determined.

Also, relative to commercially availableTablet C_maxValue, C obtained by administering a solid dosage form or pharmaceutical composition of the invention_maxValues of at least about 1.1, or at least about 1.2, or at least about 1.3, or at least about 1.4, or at least about 1.5, or at least about 1.6 or more, or at least about 2.0, or at least about 2.5, or at least about 3.0, under similar conditions to determine C_maxThe value is obtained.

It is another object of the present invention to reduce or eliminate the food effect. Thus, in another aspect, the present invention relates to a pharmaceutical composition or solid dosage form comprising one or more fibrates in the form of a granulate, wherein the composition or solid dosage form does not exhibit a significant adverse food effect, such as by an AUC of at least about 0.85, upon oral administration to a mammal in need thereof_fed/AUC_fastedValues (at least 0.75 at the lower 90% confidence limit) are demonstrated. In particular embodiments, the pharmaceutical compositions or solid dosage forms of the invention have an AUC of about 0.9 or higher, e.g., about 0.95 or higher, about 0.97 or higher, or about 1 or higher_fed/AUC_fastedThe value is obtained.

In other words, the difference between the measured bioequivalence parameters after oral administration to a mammal with and without food, respectively, is less than 25%, e.g., less than 20%, less than 15%, less than 10% or less than 5%.

In another aspect, the present invention relates to a pharmaceutical composition in the form of granules and a solid dosage form comprising a fibrate, wherein the composition of the invention administered orally to a mammal in need thereof is substantially bioequivalent to a commercially available product comprising the same fibrate, when administered at the same or lower dose as the commercially available product comprising the same fibrate. In a particular embodiment thereof, the dose is up to about 98% w/w, e.g., up to about 95% w/w, up to about 90% w/w, up to about 85% w/w, up to about 80% w/w, up to about 75% w/w, up to about 70% w/w, up to about 65% w/w, up to about 60% w/w, up to about 55% w/w, or up to about 50% w/w of the dose of fibrate administered in the form of a commercially available product containing the same fibrate.

Generally, bioequivalence is determined by at least one of the following parameters: t is t_max(time to reach maximum plasma concentration), c_max(maximum plasma concentration), AUC_0-t(area under the curve from time 0 to t), AUC_0-infinity(area under the curve from time 0 to time infinity), W₅₀(plasma concentration of c_max50% or more of time length), W₇₅(plasma concentration of c_max75% or higher) and/or MRT (mean residence time).

The major problem with treatment with fibrates is the large intra-or inter-individual variation. Thus, in a further aspect, the present invention relates to a pharmaceutical composition in the form of particles comprising one or more fibrates, wherein oral administration of said composition to a mammal in need thereof under the same conditions and at a dose providing the same therapeutic effect reduces inter-and/or intra-individual variation as compared to the inter-or intra-individual variation between commercially available individuals containing the same fibrate product.

In the comparative test described above, when the fibrate is fenofibrate, the commercially available product is in the form of tabletsIs/are as followsOr, alternatively, in the form of capsulesWhen the fibrate is gemfibrozil, a suitable commercially available product isWhen the fibrate is bezafibrate, a suitable commercially available product isWhen the fibrate is clofibrate, a suitable commercially available product isWhen the fibrate is ciprofibrate, a suitable commercially available product is

A convenient method for determining whether a suitable amount of fibrate has been absorbed may be by determining the amount of fibrate excreted via the feces, but unchanged. Thus, in one embodiment the invention relates to a solid pharmaceutical composition or a solid dosage form, wherein at most about 25% w/w, such as at most about 20% w/w, at most about 15% w/w, at most about 10% w/w, at most about 5% w/w of the fibrate in said composition is excreted after oral administration.

Production method

The particulate composition of the present invention may be prepared by any method suitable for mixing poorly water soluble active substances. The pharmaceutical compositions may be prepared by any convenient method, such as granulation, mixing, spray drying, and the like. A particularly useful process is that disclosed in international application publication No. WO03/004001 which describes a process for the preparation of particulate material by a controlled agglomeration process, i.e. a process which enables controlled growth of particles in size. The method comprises spraying a first composition comprising an active substance and a vehicle in liquid form onto a solid support. Typically, the vehicle has a melting point of at least 5 ℃, but the melting point must be below that of the active substance. In the present invention, the melting point of the vehicle should not exceed 250 ℃.

It is within the skill of the person skilled in the art to select, using ordinary knowledge and routine experimentation, a pharmaceutically acceptable vehicle capable of dispersing or completely or at least partially dissolving an active substance and having a melting point within the desired range.

Suitable vehicles in the present description are, for example, the materials mentioned as vehicles or oily substances (oil materials) and disclosed in WO 03/004001. An advantageous aspect of using the controlled agglomeration method described in WO03/004001 is that it is possible to use a relatively large amount of liquid system for the particulate material without unwanted particle size growth. Thus, in one embodiment of the invention, the particulate material of the pharmaceutical composition has a geometric weight average diameter d_gw≧ 10 μm, such as ≧ 20 μm, 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, such as from about 100 to 1500 μm, from about 100 to about 1000 μm, or from about 100 to about 700 μm, or up to about 400 μm or up to 300 μm, such as from about 50 to about 400 μm, such as from about 50 to about 350 μm, from about 50 to about 300 μm, from about 50 to about 250 μm, or from about 100 to about 300 μm.

The compositions and dosage forms of the present invention are preferably formed by spray drying techniques, controlled agglomeration, lyophilization or coating of carrier particles or any other method of removing solvent. The dried product contains the active substance, preferably in dissolved form, completely dissolved in the form of a solid solution or partially dissolved in the form of a solid dispersion (including molecular dispersions and solid solutions).

However, it is preferred that the compositions and dosage forms of the present invention are produced by a process comprising the steps of:

i) producing the vehicle in liquid form, i.e. dissolving it if it is solid at room temperature,

ii) a vehicle which remains in the liquid state at a temperature below the melting point of the fibrate,

iii) dissolving a desired amount of fibrate in the vehicle,

iv) spraying the resulting solution onto a solid support having a temperature below the melting point of the vehicle,

v) mechanically working the resulting composition to obtain particles, i.e. a particulate material, and

vi) optionally subjecting the particulate material to conventional methods to prepare a solid dosage form.

In principle, pharmaceutical compositions comprising the active substance in at least partially solid dispersion or solution form can be prepared using any suitable method known in the art for preparing pharmaceutical compositions. The solid dispersion can be obtained in different ways, for example by using an organic solvent or by dispersing or dissolving the active substance in another suitable medium, for example an oily substance present in liquid form at room temperature or at elevated temperature. Solid dispersions are prepared by dissolving a physical mixture of the active substance (e.g., drug substance) and the carrier in a common organic solvent, followed by solvent evaporation (solvent method). The carrier is typically a hydrophilic polymer. Suitable organic solvents include pharmaceutically acceptable solvents in which the active substance is soluble, such as methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetone or mixtures thereof.

Suitable water-soluble carriers include polymers such as polyethylene glycol, poloxamers, polyoxyethylene stearates, poly-E-caprolactone, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinyl acetate copolymer PVP-PVA (Kollidon VA64), polymethacrylic acid polymers (Eudragit RS, Eudragit RL, Eudragit NE, Eudragit E), polyvinyl alcohol (PVA), Hydroxypropylcellulose (HPC), Hydroxypropylmethylcellulose (HPMC), methylcellulose, and poly (ethylene oxide) (PEO).

Polymers containing acidic functional groups may be suitable for use in solid dispersions which release the active substance within a preferred pH range to provide acceptable absorption in the intestine. These polymers may be selected from one or more of the following: hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), alginates, carbomers, carboxymethylcellulose, methacrylic acid copolymers (Eudragit L, Eudragit S), shellac, Cellulose Acetate Phthalate (CAP), starch glycolate, polacrilin, methylcellulose acetate phthalate, hydroxypropyl acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate and cellulose acetate trimellitate.

The weight ratio of active to polymer may be in the range of about 3: 1 to about 1: 20. Of course, narrower ranges from about 3: 1 to about 1: 5, such as from about 1: 1 to about 1: 3, and the like, may also be used.

Instead of using an organic solvent-based process, it is also possible to obtain a solid dispersion or a solid solution of one or more fibrates by dispersing and/or dissolving the active substance in the carrier composition used in the controlled coacervation process. Stabilizers and the like may be added to ensure stability of the solid dispersion/solution.

Pharmaceutical excipients and additives

In the present specification, the term "pharmaceutically acceptable excipient" refers to any material which is inert in the sense that it does not itself have substantially any therapeutic and/or prophylactic effect. These excipients may be added in order to obtain pharmaceutical, cosmetic and/or food compositions having acceptable technical characteristics.

Examples of suitable excipients for use in the compositions or solid dosage forms of the present invention include fillers, diluents, glidants, disintegrants, binders, lubricants and the like or mixtures thereof. Since the compositions or solid dosage forms of the present invention may be used for different purposes, excipients are generally selected in view of these different uses. Other pharmaceutically acceptable excipients which are suitable for use are, for example, acidifying agents, alkalinizing agents, preservatives, antioxidants, buffers, chelating agents, colorants, complexing agents, emulsifiers and/or solubilizers, flavorings and fragrances, humectants, sweeteners, wetting agents, etc.

Examples of suitable fillers, diluents and/or binders include lactose (e.g. spray dried lactose, alpha-lactose, beta-lactose, lactose,Each stageOr Fast-) Microcrystalline cellulose (each stage)MingOr Solka-) Hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substituted), hydroxypropylmethyl cellulose (HPMC) (e.g., Methocel E, F and K from Shin-Etsu Co., Ltd.),MethosoSH, such as Methocel E and Methosose 60 SH, 4,000cps F and Methosose 65 SH, 4,000, 15,000 and 100,000cps K; and 4,000, 15,000, 39,000, and 100,000 grades of methose 90 SH), methylcellulose polymers (e.g., Methocel A4C, Methocel a15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrin, maltodextrin, starch or modified starches (including potato starch, corn starch, and rice starch), calcium phosphates (e.g., calcium alkaline phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen, and the like.

Specific examples of diluents are e.g. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextran, dextrin, glucose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar and the like.

Specific examples of disintegrants are e.g. alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl starch (e.g. sodium starch glycolate), starch gum, gumAnd) And the like. Specific examples of binders are e.g. gum arabic, alginic acid, agar, carrageenan calcium, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, pectin, PEG, polyvinylpyrrolidone, pregelatinized starch and the like. .

The second composition may also contain a glidant and a lubricant. Examples include stearic acid, magnesium stearate, calcium stearate or other metal stearates, talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silicon dioxide, hydrogenated vegetable oil, corn starch, sodium stearyl fumarate, polyethylene glycol, alkyl sulfates, sodium benzoate, sodium acetate, and the like.

Other excipients which may be included in the compositions or solid dosage forms of the invention are, for example, flavoring agents, coloring agents, taste-masking agents, pH-adjusting agents, buffering agents, preservatives, stabilizing agents, antioxidants, wetting agents, humidity-adjusting agents, surfactants, suspending agents, absorption enhancing agents, agents for modified release, and the like.

Other additives in the compositions or solid dosage forms of the invention may be antioxidants, such as ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopheryl acetate, tocopheryl hemisuccinate, TPGS or other tocopherol derivatives, and the like. The carrier composition may also contain, for example, a stabilizer. The concentration of the antioxidant and/or stabilizer in the carrier composition is typically from about 0.1% w/w to about 5% w/w.

The compositions or solid dosage forms of the present invention may also contain one or more surfactants or substances with surface active characteristics. These substances participate in wetting the sparingly soluble active substance and thus contribute to an increase in the solubility of the active substance. Suitable surfactants for use in the compositions or solid dosage forms of the invention are surfactants, such as hydrophobic and/or hydrophilic surfactants, for example those disclosed in WO 00/50007 to Lipocine, inc.

Specific examples of suitable surfactants are polyethoxylated fatty acids, such as fatty acid mono-or diesters of polyethylene glycol or mixtures thereof, for example polyethylene glycol and mono-or diesters of lauric, oleic, stearic, myristic, ricinoleic acid, polyThe glycol may 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, polyethylene glycol glycerol fatty acid esters, i.e. esters as mentioned above but present in the form of glycerides of individual fatty acids; glycerol, propylene glycol, ethylene glycol, PEG or sorbitol esters formed with, for example, vegetable oils such as hydrogenated castor oil, almond oil, palm kernel oil, castor oil, almond oil, olive oil, peanut oil, hydrogenated palm kernel oil and the like, polyglycerol esters such as polyglycerol stearate, polyglycerol oleate, polyglycerol ricinoleate, polyglycerol linoleate, propylene glycol fatty acid esters such as propylene glycol monolaurate, propylene glycol ricinoleate and the like, mono-and diglycerides such as glycerol monooleate, glycerol diyl dioleae, glycerol mono-and/or dioleate, glycerol caprylate, glycerol caprate and the like; sterols and sterol derivatives; polyethylene glycol sorbitan fatty acid ester (PEG-sorbitan fatty acid ester) such as esters of PEG having various molecular weights as indicated above, and variousSeries; polyethylene glycol alkyl ethers such as PEG oleyl ether and PEG dodecyl ether; sugar esters such as sucrose monopalmitate and sucrose monolaurate; polyethylene glycol alkylphenols, e.g. polyethylene glycol alkyl phenolsX or N series; polyoxyethylene-polyoxypropylene block copolymers, for exampleA series of,A series of,And the like. The generic name of these polymers is "poloxamers", and the relevant examples in this specification are poloxamers 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 asSeries orSeries such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate and the like; lower alcohol fatty acid esters such as oleate, isopropyl myristate, isopropyl palmitate and the like; ionic surfactants, including cationic, anionic and amphiphilic ionic surfactants such as fatty acid salts, bile salts, phospholipids, phosphate esters, carboxylate esters, sulfate and sulfonate esters, and the like.

When a surfactant or mixture of surfactants is present in the composition or solid dosage form of the invention, the concentration of the surfactant is typically in the range of from about 0.1 to 80% w/w, such as from about 0.1 to about 20% w/w, from about 0.1 to about 15% w/w, from about 0.5 to about 10% w/w, or alternatively from about 0.10 to about 80% w/w, such as from about 10 to about 70% w/w, from about 20 to about 60% w/w or from about 30 to 50% w/w.

In a particular aspect of the invention, at least one of the one or more pharmaceutically acceptable excipients is selected from silicic acid or derivatives or salts thereof, including silicates, silica and polymers thereof; magnesium aluminium silicate and/or silicate (magnesium aluminium)um alumometasilicate), bentonite, kaolin, magnesium trisilicate, montmorillonite and/or saponite, Nuesellin^TM。

Absorbent material

Materials such as those mentioned immediately above are particularly suitable as absorbent materials for oily substances in pharmaceuticals, cosmetics and/or foodstuffs. In a particular embodiment, the material is used as an absorbent material for oily substances in pharmaceuticals. Materials that have the ability to act as absorbent materials for oily substances are also referred to as "oil absorbent materials".

Further, in the present specification, the term "absorption" is used to mean "absorption" and "adsorption". It is to be understood that whichever term is used, it includes absorption and adsorption phenomena. The terms "absorbent material" and "oil absorbent material" have the same meaning.

The absorbent materials suitable for use in the present invention are pharmaceutically acceptable solid materials which, when tested as described herein: 1) which has an oil absorption threshold (oilthreshold value) of 10% or more, further satisfies one or both of i) and ii) when tested according to the threshold test method disclosed herein, and when the material is used in the composition of the present invention:

i) the composition releases at least 30% of the hydrophobic or hydrophilic or water-miscible vehicle when tested according to the release test;

ii) the composition in the form of a tablet contains at least about 90% w/w of an oil absorbing material and exhibits a disintegration time of up to 60 minutes when tested according to the Ph.

The material is particularly suitable for use as an absorbent material for oily substances in pharmaceuticals, cosmetics and/or foodstuffs, in particular in pharmaceuticals.

It is important that the oil absorbent material meet at least two criteria. One of the tests is mandatory, i.e. a Threshold Test (Threshold Test) must be met. This test measures how much of the oily substance the oil absorbing material is able to absorb while maintaining the proper flow characteristics. It is important that the oil absorbing material used in the present invention (with or without oil absorption) has suitable flowability so that it can be readily mixed with other excipients and/or further processed into compositions without significant problems relating to, for example, adhesion to the equipment in which it is used. The assay is described below in the materials and methods section and provides an illustration of how the assay can be performed. The threshold test involves determining the flowability of solid materials loaded with different amounts of oil.

As can be seen from the above, the oil absorption threshold must generally exceed 10%, and the oil absorbing material typically has an oil absorption threshold of at least about 15%, such as at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 45%.

A material particularly suitable for use in the present invention, aerosearl 300, has a very high oil absorption threshold of about 60%. Thus, materials having an oil absorption threshold of at least 50%, such as at least about 55% or at least about 60%, are used in particular embodiments of the invention.

Furthermore, the oil absorbing material used in the present invention must satisfy at least one other Test, namely, Release Test (Release Test) and/or disintegration Test.

The release test measures the ability of an oil absorbing material to release oil absorbed into the material upon contact with water. This ability is very important, especially in the case of oily substances comprising an active substance. If the oil absorbing material is not capable of releasing oil from the material, there is a major risk that the active substance is released from the material to only a small extent. Thus, problems relating to bioavailability such as poor adsorption will occur in these cases.

A requirement of a release test is that the solid pharmaceutically acceptable material releases at least about 30%, such as at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% of the oil when tested as described herein. From the examples herein, suitable oil absorbing materials such as Aeroperl300 have much higher release. Thus, in particular embodiments of the invention, the solid pharmaceutically acceptable material releases at least about 65%, such as at least about 70%, at least about 75%, or at least about 80% of the oil when tested as described herein.

Disintegration tests were carried out not on solid materials in the form of granules but on tablets prepared with solid materials. The requirements with respect to disintegration are very important in order to ensure that when a solid dosage form comprises a solid material, said solid material does not provide the dosage form with undesired properties, such as undesired disintegration and bioavailability properties of the active substance contained in the dosage form. For some materials suitable for use in the present invention it is possible to compact tablets which themselves contain 100% w/w solid material. If this is the case, then the test is performed on such tablets. However, it is envisaged that there may be circumstances where it is difficult to prepare tablets from solid materials alone. In these cases, it is possible to add pharmaceutically acceptable excipients, usually used for the preparation of compressed tablets, at concentrations of up to 10% w/w or less. Examples of suitable pharmaceutically acceptable excipients include fillers, diluents, binders and lubricants. However, excipients generally classified as disintegrants should be avoided.

Thus, a solid pharmaceutically acceptable material for use in the tablet form of the present invention should have a disintegration time of at most 1 hour when tested as described herein, the tablet containing about 90% w/w or more, 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% of the pharmaceutically acceptable material when tested according to the ph.

In other embodiments, the solid pharmaceutically acceptable material present in tablet form when tested as described herein has a disintegration time of up to about 50 minutes, such as up to about 40 minutes, up to about 30 minutes, up to about 20 minutes, up to about 10 minutes or up to about 5 minutes, and the tablet contains about 90% w/w or more, 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% of the pharmaceutically acceptable material when tested according to the ph.

In a particular embodiment, the solid material used as absorbent material meets all three tests. Thus, when tested as described herein, the solid pharmaceutically acceptable material i) has an oil absorption threshold of at least about 10%, such as at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least 60%, ii) releases at least about 30%, such as at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% of the oil, and iii) the tablet form has a disintegration time of at most 1 hour, such as at most about 50 minutes, at most about 40 minutes, at most about 30 minutes, at most about 20 minutes, at most about 10 minutes, or at most about 5 minutes, the tablet contains about 90% w/w or more, 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% of the pharmaceutically acceptable material when tested according to the ph.

Other particular embodiments of the present invention are those wherein the solid pharmaceutical material used as an absorbent material in the composition of the present invention when tested as described herein

i) Has an oil absorption threshold of at least about 55%;

solid pharmaceutical materials when tested as described herein

ii) releases at least about 75% of the oil; and/or

Solid pharmaceutical material in tablet form when tested as described herein

iii) has a disintegration time of at most about 10 minutes, the tablet containing about 97.5% w/w of the pharmaceutically acceptable material when tested according to the Ph.

The solid pharmaceutically acceptable material used as absorbent material in the composition of the present invention is generally a particulate material in the form of, for example, powder, granules, and the like.

These particulate materials suitable for use as oil absorbing materials typically have a density of about 0.15g/cm³Or more, e.g., at least about 0.20g/cm³Or at least about 0.25g/cm³The bulk density of (a).

Further, the oil absorbing material typically has an oil absorption value of at least about 100g oil/100 g, such as at least about 150g oil/100 g, at least about 200g oil/100 g, at least about 250g oil/100 g, at least about 300g oil/100 g, or at least about 400g oil/100 g of the pharmaceutically acceptable material. The oil absorption values were determined as described in the experimental section herein.

The present inventors have found that a common feature of some materials suitable for use as oil absorbing materials is a relatively large surface area. Thus, the pharmaceutically acceptable material for use as the oil absorbing material of the present invention may have at least 5m²G is, for example, at least about 25m²A/g of at least about 50m²A/g of at least about 100m²A/g of at least about 150m²A/g of at least about 200m²A/g of at least about 250m²/g or at least about 275m²BET surface area in g.

As mentioned above, one feature of the pharmaceutically acceptable material used as the oil absorbing material of the present invention is that it maintains good fluidity even if it is loaded with an oily substance. Thus, flowability of a pharmaceutically acceptable material loaded with 25% w/w or more, such as 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 meets the ph.

It is clear that the oil absorbing material may comprise silicic acid or a derivative or salt thereof (e.g. silica or a polymer thereof) as a pharmaceutically acceptable excipient. However, depending on the mass used, the silica may be a lubricant or it may be an oil absorbing material. The quality of satisfying the latter function seems to be of utmost importance.

In a particular embodiment, the composition or solid dosage form of the invention comprises a pharmaceutically acceptable excipient having a structure corresponding to that of300 by weight of the silica.

The use of the oil absorbing material in the composition or dosage form of the invention is very advantageous in the preparation of pharmaceutical, cosmetic, nutritional and/or food compositions, wherein the composition comprises an oily substance. One of the advantages is the possibility of incorporating relatively large amounts of oily substances but still having a solid form of the material. Thus, by using the oil absorbing material of the present invention it is possible to prepare solid compositions having a relatively high loading of oily substances. In the pharmaceutical field, it would be advantageous to be able to incorporate relatively large amounts of oily substances into solid compositions, in particular in cases where the active substance does not have suitable properties of water solubility (e.g. poor water solubility), stability in aqueous media (i.e. degradation occurs in aqueous media), oral bioavailability (e.g. low bioavailability), etc., or when it is desired to modify the release of the active substance in the composition to obtain controlled, delayed, sustained and/or pulsed delivery of the active substance. Thus, in a particular embodiment, it is used for the preparation of a pharmaceutical composition.

The oil absorbing material for processing into the solid composition typically absorbs about 5% w/w or more, such as 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, about 90% w/w or more, or about 95% w/w or more of the oil or substance, and still be a solid material.

Oily substance

An important aspect of the present invention is a composition or solid dosage form comprising an oily substance.

In the present specification, the term "oily substance" broadly includes oils, paraffins, semi-solid materials and materials which are commonly used in the pharmaceutical industry as solvents (e.g. organic solvents) or co-solvents, and also therapeutic and/or prophylactic actives which are in liquid form at ambient temperature; the term also includes emulsions such as microemulsions and nanoemulsions (nanoemulsions) as well as suspending agents. The oil and oil-like material that can be absorbed is generally liquid at ambient or elevated temperatures (for practical reasons, the maximum temperature is about 250 ℃). It may be a hydrophilic, lipophilic, hydrophobic and/or amphiphilic material.

Oily substances suitable for use in the present invention are substances or materials having a melting point of at least about 10 ℃ and at most about 250 ℃.

In particular embodiments of the invention, the oily substance has a melting point of about 5 ℃ or more, for example about 10 ℃ or more, about 15 ℃ or more, about 20 ℃ or more or about 25 ℃ or more.

In other embodiments of the invention, the oily substance has a melting point of at least about 25 ℃, such as at least about 30 ℃, at least about 35 ℃ or at least about 40 ℃. For practical reasons, the melting point may not be too high in general, and the oily substances therefore generally have a melting point of at most about 300 ℃, for example at most about 250 ℃, at most about 200 ℃, at most about 150 ℃ or at most about 100 ℃. If the melting point is higher, a relatively high temperature may promote, for example, oxidation or other types of degradation of the active substance when a therapeutically and/or prophylactically active substance is included.

In the present specification, the melting point is determined by DSC (differential scanning calorimetry). The melting point was determined as the temperature at which the linearly increasing DSC curve intersects the temperature axis (see figure 1 for further details).

Oily substances of interest are generally substances which are used as so-called melt binders (melt binders) or solid solvents (in the form of solid dosage forms) in the manufacture of medicaments or as co-solvents or ingredients in medicaments for topical use. Which may be hydrophilic, hydrophobic and/or have surface-active properties. Oily substances which are generally hydrophilic and/or hydrophobic are suitable for the production of pharmaceutical compositions containing therapeutically and/or prophylactically active substances which have a relatively low water solubility and/or are suitable for use when the release of the active substance from the pharmaceutical composition is designed to be established, i.e. immediate or unmodified. Hydrophobic oily substances, on the other hand, are generally used in the manufacture of modified release pharmaceutical compositions. The considerations given above are simplified to illustrate the general principles, but in many cases other oily substances and other combinations of purposes are relevant, and thus the above examples should in no way limit the invention.

Generally, suitable hydrophilic oily substances are selected from: polyether glycols, for example, polyethylene glycol, polypropylene glycol; polyoxyethylene; polyoxypropylene; poloxamers and mixtures thereof, or they may be selected from: xylitol, sorbitol, potassium sodium tartrate, sucrose tribehenate, glucose, rhamnose, lactitol, behenic acid, hydroquinone monomethyl ether, sodium acetate, ethyl fumarate, myristic acid, citric acid, Gelucire 50/13 or other Gelucire types, such as Glucire44/14 and the like, Glucire 50/10, Glucire 62/05, Sucro-ester 7, Sucro-ester11, Sucro-ester 15, maltose, mannitol, and mixtures thereof.

Suitable hydrophobic oily substances may be selected from linear saturated hydrocarbons, sorbitan esters, paraffins; fats and oils such as cocoa butter, beef tallow, lard, polyether glycol esters; higher fatty acids such as stearic acid, myristic acid, palmitic acid, higher alcohols such as cetyl alcohol, stearyl alcohol, low melting waxes such as glyceryl monostearate, glyceryl monooleate, hydrogenated tallow, myristyl alcohol, stearyl alcohol, substituted and/or unsubstituted monoglycerides, substituted and/or unsubstituted diglycerides, substituted and/or unsubstituted triglycerides, yellow beeswax, white beeswax, carnauba wax, castor wax, Japan wax, acetylated monoglycerides; NVP polymers, PVP polymers, acrylic polymers, or mixtures thereof.

In an interesting embodiment, the oily substance is a polyethylene glycol having an average molecular weight in the range of from about 400 to about 35,000, such as from about 800 to about 35,000, from about 1,000 to about 35,000, such as 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, a molecular weight of from about 35,000 to about 100,000 of the polyethanol may be used.

In another interesting embodiment, the oily substance is a polyethylene oxide having a molecular weight of from about 2,000 to about 7,000,000, e.g., 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, e.g., from about 100,000 to about 1,000,000, from about 100,000 to about 600,000, from about 100,000 to about 400,000, or from about 100,000 to about 300,000.

In another embodiment, the oily substance is a poloxamer, such as poloxamer 188, poloxamer 237, poloxamer 338 or poloxamer 407 or other block copolymers of ethylene oxide and propylene oxide such asAnd/orAnd (4) series.Suitable block copolymers of the series include polymers having a molecular weight of about 3,000 or more, for example from about 4,000 to about 20,000 and/or a viscosity (Brookfield) of from about 200 to about 4,000cps, for example from about 250 to about 3,000 cps. Suitable examples includeF38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F127, 10R8, 17R8, 25R5, 25R8, and the like. Is suitably aThe series of block copolymers include polymers having a molecular weight of about 8,000 or more, such as from about 9,000 to about 35,000 and/or a viscosity (Brookfield) of from about 500 to about 45,000cps, such as from about 600 to about 40,000. The above viscosity of a substance which is pasty at outdoor temperature was determined at 60 ℃ and the above viscosity of a substance which is solid at room temperature was determined at 70 ℃.

The oily substance may also be a sorbitan ester, for example sorbitan diisostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquiisostearate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan triisostearate, sorbitan trioleate, sorbitan tristearate or mixtures thereof.

Of course the oily substance may also comprise a mixture of different oily substances, for example a mixture of hydrophilic and/or hydrophobic materials. Other suitable oily substances may be solvents or semi-solid excipients, such as propylene glycol, polyglycolized glycerides (including Gelucire 44/14), mixed fatty materials of vegetable origin including cocoa butter, carnauba wax, vegetable oils such as almond oil, coconut oil, corn oil, cottonseed oil, sesame oil, soybean oil, olive oil, castor oil, palm kernel oil, peanut oil, rape oil, grapeseed oil and the like, hydrogenated vegetable oils such as hydrogenated peanut oil, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated castor oil, hydrogenated coconut oil; natural fatty materials of animal origin including beeswax, lanolin, fatty alcohols including cetyl alcohol, stearyl alcohol, lauryl alcohol, myristyl alcohol, palmityl alcohol, stearic fatty alcohols; esters including glyceryl stearate, glycol stearate, ethyl oleate, isopropyl myristate; liquid transesterified semi-synthetic glycerides including Miglycol 810/812; amides or fatty alcohol amides including stearamide ethanol, diethanolamide of fatty coconut acids, acetic acid mono-and diglycerides, citric acid mono-and diglycerides, lactic acid mono-and diglycerides, polyglycerol esters of fatty acids, polyglycerol polyricinoleate, propylene glycol esters of fatty acids, sorbitan monostearate, sorbitan tristearate, sodium stearoyl lactylate, calcium stearoyl lactylate, diacetyl tartaric acid mono-and diglycerides and the like.

The pharmaceutical composition or solid dosage form of the invention may have about 5% w/w or more in the composition or dosage form, for example, an oily substance concentration of 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, about 90% w/w or more, or about 95% w/w or more.

In a particular embodiment, the concentration of the oily substance of the composition or solid dosage form of the invention is in the range of from about 20% to about 80% w/w, for example from about 25% to about 75% w/w.

One of the advantages is that it is possible to integrate relatively large amounts of oily substances while still retaining solid material. Thus, it is possible to prepare a solid composition having a relatively high oily substance amount by using the oil absorbing material of the present invention. Within the pharmaceutical field, it would be advantageous to be able to incorporate relatively large amounts of oily substances into solid compositions, especially where the active substance does not have suitable properties of water solubility (e.g. poor water solubility), stability in aqueous media (i.e. degradation occurs in aqueous media), bioavailability for oral administration (e.g. low bioavailability), etc., or where it is desired to modify the release of the active substance in the composition to obtain controlled, delayed, sustained and/or pulsed delivery of the active substance.

A further advantage is that the particulate material obtained is a free-flowing powder and is therefore readily processed into, for example, solid dosage forms such as tablets, capsules or sachets. Generally, the particulate material has properties suitable for producing tablets by direct compression without the addition of large amounts of other additives. A suitable test method for testing the flowability of particulate material is the method described in ph.eur. which measures the flow rate of material through a funnel having a 10.0mm diameter nozzle (orifice) to test flowability.

In an embodiment of the invention, at least part of the fibrate may be present in the composition in the form of a solid dispersion comprising a molecular dispersion and a solid solution. Typically, 10% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, such as 95% or more or about 100% w/w of the active substance is present in the composition in dissolved form.

Solid dosage form

The pharmaceutical compositions of the present invention are in the form of granules and may be used as such. However, in many cases it will be more convenient to present the composition in the form of granules, pellets, microspheres, nanoparticles, and the like, or in the form of solid dosage forms including tablets, troches, beads, capsules, grains, pills, granules, powders, pellets, sachets, lozenges, troches, and the like.

The solid dosage form of the invention may be a single unit dosage form or it may exist as a multiple depot (polydepot) dosage form containing a plurality of individual units, e.g. microtablets, beads and/or granules.

Typically, the pharmaceutical composition or solid dosage form of the invention is administered by the oral, buccal or sublingual route of administration.

The invention also relates to the above-mentioned expressions. Compositions/solid dosage forms for releasing the active substance in a fast release, sustained release or modified release manner are within the scope of the present invention.

The solid dosage form of the present invention comprises the above-described pharmaceutical composition in the form of granules. The details and details disclosed in this main aspect of the invention have been applied mutatis mutandis to the other aspects of the invention. Thus, the characteristics described and/or claimed herein for increased bioavailability, altered bioavailability parameters, reduced adverse food effects, and release of one or more fibrates of a pharmaceutical composition in particulate form are equally applicable to the solid dosage forms of the present invention.

Typically, the concentration of the pharmaceutical composition in particulate form is in the range of from about 5 to 100% w/w, such as 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% of the dosage form. In an embodiment of the invention, the concentration of the pharmaceutical composition in the form of particles is 50% w/w or more of the dosage form.

The solid dosage forms of the present invention are very stable. For example, the fibrate is present in an amount of at least 90%, or at least 95%, or at least 100% relative to the amount prior to storage, when measured after storage for three months at a temperature of about 40 ℃ and a relative humidity of about 75%. The physical stability is also very high, as can be seen from the examples below.

The solid dosage forms of the present invention may be obtained by processing the particulate material of the present invention by techniques well known to those skilled in the art. Typically, this involves the further addition of one or more of the pharmaceutically acceptable excipients mentioned herein.

The compositions or solid dosage forms of the present invention can be designed to release one or more fibrates in any suitable manner so long as the increase in bioavailability is maintained. Thus, the active substance may be released relatively rapidly to obtain an increased initial effect, which may be administered in a manner following zero or first order kinetics or which may be released in a controlled or modified manner to obtain a predetermined release profile. Common formulations are also within the scope of the invention.

The compositions or solid dosage forms of the present invention may also be coated with film coatings, enteric coatings, modified release coatings (release coatings), protective coatings, anti-adhesive coatings, and the like.

The solid dosage forms of the invention may also be coated to obtain suitable properties, for example with respect to the release of the active substance. Coatings may be used on single unit dosage forms (e.g., tablets, capsules) or they may be used on multiple library dosage forms or individual units thereof.

Suitable coating materials are, for example, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic polymers, ethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol, sodium carboxymethylcellulose, cellulose acetate phthalate, gelatin, methacrylic acid copolymers, polyethylene glycol, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zein.

Plasticizers and other ingredients may be added to the coating material. The same or different active substances can also be added to the coating material.

The pharmaceutical composition or solid dosage form of the present invention is designed to release the fibrate in a suitable manner. Specific release patterns are disclosed in the appended claims. Specific relevant absorption patterns are also given here.

Other embodiments of the invention

In another aspect, the present invention relates to a solid pharmaceutical composition comprising one or more fibrates and one or more oily substances in particulate form, said composition having a suitable flowability determined according to the method described in ph.eur. as determined by measuring the flow rate of the composition through a funnel having a 10.0mm mouthpiece. In order to avoid sticking to the production and/or filling equipment, it is very important that the particulate material flows smoothly. This feature is also important in case the particulate material is intended to be further processed into other types of preparations, such as solid dosage forms.

Another aspect of the present invention relates to a solid pharmaceutical composition in particulate form comprising one or more fibrates, one or more oily substances and one or more oil absorbing materials which i) has an oil absorption threshold of 10% or more and satisfies at least one of the following when tested according to the threshold test herein:

ii) releases at least 30% of the oil when tested according to the release test herein, and

iii) the tablet form has a disintegration time of at most 1 hour, the tablet containing about 90% w/w or more of the oil absorbing material when tested according to the Ph. In certain cases, it has been found to be advantageous to incorporate an absorbent material into the composition so that, for example, a high concentration of oily substances is obtained. In case the oily substance has a melting point of at most about 250 ℃, an integrated absorbent material may be particularly suitable. Examples of suitable oily substances and absorbent materials are given here.

In other particular embodiments, the fibrate is present in the form of an at least partially solid dispersion (including a solid solution).

In other embodiments, the present invention relates to a solid pharmaceutical composition or solid dosage form in the form of granules comprising one or more fibrates dissolved in one or more oily substances. In this respect, the fibrate is present in the particulate composition in the form of a solid solution and the presence of the solid solution can be detected by the DSC test as mentioned herein. In this respect, the granular composition is prepared by dissolving the fibrate in the oily substance and spraying the mixture (optionally after addition of other active substances and/or of one or more pharmaceutically acceptable excipients) on the carrier described herein, optionally at elevated temperature. Preferably, the concentration of oily substance is at least about 10% w/w.

Materials and methods

Material

Fenofibrate (supplied by Sigma)

Lactose monohydrate 200 mesh (from DMV)

The amount of the granulated silicon dioxide is,300，(Degussa)

polyethylene glycol 6000 (polyethylene glycol 6000),e6000 (from BASF)

The preparation method comprises the following steps of (1) poloxamer 188,f-68 (from BASF)

The glycerol monostearate is obtained by mixing the raw materials,MD50, (from Danisco cutter), ph.

Avicel PH200 (microcrystalline cellulose) (from FMC)

Magnesium stearate

Tablets, capsules or granules may be coated enterically with different types of polymers such as hydroxypropylmethylcellulose acetate succinate (Aqoat), cellulose acetate phthalate CAP, hydroxypropylmethylcellulose phthalate HPMCP or methacrylic acid copolymers such as Eudragit L30D, Eudragit100/S, Eudragit 100/L.

Tricor tablet formulation

Tablets are tablets containing fenofibrate, useful for oral administration, containing 54mg or 160mg of micronized fenofibrate per tablet.

The tablets contained the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide, xanthan gum and pigment.Used as lipid regulating agent. Ingested with foodThe recommended dosage of (B) is 54-160 mg/day. Provided at strengths of 54 and 160mgTablets, but provided at strengths of 67 and 200mgAnd (4) capsules. The tablet has higher bioavailability than capsule. Other trade namesOr

Lipanthyl formulations

By co-micronizing fenofibrate and a solid surface active ingredient to produce an intimate and finely dispersed mixture of the two ingredients67M。

Device

Laboratory scale fluidized bed apparatus: stream-1.

The melt feed unit is a prototype consisting of separate units for gas sources for heating the atomizer, pressure tank and feed tube. The granules were manually sieved and mixed with an ultra granular (extragranular) excipient in a Turbula mixer.

Tablet pressing was performed on a single punch press Diaf (TM) 20.

Method

According to the method of the present invention, the fenofibrate drug is dissolved in a molten vehicle and applied on a granular carrier as follows:

the vehicle was melted in a beaker placed in a microwave oven. The beaker was transferred to a temperature controlled hotplate equipped with a magnetic stirrer. Fenofibrate was slowly dissolved in the melt at a temperature of 75 ℃ under magnetic stirring. The hot solution was transferred to a pressure tank to melt spray the carrier in the fluidized bed. The granular product was released from the fluidized bed and manually screened through a 0.7mm or 1.0mm sieve. The screened product was mixed with magnesium stearate in a Turbula mixer for 0.5 minutes. If the ultra-particulate phase has to be integrated, the ultra-particulate phase is premixed with the particles in a Turbula mixer for 3 minutes.

Tablet pressing was performed on a single punch press Diaf (TM) 20.

Threshold test

The test consists of determining the flowability of the invention by measuring the flow rate of the material through a funnel having a 10.0mm diameter nozzle, according to the method described in ph.

Viscolio (medium chain triglyceride MCT; Miglyol 812N from Condea) was added to 100g of a solid pharmaceutically acceptable material and mixed by hand, said material being the material examined for the use according to the invention. The resulting mixture was screened through a 0.3mm screen to ensure a uniform mixture. The oil was added stepwise until a stream of 100g of the mixture could not flow through the nozzle. If the test materials have a high total volume (as for example Aeroperl 300), only 50g of the mixture is used when testing these mixtures. The maximum oil concentration at which the material can be kept flowing is called the threshold value (expressed in% w/w).

Release test

14.3mg of a fat-soluble coloring material Sudan II (BDH) obtained from BDH VWR International) Dissolved in 50.0g of viscoleo (fractionated medium chain triglycerides).

10g of oil was added to 10.0g of solid pharmaceutically acceptable material and mixed until the oil was completely absorbed into the solid material, which was the material examined for use according to the invention. The mixture was then sieved through a 0.3mm sieve to obtain a uniform mixture.

1.00g of the mixture was transferred to a centrifuge tube and 3.00ml of water was added. The suspension was mixed in a blood sample tumbler (blood sample turner) for 1 hour and then centrifuged at 5000rpm for 10 minutes. The upper phase of oil and water was carefully transferred to a beaker and the water was evaporated in an oven at 80 ℃ until the weight was constant. The amount of oil released from the solid material was calculated based on the weight of the residue after evaporation of the aqueous phase.

Disintegration test

Disintegration time was determined as described in ph.

Solubility test

The assay was performed according to ph.eur 2.9.3 using a stirring apparatus (paddle appaatus). Quantitation was performed using HPLC with UV detection.

Medium: 900ml of water containing 0.75% Sodium Lauryl Sulfate (SLS)

Rotation speed: 50rpm

Temperature: 37 deg.C

Sampling time: 10. 20, 30, 45 and 60 minutes

Acceptance criteria: > 75% at 45 min

Determination of bulk density

Bulk density was measured by pouring 100g of the powder into a 250ml graduated cylinder. Bulk density is defined as the tapped bulk density in g/ml. Determination was performed as per ph.

Determination of oil absorption value

The oil absorption value was determined by adding a well-defined amount (10g) of viscoleo to a well-defined amount of the test pharmaceutically acceptable material (100 g). The oil absorption value (expressed as g viscoleo/100g of material) was reached when a further 10g of oil resulted in a material with unsuitable flow properties, i.e. the material did not meet the requirements that were required to be met when tested according to ph.

Determination of BET surface area

The apparatus used was a micromeritics Gemini 2375. The method used was according to USP volumetric method based on a multi-point determination.

Determination of flowability

Flowability was determined by measuring the flow rate of the material through a funnel having a nozzle diameter of 10.0mm, according to the method described in ph.

Determination of weight change

The tablets prepared in the examples herein were subjected to a weight change test according to ph.

Determination of average tablet hardness

The tablets prepared in the examples herein were subjected to a tablet hardness test using a Schleuniger Model 6D instrument and following the general instructions for the instrument.

Determination of solid solutions

According to the invention, the fibrate is dissolved in the vehicle. In particular, tests involving differential scanning calorimetry were performed. The granular composition, solid dosage form or mixture of vehicle and fibrate (after the formation of the presumed solid solution) is tested. Standard DSC equipment connected to a PC was used.

Sample size: 10mg in an aluminum pan

Heating rate: 5 deg.C/min, from 27 deg.C to 110 deg.C

Evaluation: if no endothermic peak (endotherm peak) of the fibrate is observed and if the interval of melting does not shift significantly compared to the vehicle alone, the fibrate is considered to be present in the dissolved or amorphous state.

Geometric weight mean diameter d _gw Is determined

The geometric weight average diameter was determined by using a laser diffraction dispersion method on the obtained particles (or starting materials) in air. The measurements were carried out in a Sympatec Helos device recording the distribution of the same sphere diameter at a dispersion pressure of 1 bar. The distribution is fit to a volume-size lognormal distribution. As used herein, "geometric weight mean diameter" refers to the mean diameter of a volume-size lognormal distribution.

In vivo studies in Beagle dog (Beagle dog)

For the purpose of determining the relative to a commercially available fenofibrate tablet formulationBioavailability of the compositions of the invention was studied in vivo using beagle dogs.

Experimental work was performed in Denmark using 4 male beagle dogs, each dog weighing 12-18kg (starting weight). The study was conducted in an open, non-randomized, crossover study format. Each animal is its own control. Oral doses of fenofibrate were administered according to the following data. Dogs were fasted overnight prior to dosing (water ad libitum) and fed 5 hours after dosing (water ad libitum). Each dog was dosed with a defined dose of fenofibrate without regard to the weight of the dog.

Blood samples were collected outside the jugular vein at the following time points: before application, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours after application. 4ml of blood was collected, mixed with EDTA and the sample frozen (-80 ℃). Blood samples were analyzed using on-line extraction LC/MS and the results are expressed in mg/mL.Using pharmacokinetic softwareThe determined whole blood concentration profile of fenofibrate was processed (Pharsight, California; USA) to calculate pharmacokinetic parameters. Dose adjustments were made to all data as needed.

The following examples, which are intended to illustrate the invention, do not limit the scope of the invention. Pharmaceutical compositions and dosage forms of the invention are exemplified in examples 1-7. The results of the in vitro solubility test of the dosage forms of the invention are shown in example 8. The results of the stability test of the dosage form of the present invention are shown in example 9. Results of in vivo comparative studies (plasma concentrations) in beagle dogs can be found in examples 10-12.

Example 1

Immediate release tablet with improved bioavailability

Fenofibrate was dissolved at a concentration of 17% in polyethylene glycol 6000 and poloxamer 188 (70: 30w/w ratio) at 75 ℃. 244g of the melted solution was sprayed onto 200g of lactose in a fluidized bed stream-1 at 75 ℃. The granulated product was screened through a 0.7mm sieve and mixed with magnesium stearate in a Turbula mixer for 0.5 minutes. The mixture was compressed into 10mm tablets having a strength of 50mg (540mg cup-shaped tablets with compound (tableted with compound cup shaped)).

Substance(s)	％	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
Total of	100.00	537.45

Average disintegration time: 26 minutes, hardness: 45N

Example 2

Immediate release tablet with improved bioavailability

As described in example 1, a 10mm tablet of 50mg strength (540mg cup-shaped tablet with compound) and the following composition was prepared:

substance(s)	％	mg
			Fenofibrate	9.30	50.00
Lactose	44.78	240.64
			PEG 6000	45.43	244.12
Magnesium stearate	0.50	2.69
			Total of	100.00	537.45

Average disintegration time: 21 minutes, hardness: 55N

Example 3

Immediate release tablet with improved bioavailability

As described in example 1, a 10mm tablet of 50mg strength (540mg cup-shaped tablet with compound) and the following composition was prepared:

substance(s)	％	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
Total of	100.00	537.45

Average disintegration time: 22 minutes, hardness: 48N

Example 4

Immediate release tablet with improved bioavailability

Fenofibrate was dissolved in polyethylene glycol 4000 at a concentration of 17% at 75 ℃. 244g of the melted solution was sprayed onto 200g of lactose in a fluidized bed stream-1 at 75 ℃. The granulated product was screened through a 0.7mm sieve and mixed with magnesium stearate in a Turbula mixer for 0.5 minutes. The mixture was compressed into 10mm tablets with a strength of 50mg (540mg cup-shaped tablets with compound).

Substance(s)	％	mg
			Fenofibrate	930	50.00
Lactose	44.78	24064
			PEG 4000	45.43	244.12
Magnesium stearate	0.50	2.69
			Total of	100.00	537.45

Average disintegration time: 21 minutes, hardness: 55N

Example 5

Immediate release tablet with improved bioavailability

Fenofibrate was dissolved in polyethylene glycol 4000 at a concentration of 17% at 75 ℃. 244g of the dissolved solution was sprayed onto a mixture of 190g of lactose and 10g of Sodium Dodecyl Sulfate (SDS) in a fluidized bed stream-1 at 75 ℃. The granulated product was screened through a 0.7mm sieve and mixed with magnesium stearate in a Turbula mixer for 0.5 minutes. The mixture was compressed into 10mm tablets with a strength of 50mg (540mg cup-shaped tablets with compound).

Substance(s)	％	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
Total of	100.00	537.45

Average disintegration time: 18 minutes, hardness: 65N

Example 6

Immediate release tablet with improved bioavailability

Fenofibrate is dissolved at a concentration of 30% in polyethylene glycol 4000 and poloxamer 188 (70: 30w/w ratio) at 75 ℃. 466g of the melted solution were sprayed onto 200g of Aeroperl300 in a fluidized bed stream-1 at 75 ℃. The granulated product was screened through a 0.7mm sieve and mixed with magnesium stearate in a Turbula mixer for 0.5 minutes. The mixture was compressed into 13.5mm tablets with a strength of 150mg (720mg cup-shaped tablets with compound).

Substance(s)	％	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
Total of	100.00	717.88

Average disintegration time: 35 minutes, hardness: 35N

Example 7

Formulations of the invention

Tablets having a strength of 50mg and 160mg respectively and having the following composition were prepared as described in examples 1, 4 and 6:

substance(s)	Composition (I)	Amg	Bmg	Cmg	Dmg	Emg
							Medicine	Fenofibrate	160.09	50.05	50.08	50.09	159.99
Medium 1	PEG6000PEG4000GMS(Rylo)	208.12--	171.09--	124.29--	-24457-	--86.15
							Medium 2	Poloxamer 188	89.19	73.33	53.27	-	-
Carrier	Lactose Aeroparrl 300	356.51-	231.87-	-63.89	232.02-	163.01-
							Excipient	Magnesium stearate Avicel	409-	2.65-	1.47-	5.32-	8.35417.50
Total of		81800	52900	293.00	532.00	835.00
							Hardness of	N	60	44	44	47	102
Disintegration time	Minute (min)	25	14	30	48	＞55
							Diameter of	Mm	Ob1ong	12	12	10	Oblong

Example 8

Solubility test

Tablet formulation a of the present invention in example 7 was subjected to the solubility test described in the methods section with the following results:

time (min)	% dissolution
		0	0
10	28
		20	56
30	74
		45	88
60	97

Example 9

Stability test

Samples of the tablet formulation a of the invention in example 7 were stored under the following conditions and subjected to the solubility (stability) test described in the methods section after 1 month and 3 months of storage, respectively; "% dissolved" indicates the percentage of fenofibrate dissolved after 45 minutes:

a sample of the tablet formulation a of the present invention in example 7 was stored and subjected to the fibrate assay under the following conditions, respectively, and the results were as follows:

samples of inventive tablet formulation a from example 7 were stored under the following conditions, respectively, and subjected to degradation product testing according to ph.eur. (degradation product A, B, G and unknown product cumulatively into a total degradation product; HPLC method) with the following results:

example 10

In vivo study in dogs

160mg of formulation A of example 7 was used in beagle dogs as described in the methods section above, relative to 160mgThe results of the in vivo study of formulation A (batch No.: 098212E21) were as follows:

blood concentration (mL/mL) after administration of the formulation (average of 4 dogs):

relative bioavailability based on AUC (according to the invention, A-): 306 percent. Relative to c_max(according to the invention, A-)：356％。

Example 11

In vivo study in dogs

160mg of formulation A of example 7 was used in beagle dogs as described in the methods section above, relative to 160mgThe results of a second in vivo study of formulation A (batch No.: 098212E21) were as follows:

blood concentration (mg/mL) after administration of the formulation (average of 4 dogs):

relative bioavailability based on AUC (invention, A-): 198 percent. Relative to c_max(invention, A-)：238％。

Example 12

In vivo study in dogs

As described in the methods section above, 2X 50mg of formulation B, C of example 7 and D were used in beagle dogs versus 2X 67mg(batch No.: 75641) and the results are as follows:

blood concentration (mg/mL) after administration of the formulation (average of 4 dogs):

relative bioavailability based on AUC (invention, B-67M): 532 percent. Relative to c_max(invention, BA-67M)：548％。

Relative bioavailability (invention, C ^) based on AUC67M): 228 percent. Relative to c_max(invention, C-67M)：161％。

Relative bioavailability based on AUC (invention, D-67M): 424 percent. Relative to c_max(invention, D-67M)：329％。

Claims (18)

1. A tablet of fenofibrate contained in a vehicle that is hydrophobic, hydrophilic or miscible with water, wherein (i) the vehicle comprises a polyethylene glycol and a poloxamer in a weight ratio of between 1: 3 and 10: 1, the polyethylene glycol having an average molecular weight of 3000-35000 and (ii) the tablet comprises 10-35% by weight of fenofibrate, based on 100% of the total weight of the tablet.

2. The tablet of claim 1, wherein the poloxamer is poloxamer 188.

3. The tablet of claim 1, wherein the polyethylene glycol has an average molecular weight of about 6000.

4. The tablet of claim 1, wherein the vehicle is non-aqueous.

5. The tablet according to claim 1, wherein the concentration of fenofibrate in the vehicle is from 10% w/w to 90% w/w, calculated on the total weight of fenofibrate and vehicle.

6. The tablet of claim 1, further comprising one or more pharmaceutically acceptable excipients.

7. The tablet of claim 6, wherein the pharmaceutically acceptable excipient is selected from the group consisting of fillers, diluents, disintegrants, binders, glidants, and lubricants.

8. A tablet according to claim 6 wherein at least one pharmaceutically acceptable excipient is silicic acid or a derivative or salt thereof.

9. The tablet according to claim 6, wherein at least one pharmaceutically acceptable excipient is a silicic acid or a derivative or salt thereof selected from the group consisting of: silicates, silica; magnesium aluminum silicate, magnesium aluminum orthosilicate, bentonite, kaolin, magnesium trisilicate, montmorillonite and/or saponite.

10. The tablet of claim 6, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of: silicon dioxide, magnesium aluminum silicate and magnesium aluminum orthosilicate.

11. The tablet of claim 1, further comprising a pharmaceutically acceptable additive selected from the group consisting of flavoring agents, coloring agents, taste-masking agents, pH-adjusting agents, buffering agents, preservatives, stabilizers, antioxidants, wetting agents, humidity-adjusting agents, surfactants, suspending agents, and absorption enhancers.

12. The tablet of claim 1 which is a unit dosage form.

13. A tablet according to claim 1, wherein the individual units of the tablet are coated with a coating selected from the group consisting of film coatings, modified release coatings, enteric coatings, protective coatings and anti-adhesive coatings.

14. The tablet according to claim 1, wherein the fenofibrate is embedded in a matrix that releases the fenofibrate by diffusion.

15. The tablet of claim 14, wherein the matrix remains substantially intact during drug release.

16. The tablet according to claim 1, wherein the fenofibrate is embedded in a matrix that releases the fenofibrate by erosion.

17. The tablet according to claim 1, wherein the fenofibrate is released from the dosage form by diffusion through a substantially water-insoluble coating.

18. The tablet according to claim 1, wherein the fenofibrate is stable.