KR20080004600A - A tablet comprising a fibrate - Google Patents

Abstract

Stable tablets and pharmaceutical compositions in particulate form comprising a fibrate, for example fenofibrate, dissolved or dispersed in an non-aqueous vehicle with improved bioavailability, thereby eliminating the food effect so that the tablet or composition can be administered to a patient irrespective of being in fed or fasted state.

Description

Tablets containing fibrate {A TABLET COMPRISING A FIBRATE}

The present invention relates to novel solid dosage forms and pharmaceutical compositions comprising fibrates, in particular fenofibrate. In particular, the present invention discloses solid dosage agents with improved bioavailability and, therefore, dosing agents with reduced content of active ingredients compared to conventional standard unit dosages. Solid dosage agents of the present invention include fibrate dissolved in a suitable vehicle or mixture of vehicles. Such dosage agents are especially intended for oral use and exhibit good storage stability, i.e. they are stable. The invention also relates to methods of making solid dosage agents and pharmaceutical compositions and uses thereof.

Fibrate is a lipid modulator. Examples of fibrate include gemifibrozil, fenofibrate, bezafibrate, clofibrate and cipropibrate. The compounds are considered prodrugs and metabolized into their active metabolites in vivo. The following is based on specific examples of fibrates, ie fenofibrate, for illustrative purposes only. Fenofibrate is chemically referred to as 2- [4- (4-chlorobenzoyl] -2-methyl-propanoic acid, 1-methylethyl ester and has the following structure:

Fenofibrate is a white solid. This compound is water insoluble. Melting point is 79-82 degreeC. Fenofibrate is metabolized to the active substance fenofibric acid. Fenofibric acid has a loss half life of about 20 hours. Determination of fenofibric acid detectable amount in blood of a patient can reflect the efficacy of fenofibrate uptake. Fenofibric acid reduces total cholesterol (total-C), LDL-C, apo-lipoprotein B, total triglycerides and triglyceride suspended lipoproteins (VLDL) in patients under treatment. In addition, treatment with fenofibrate results in an increase in high density lipoprotein (HDL), and apo-lipoproteins apoAI and apo AII. Fenofibrate acts as an effective lipid modulator that provides unique and clinical advantages over existing products of the fibrate family of drug substances. Fenofibrate causes a substantial reduction in plasma triglyceride levels in patients with hypertriglyceridemia and plasma cholesterol and LDL-C levels in patients with hypercholesterolemia and mixed dyslipidemic.

Fenofibrate also reduces serum uric acid in subjects suffering from hyperuricemia and normal subjects by increasing urinary excretion of uric acid.

Elevated levels of total cholesterol, low density lipoprotein cholesterol (LDL-C), and apo-lipoprotein B (apo B) have been demonstrated by clinical studies to be associated with human atherosclerosis. Reduced levels of high density lipoprotein cholesterol (HDL-C) and its transport complex, apolipoprotein A (apo AI and apo AII), are associated with the development of atherosclerosis.

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

In addition, lipid improvement seen in fenofibrate therapy is associated with reduced progression to microalbuminuria in patients with type II diabetes. Recent studies have shown that fenofibrate treatment for more than three years is effective in reducing the progression of kidney disease in patients with type II diabetes without diabetic kidney disease (Am. J. Kidney Dis. 2005, vol. 45, p. 485 -493).

Fenofibrate is also pointed out as an adjunct diet for the treatment of hypertriglyceridemia (Fredrickson type IV and V hyperlipidemia) adult patients. Improving glycemic control in diabetic patients with fasting atherosclerosis will typically reduce fasting triglycerides and can eliminate the need for pharmacological interventions.

Fibrate is a drug substance known to be poorly and variably absorbed after oral administration. Typically they are prescribed to be taken with food to increase bioavailability.

Efforts to increase the bioavailability of the drug and thereby its efficacy have led to many improvements in the form of the most commonly used fibrate and fenofibrate dosage forms. However, there is still a need for improved dosage agents compared to the compositions currently used which include those that provide crystalline fenofibrate in micronized form. In particular, the difference in the bioavailability of the fasting patient's drug versus the postprandial drug's bioavailability can be substantially reduced or overcome, and / or in the individual observed and / or presently treated with a commercially available product. There remains a need for compositions and dosage agents that exhibit suitable bioavailability that can substantially reduce or overcome the differences between individuals. Moreover, there is also a need for new dosage agents and / or compositions that can reduce the observed side effects.

In particular, a fibrate is dissolved and is represented as a composition that is not a soft dosage agent in the form of powders, granules, granulates, particles, beads, pellets or other forms of particulate material or liquid media. There is an unmet need for developing solid compositions in particulate form.

Summary of the Invention

We dissolve fibrate, for example fenofibrate, in a suitable vehicle and use the resulting composition for the preparation of solid dosage agents (ie, fibrate is present in solid solution as a dosage form that excludes material in liquid form). It has been found that the bioavailability of can be significantly enhanced. The present invention provides pharmaceutical compositions and formulations that exhibit a release profile that greatly enhances in vivo bioavailability in patients in need thereof, which specifically eliminates or significantly reduces food effects. In particular, the inventors have been successful in preparing solid dosage agents such as tablets containing fibrate in dissolved form. The advantages of stable solid dosage agents useful for oral administration are very well known.

Thus, in a first aspect the invention relates to solid oral dosage forms comprising fibrate dissolved in a vehicle that is hydrophobic, hydrophilic or water-miscible. Useful solid dosage agents are in the form of tablets, beads, capsules, granules, pills, granules, granules, powders, pellets, sachets or troches, and useful fibrate may be fenofibrate, bezafibrate, Active metabolites and analogs thereof, including any related fibric acid such as clofibrate, cipropibrate and fenofibric acid. Preferably, the fibrate is selected from the group consisting of 160 mg, 145 mg, 130 mg, 120 mg, 110 mg, 100 mg, 33 mg, 37 mg, 40 mg, 43 mg, 48 mg and 87 mg of fenofibrate Fenofibrate present in the solid dosages of the present invention in an amount.

In a second aspect the present invention relates to a pharmaceutical composition comprising fibrate dissolved in a vehicle that is hydrophobic, hydrophilic or water-miscible; In a further aspect the invention relates to a pharmaceutical solid composition in particulate form comprising a fibrate, hydrophobic or hydrophilic or water-miscible vehicle and an oil-sorption material, wherein the composition exhibits an oil threshold of at least 10%.

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

정제 및 Lipanthyl 및 Antara™ 캡슐과 비교할 때, 본 발명의 고형 투약제 및 조성물에서 페노피브레이트의 생체이용률이 상당히 증대되어 나타남을 보여주고 있다.Further aspects of the present invention will become apparent from the following description. Clinical trial studies (see examples herein) show that the fenofibrate solid dosages and pharmaceutical compositions of the present invention eliminate or significantly reduce the food effect when compared to commercially available fenofibrate drugs. It may be administered either in a state or postprandial state, ie absorption is relatively independent of whether the patient takes the composition or dosage with or without any meal. Accordingly, the present invention allows a patient to take only one tablet at any time each day as compared to commercially available fenofibrate-containing drugs, which must be taken with food to obtain the desired bioavailability of the active ingredient. To do that. In addition, the in vivo comparative test of dogs (see Examples herein) is a commercially available solid dosage agent, ie Tricor, comprising the same active ingredient.

Tablets and Lipanthyl Compared to Antara ™ capsules, it has been shown that the bioavailability of fenofibrate is significantly increased in the solid dosages and compositions of the present invention.

Furthermore, it is strongly accepted that the present invention provides compositions of fibrate and / or solid dosage agents that can significantly reduce the differences in and / or between individuals generally observed after oral administration. It is also expected that modified release of fibrate may reduce the frequency of side effects associated with the stomach. Moreover, it is expected that significantly higher amounts of fibrate will be absorbed and thus excreted through the excrement unchanged in an equivalently smaller amount, which results in a lower daily dosage of the active ingredient, for example, It is meant that 120 mg tablets or even 110 mg tablets comprising the pharmaceutical composition of the invention can be administered to a patient.

details

Justice

As used herein, the term "active ingredient" or "active pharmaceutical ingredient" provides a pharmacologically active or other direct effect in the diagnosis, healing, alleviation, treatment, or prevention of a disease, or in the body of a human or other animal. By any ingredient intended to affect any function or structure. The term includes components present in a modified form of a drug product that may undergo chemical changes in the manufacture of the drug product and are intended to provide a particular activity or effect.

In this context, the term “hydrophilic” refers to “water-loving”, ie, hydrophilic molecules or portions of molecules that are typically electrically polarized and may form hydrogen bonds with water molecules so that they are oil or other “non-polar” Refers to making it easier to dissolve in water than a solvent.

In this context, the term “amphiphilic” refers to a molecule (as surfactant) having a polar water-soluble group attached to a water-insoluble hydrocarbon chain. Thus, one end of the molecule is hydrophilic (polar) and the other is hydrophobic (non-polar).

In this context, the term “hydrophobic” means a compound that tends to be electrically neutral and non-polar, favoring other neutral and nonpolar solvents or molecular environments.

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

As used herein, the term “vehicle” means any solvent or carrier in a pharmaceutical product that does not have any pharmacological role. For example, water is the vehicle for silica, and propylene glycol is the vehicle for many antibiotics.

In the present context, the term “solid dispersion” means a drug or active ingredient or substance, ie, typically fine particulate dispersion dispersed at particulate level in an inert vehicle, carrier, diluent or matrix in the solid state.

In this context, the term “solid solution” means a drug or active ingredient or substance dissolved at the molecular level in an inert vehicle, carrier, diluent or matrix in the solid state.

As used herein, the term “analogue” means a chemical compound that is structurally similar to another.

The term "drug" means a compound intended for use in diagnosis, healing, alleviation, treatment or disease prevention for humans or other animals.

In this context, the term "drug agent" refers to the form in which the drug is delivered to the patient. It may be parenteral, topical, tablet, oral (liquid or dissolved powder), suppositories, inhalants, transdermal and the like.

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

또는 Antara™ 시중에서 구입가능한 유사한 페노피브레이트-포함 제품의 값에 대해 80 ~ 125 % 내에 있는 경우, 두 조성물이 생물학적 등가성을 갖는 것으로 여겨진다. As used herein, the term “biological equivalence” refers to the scientific criteria when comparing certain generic and brand name drugs to each other. For example, if a drug is cycled at the same rate when given at similar doses under similar conditions, the drug is biologically equivalent. Parameters often used in bioequivalence studies include t _max , c _max , AUC _{0 -infinity} and AUC _{0 -t} . Other related parameters are W ₅₀ , W ₇₅ And / or MRT. Thus, one or more of these parameters can be applied when determining the presence of biological equivalency. Moreover, in this context, the value of the parameter used is the TriCor used in the test.

Or when the composition is within 80 to 125% relative to the value of an Antara ™ commercially available fenofibrate-containing product.

In this context, “t _max ” means time to reach maximum plasma concentration (c _max ) after administration; AUC _{0 -infinity} or AUC means the area from time 0 to infinity under the plasma concentration versus time curve; AUC _0-t means the area from time 0 to time t under the plasma concentration versus time curve; W ₅₀ means the time when the plasma concentration is at least 50% of the c _max ; W ₇₅ means the time when the plasma concentration is at least 75% of the c _maximum ; MRT means the retention time of a fibrate, such as fenofibrate (and / or an analog thereof).

In this context, the term “medicament” or “medicament” means a compound used to treat a disease, injury or pain. Medicines are precisely classified into "prophylactic", ie, techniques of maintaining health and "therapeutic", ie, techniques of health recovery.

In this context, “controlled release” and “modified release” are equivalent terms that address any type of release of fenofibrate from a composition of the invention that is suitable for obtaining a specific therapeutic or prophylactic response after administration to a subject. It is intended to be. One skilled in the art knows how controlled release / modified release differs from that of regular tablets or capsules. The terms "release in a controlled manner" or "release in a modified manner" have the same meaning as described above. The terms include slow-moving type release (slow release: As a result, c _max is lower and, t _max is over t _1/2 is not changed delayed), prolonged release (extended release: As a result, c _max is lowered, t over the _maximum delay, apparent t _1/2 is sometimes longer); Delayed release (delayed release: As a result, c _max is delayed a delay time and thus the t _max according but unchanged, t _1/2 is not changed), and the pulse-like discharge (pulsatile release), a sudden release (burst release) , Sustained release, prolonged release, chrono-optimized release, fast release, to enhance the initiation level of action. The term also encompasses the use of various enzymes or pH changes, for example, to control the release of certain conditions in the body, eg, drug substance.

In this context, the term “erosion” or erosion means gradual breakage of the surface or structure of a material, for example a tablet or a coating of a tablet.

Active drug substance

The drug or active substance of the dosage forms and pharmaceutical compositions of the invention is fibrate. Examples of useful fibrates include bezafibrate, cipropibrate, clinofibrate, clofibrate, etophylline, clofibrate, fenofibrate, gemfibrozil, pyrifibrate, simfibrate and tocofibrate; Particularly useful are active metabolites and analogs thereof, including any related fibric acid such as gemfibrozil, fenofibrate, bezafibrate, clofibrate, cipropibrate and 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 fibrate and / or fibric acids.

The concentration of fibrate in the vehicle may be at least 10% w / w based on the total weight of the 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 25% w / based on the total weight of the fibrate and vehicle at least w, or at least 30% w / w, in particular at least 35% w / w; The concentration of fibrate in the vehicle is 90% w / w or less, or 80% w / w or less, or 75% w / w or less, or 70% w / w or less, or 60, based on the total weight of the fibrate and vehicle no more than% w / w, or no more than 50% w / w, or no more than 40% w / w, or no more than 35% w / w based on the total weight of the fibrate and vehicle. Preferably, the fibrate is completely dissolved in the non-aqueous vehicle. However, minor generation of crystalline or microcrystalline active drugs may not affect the enhanced bioavailability of the solid dosage agents and pharmaceutical compositions of the present invention. Thus, at least 90% w / w 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 fenofibrate is completely dissolved in the vehicle or vehicle system to be present in the dosage or pharmaceutical composition.

In addition to the content of fibrate, the dosage and pharmaceutical compositions of the present invention may comprise an additional active drug substance, preferably one additional drug substance. Preferably, the additional drug substance is of the type generally employed for the same indication as the fibrate. A specific example is ethytimibe. However, combination products comprising two, three or four active ingredients for different indications or therapies as well as combination products with three or even four drug substances used for the same indication are contemplated.

Examples of additional drug substances include other antilipidemic agents such as statins; Lipid modulators such as: acipimox, vinibibrate, etofibrate, niceritrol, nicofibrate, pyridazyl, ronifibrate, tocopheryl nicotinate; Combination with cardiovascular drugs such as ace inhibitors: alasepril, benazepril, captopril, silazapril, delapril, enalapril, enalapril, posinopril, imidapril, ricinopril, Moexipril, perindopril, quinapril, ramipril, spirapril, temocapryl, teprotide, transdorapril, jofenofril; Calcium channel blockers such as: amlodipine, aranidipine, azelnidipine, varnidipine, benidipine, bepridil, silnidipine, diltiazem, eponidipine, felodipine, galopamil, isradipine, lassidi Pin, lercanidipine, manidipine, mibepradil, nicardidipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nirenedipine, verapamil; Alpha-blockers such as: alfuzosin, bunazosin, doxazosin, indoramine, naphthopidyl, phenoxybenzamine, phentolamine, prazosin, tamsulosin, terrazosin, thymoxamine, tolazoline, urapidil; Beta-blockers such as: acebutolol, alprenolol, amosulolol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, butsinolol, bunitrolol, butane Pranolol, carazolol, carteolol, carvedilol, celiprolol, esmolol, indenolol, labetalol, landiolol, levobtaxolol, levobutolol, mepindolol, metipranolol, metoprolol, nadolol, Nebivolol, nipradilol, oxprenolol, phenbutolol, pindolol, propanolol, sotalol, thalolinol, tertatolol, timolol; Angiotensin ii blockers such as: candesartan, eprosartan, irbesartan, rosartan, olmesartan, reference tasosartan, misartan, valsartan; Vasodilation New economies such as: cadmium azine, diazoxide, dihydralazine, endedral azine, hydralazine, minoxidil, toralazine, tolazoline, carbochromen, cinefazet, for reference Chlorida Rol, dirazep, etaphenone, pendylin, hexobendine, oxyphedrine, trapidyl, trimetazidine, azafetin, methane, bencyclane, buplomedil, butalamine, calcitonin gene-related peptide, ceti Dill, cinefazide, cyclandelate, di-isopropylammonium dichloroacetate, pasudil, fenprodil, inositol nicotinate, naphthydrofuryl, nicotinyl alcohol, oxpentetiphylline [pentoxyphylline], penti Filin, fipratechol, propentophylline, lauvacin, xanthin ecotinat; Centrally acting hypertensives: apraclonidine, brimonidine, clonidine, guanabenz, guanapasin, methyldopa, moxonidine, rilmenidine, thiamenidine; Antiarrhythmic medications such as: azmalin, civenzoline, disopyramid, hydroquinidine, pyrmenol, procainamide, quinidine, aphridine, mexyltine, tocainide, diprafenone, encainide, flecainide , Lorcainide, physicinide, propaphenone, bretillium, acecainide, amiodarone, azimilide, bretyllium, sibenzoline, dophenylide, ibutylide, nifecalant, sotalol, sibenzoline, verapamil ; Antithrombotic agents such as: apsizimab, aspirin, cilostazol, clopidogrel, chlorichromen, dipyridamole, ditazole, eftipibatide, indobufen, ramipevan, orbopiban, picotamide, sasa Lepogrerate, cibrapivan, ticlopidine, tyropiban, trapidil, triflusal, zemylopiban; Diuretics such as: acetazolamide, brinzolamide, diclofenamide, dorzolamide, metazolamide, azosemide, bumetanide, ethacrynic acid, etozoline, pruceamide, pyretanide, tora Semid, isosorbide, mannitol, amylolide, canrenone, potassium canrenoate, spironolactone, triamterene, altizide, bemethidide, bendrofluazide, benzthiazide, butizide, chlorothia Zide, chlortalidone, clofamid, cyclopentthiazide, cyclothiazide, epitide, hydrochlorothiazide, hydroflumethiazide, indafamid, mebutideide, mepruside, methiclothiazide, Meticlan, metolazone, polythiazide, quinetazone, teclothiazide, trichloromethiazide, tripamide, zipamide; Antidiabetic drugs such as: acarbose, acetohexamide, biguanide, buformin, carbutamide, chloropropamide, epalestat, glybenclamide, glybornuride, glyclazide, Glymeprid, Glypide, Glyquidone, Glycentiide, Glysolamide, Glysoxide, Glybuzol, Glyclopyramid, Glycyclamide, Glymidine Sodium, Metformin Hydrochloride, Midagazole, Migitol , Nateglinide, phenformin hydrochloride, pimagedin, pioglitazone hydrochloride, pramtinide, repaglinide, rosiglitazone, sorbvinyl, tolazamide, tolbutamide, troglitazone, boligose; Substances such as: Q10, vitamins (nicotinamide, pyridoxine HCL, B12, tocopherol, ascorbic acid, etc.), and common antioxidants are also included in useful combinations.

Additional drug substances or substances may also be used or included in combination with drugs that may cause undesirable levels of triglycerides and / or cholesterol. Thus, the compositions according to the invention can be used or included in combination with drugs, for example retroviral protease inhibitors such as isotretinoin or HIV protease inhibitors, antipsychotics such as olanzapine and the like.

As mentioned, combination products with fibrates are not limited to the combination of two active substances and triple or quadruple therapy may also be of particular note.

Vehicle

Useful vehicles in this context are vehicles that are water-miscible, hydrophilic or hydrophobic. Useful vehicles are non-aqueous materials.

Examples of hydrophobic vehicles useful in the present invention include straight chain saturated hydrocarbons, paraffins; Fats and oils such as cacao butter, tallow, laards; Higher fatty acids such as stearic acid, myristic acid, palmitic acid; Hydrogenated tallow, substituted and / or unsubstituted triglycerides, lead, white lead, carnauba wax, castor wax, wax and mixtures thereof.

, 예를 들어 Gelucire 44/14 로 판매되는 많은 제품 중 하나일 수 있다.Examples of water-miscible vehicles useful in the present invention include water-miscible polar lipids such as sorbitan esters, polyether glycol esters; Higher alcohols such as cetanol, stearyl alcohol; Glyceryl monooleate, 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 is also advantageously polyglycolated glycerides such as the registered trade name Gelucire

For example, it may be one of many products sold as Gelucire 44/14.

Examples of useful hydrophilic or water-miscible vehicles include polyvinylpyrrolidone, polyvinyl-polyvinylacetate copolymer (PVP-PVA), polyvinyl alcohol (PVA), PVP polymers, acrylic polymers, polymethacrylic polymers ( Eudragit RS; Eudragit RL, Eudragit NE, Eudragit E), myristyl alcohol, cellulose derivatives comprising: hydroxypropyl methyl-cellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxy-methylcellulose , Hydroxyethyl cellulose, pectin, cyclodextrin, galactomannan, alginate, carrageenate, xanthan gum and mixtures thereof.

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

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

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

In a preferred embodiment of the invention, the vehicle is polyethylene glycol (PEG), preferably polyethylene glycol (PEG) having an average molecular weight of at least 3000, more preferably at least 4000, and optionally a poloxamer such as poloxamer 188 And a preferred weight ratio of 1: 3 to 10: 1, preferably 1: 1 to 5: 1, more preferably 3: 2 to 4: 1, especially 2: 1 to 3: 1, especially about 7: 3 Mixed polyethylene glycol (PEG).

Bioavailability

(Tricor

) 의 흡수 정도는 공복 상태와 비교할 때 식사시 약 35 % 까지 증가된다.In general, it is known that absorption and bioavailability of a therapeutically active substance can be influenced by a variety of factors when administered orally. Such elements include the presence of food in the gastrointestinal tract, and in general, the gastrointestinal retention time of the drug substance is considerably longer in the presence of food than the fasting state. If the bioavailability of the drug substance is affected beyond a certain level due to the presence of food in the gastrointestinal tract, the drug substance is considered to have a food effect. Food effects are important because there is a risk associated with the administration of the drug substance to patients who have recently consumed food. This risk stems from the possibility that the patient may adversely affect absorption into the bloodstream, such that the patient will suffer from insufficient absorption to receive treatment for the condition. For example, in the case of fenofibrate, the situation is different in that food increases the intake rate. Thus, a lack of intake of food simultaneously with the drug substance may cause insufficient absorption. Commercially available product Lipanthyl containing fenofibrate (Abbott Laboratories)

(Tricor

) Absorption is increased by about 35% at mealtime compared to fasting.

As described above, there is still a need for new pharmaceutical compositions comprising at least one fibrate in which the bioavailability of the active compound is suitable and / or the food effect is reduced or eliminated. In the present context, the term “suitable bioavailability” can improve the bioavailability when administration of the composition according to the invention is compared with the bioavailability obtained after administration of the active substance (s) to a general tablet; Or is intended to mean that the bioavailability is at least the same or improved as compared to the bioavailability obtained after administration of a commercially available product containing the same active substance (s) in the same amount. In particular, it is desirable to reduce the dosage administered as much as possible by obtaining a more complete intake of the active compound. Furthermore, pharmaceutical compositions and dosage agents comprising fibrates may also reduce or eliminate the need for food to be taken concurrently with the dosage agent, allowing the patient more freedom when the drug is administered. In addition, improved or enhanced bioavailability may lead to improved treatment as it will enable reduced doses and / or less frequent administration and reduced variability in plasma levels and the same therapeutic response even when food is not limited. For example, another method for improving treatment of a condition in which fenofibrate is directed is to balance the release of fenofibrate into the gastrointestinal tract in such a way that the plasma concentration enhancement of fenofibrate is initially obtained or delayed over time of administration, Ie by applying a modified or delayed release composition comprising at least one fibrate.

In one embodiment, the present invention is selected from the group consisting of 160 mg, 145 mg, 130 mg, 120 mg, 110 mg, 100 mg, 33 mg, 37 mg, 40 mg, 43 mg, 48 mg and 87 mg of fenofibrate To dosage forms comprising fenofibrate.

In a preferred embodiment, the solid dosage agent comprises 145 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 130 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 120 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 110 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 100 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 48 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 43 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 87 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 40 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 37 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 33 mg of fenofibrate.

For example, for fenofibrate, absolute bioavailability data based on injectable compositions are not available (primarily due to solubility problems in aqueous media). Commercially available fenofibrate containing compositions include surface-active agents and / or lipophilic media, for example. Since surface-active agents can improve bioavailability, the bioavailability of such compositions may already be sufficient. However, there is still a need for the development of flexible formulation techniques that allow the preparation of various dosage forms. Thus, the need for such improved and / or more flexible compositions may be to obtain bioavailability that is the same as or better than already seen in commercially available products.

Thus, the AUC / AUC _control value obtained by the administration of the solid dosage agent or pharmaceutical composition of the present invention is at least in the range of bioequivalence (ie, 0.80 to 1.25), or at least 1.1, or at least 1.2, or at least 1.3, or At least 1.4, or at least 1.5, or about 1.75 or more, or about 1.8 or more, or about 1.9 or more, or about 2.0 or more, or about 2.5 or more, or about 2.75 or more, or about 3.0 or more, or about 3.25 or more, or Or at least about 3.5, or at least about 3.75, or at least about 4.0, or at least about 4.25, or at least about 4.5, or at least about 4.75, or at least about 5.0, wherein the AUC values are measured under similar conditions. Basically, the relative AUC value reflects the bioavailability of two formulations comprising the same amount of active ingredient, eg, the same amount of fenofibrate.

정제의 c_최대 값과 비교할 때 본 발명의 고형 투약제 또는 약학 조성물을 투여하여 얻은 c_최대 값은 바람직하게는 생물학적 등가성의 범위 (즉, 0.80 내지 1.25), 또는 적어도 1.1 초과, 또는 적어도 1.2 초과, 또는 적어도 1.3 초과, 또는 적어도 1.4 초과, 또는 적어도 1.5 초과, 또는 적어도 1.6 이상, 또는 적어도 2.0 초과, 또는 적어도 2.5 초과, 또는 적어도 3.0 초과이고, 이때 c_최대 값은 유사한 조건 하에서 측정된 것이다.Similarly, commercially available Tricor

C _max values obtained by administration of a solid dosage agents or pharmaceutical compositions of the invention when compared with c the _maximum value of the purification is preferably a biological range of equivalence (i.e., 0.80 to 1.25), or at least 1.1 greater than, or at least 1.2 excess, Or at least 1.3, or at least 1.4, or at least 1.5, or at least 1.6, or at least 2.0, or at least 2.5, or at least 3.0, wherein the c _maximum value is measured under similar conditions.

The main object of the present invention is to reduce or eliminate food effects. Thus, the composition or solid dosage agent has a value of at least about 0.85 when administered orally to a mammal in need thereof (AUC _fasting / AUC _postprandial ), at a limit of less than 90% at least 0.75; Or at least about 0.9, or at least about 0.92, or at least about 0.95 or more, or at least about 1 or more, showing no significant food adverse effect.

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

Furthermore, such pharmaceutical compositions or solid dosage forms in particulate form of the present invention, when orally administered to a mammal in need thereof, when administered in the same or less dosage than commercially available products containing the same fibrate, It is inherently biologically equivalent to a commercially available product containing fibrate.

In specific embodiments thereof, the dosage is about 98% w / w or less, or about 95% w / w or less, or about 90% w / of the dosage of fibrate administered in the form of a commercially available product comprising fibrate or less, or about 85% w / w or less, or about 80% w / w or less, or about 75% w / w or less, or about 70% w / w or less, or about 65% w / w or less, or about Up to 60% w / w, or up to about 55% w / w, or up to about 50% w / w.

In general, biological equivalence is measured through one or more of the following parameters: t _max (maximum plasma concentration attainment time), c _max (maximum plasma concentration), AUC _{0 -t} (time 0 to time t area under curve), AUC _{0 -infinity} (area under curve of time 0 to time infinity), W ₅₀ (time period when plasma concentration is at least 50% of c _max ), W ₇₅ (time period when plasma concentration is at least 75% of c _max ) and / or MRT (average residence time).

The main problem with treatment with fibrates lies in the large differences between individuals or within individuals. The fenofibrate-comprising pharmaceutical composition in particulate form, when compared to that of a commercially available fibrate product under dosages that provide the same conditions and equivalent therapeutic effects when orally administered to a mammal in need thereof, and / or It is expected to reduce individual differences.

, 또는 대안적으로 피브레이트가 페노피브레이트인, 캡슐 형태의 Antara™ 또는 Lipanthyl

이다. 피브레이트가 겜피브로질인 경우, 시중에서 구입가능한 적절한 제품은 Lopid

이고; 피브레이트가 베자피브레이트인 경우, 시중에서 구입가능한 적절한 제품은 Bezalip

이고; 피브레이트가 클로피브레이트인 경우, 시중에서 구입가능한 적절한 제품은 Atromid

이고; 피브레이트가 시프로피브레이트인 경우, 적합한 시중에서 구입가능한 제품은 Lipanon

이다.In the comparative tests mentioned above, commercially available products are in the form of tablets Tricor

Or alternatively Antara ™ or Lipanthyl in capsule form, wherein the fibrate is fenofibrate

to be. If fibrate is gemfibrozil, a suitable product commercially available is Lopid

ego; If fibrate is bezafibrate, a suitable product commercially available is Bezalip

ego; If the fibrate is clofibrate, a suitable product commercially available is Atromid

ego; If the fibrate is cipropibrate, a suitable commercially available product is Lipanon

to be.

Manufacturing method

The particulate composition of the present invention may be prepared by any method suitable for incorporation of poorly water soluble active materials. The pharmaceutical composition may be prepared by any convenient method such as granulation, mixing, spray drying, and the like. A particularly useful method is the method described in international application WO 03/004001, which describes a controlled flocculation method, i.e. a method for producing particulate material by a method capable of controlling the increase in particle size. The method comprises spraying a first composition comprising a vehicle in active form and an active substance onto a solid carrier. Typically, the vehicle has a melting point of at least 5 ° C., which must actually be below the melting point of the active material. In the present invention, the melting point of the vehicle should not exceed 250 ° C.

It is within the skill of one of ordinary skill in the art to select, by general knowledge and routine experiments, a suitable vehicle which is pharmaceutically acceptable, capable of completely or at least partially dissolving or dispersing an active substance and having a melting point within the desired range. . Suitable carrier candidates are described in WO 03/004001, which is incorporated herein by reference.

In the present context, suitable vehicles are, for example, those mentioned as described in WO 03/004001 as well as as a vehicle or as an oil material. An advantage of using the controlled flocculation method described in WO 03/004001 is that it is possible to apply a relatively large amount of liquid system to the particulate material without an undesirable increase in particle size. Thus, in one embodiment of the invention, the particulate material of the pharmaceutical composition has a geometric weight average diameter d _gw ≧ 10 μm, for example ≧ 20 μm, about 20 to about 2000 μm, about 30 to about 2000 μm, about 50 to about 2000 μm, about 60 to about 2000 μm, about 75 to about 2000 μm, such as about 100 to about 1500 μm, about 100 to about 1000 μm or about 100 to about 700 μm, or 400 μm or less, or 300 μm or less, such as about 50 to about 400 μm, such as about 50 to about 350 μm, about 50 to about 300 Μm, about 50 to about 250 μm or about 100 to about 300 μm.

Compositions and dosage agents of the present invention are preferably formed by spray drying techniques, controlled flocculation, freeze-drying or coating on carrier particles, or other solvent removal methods. The dried product comprises the active substance which is partially dissolved as a solid dispersion comprising molecular dispersion and solid solution or completely dissolved as solid solution, preferably present in dissolved form.

However, the compositions and dosage agents of the present invention are preferably prepared by a method consisting of the following steps:

i) taking the vehicle in liquid form, ie melting the vehicle if it is solid at room temperature,

ii) maintaining the liquid vehicle at a temperature below the melting point of the fibrate,

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

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

v) mechanically manipulating the resulting composition to obtain particles, ie particulate material, and

vi) optionally, applying the particulate material to a conventional solid dosage form manufacturing method.

Pharmaceutical compositions comprising the active substance in at least partially solid dispersion or solution form can in principle be prepared using any suitable method of preparing pharmaceutical compositions known in the art. Solid dispersions may be employed in several ways, for example, by using an organic solvent, or by dispersing or dissolving the active substance in another suitable medium (eg, an oily material in liquid form at room temperature or at elevated temperatures). Can be obtained. Solid dispersions (solvent methods) are prepared by dissolving a physical mixture of tint and active substance (eg drug substance) in a general organic solvent and then evaporating the solvent. The carrier is often a hydrophilic polymer. Suitable organic solvents include pharmaceutically acceptable solvents wherein the active substance is soluble and is, for example, methanol, ethanol, methylene chloride, chloroform, ethyl acetate, acetone or mixtures thereof.

Suitable water soluble carriers include polymers such as polyethylene glycol, poloxamer, polyoxyethylene stearate, poly-epsilon-caprolactone, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinylacetate copolymer PVP-PVA ( Kollidon VA64), poly-methacrylic polymers (Eudragit RS, Eudragit RL, Eudragit NE, Eudragit E) and polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose And poly (ethylene oxide) (PEO).

Polymers containing acidic functional groups may be suitable for solid dispersions, which release the active substance in the desired pH range to provide acceptable absorption in the intestines. The polymer is hydroxypropyl methylcellulose phthalate (HMPCP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), alginate, carbomer, carboxymethylcellulose, methacrylic acid copolymer (Eudragit L, Eudragit S), shellac, cellulose acetate phthalate (CAP), starch glycolate, polyacrylic, methyl cellulose acetate phthalate, hydroxypropiocellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate and cellulose acetate trimelli At least one selected from the group comprising tate.

The weight ratio of active material to polymer can be from about 3: 1 to about 1:20. However, narrower ranges from about 3: 1 to about 1: 5, such as from about 1: 1 to about 1: 3, may also be used.

Except using methods based on organic solvents, solid solutions or solid dispersions of one or more fibrates can be obtained by dispersing and / or dissolving the active compound in the carrier composition used in the controlled flocculation method. Stabilizers and the like may be added to ensure the stability of the solid dispersion / solid solution.

Pharmaceutical excipients and additives

In the present context, the term "pharmaceutically acceptable excipient" is intended to mean any material which is inert in the sense that it is substantially free of any therapeutic and / or prophylactic effect itself. Such excipient (s) may be added to enable obtaining pharmaceutical, cosmetic and / or foodstuff compositions, which have acceptable technical properties.

Examples of suitable excipients used in the compositions or solid dosage agents according to the invention include fillers, diluents, glidants, disintegrants, binders, lubricants and the like or mixtures thereof. As a composition or solid dosage form according to the invention which can be used for other purposes, excipients are selected in view of such many uses. Other pharmaceutically acceptable excipients for proper use include, for example, acidifying agents, alkalizing agents, preservatives, antioxidants, buffers, chelating agents, colorants, complexing agents, emulsifiers and / or solubilizers, flavorings and perfumes, humec Tants, sweeteners, humectants, and the like.

, 각종 등급의 Pharmatose

, Microtose

또는 Fast-Floc

), 미세결정성 셀룰로오스 (각종 등급의 Avicel

, Elcema

, Vivacel

, Ming Tai

또는 Solka-Floc

), 히드록시프로필셀룰로오스, L-히드록시프로필셀룰로오스 (저급 치환), 히드록시프로필 메틸셀룰로오스 (HPMC) (예를 들어, Shin-Etsu, Ltd 사의 Metolose SH, Methocel E, F 및 K, 예컨대 4,000 cps 등급의 Methocel E 및 Metolose 60 SH, 4,000 cps 등급의 Methocel F 및 Metolose 65 SH, 4,000, 15,000 및 100,000 cps 등급의 Methocel K; 및 4,000, 15,000, 39,000 및 100,000 등급의 Metolose 90 SH), 메틸셀룰로오스 중합체 (예컨대, Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), 히드록시에틸셀룰로오스, 나트륨 카르복시메틸셀룰로오스, 카르복시메틸렌, 카르복시메틸히드록시에틸셀룰로오스 및 기타 셀룰로오스 유도체, 수크로오스, 아가로오스, 소르비톨, 만니톨, 덱스트린, 말토덱스트린, 전분 또는 개질된 전분 (감자 전분, 옥수수 전분 및 벼 전분 포함), 칼슘 포스페이트 (예를 들어, 염기성 칼슘 포스페이트, 칼슘 하이드로겐 포스페이트, 디칼슘 포스페이트 히드레이트), 칼슘 술페이트, 칼슘 카르보네이트, 나트륨 알기네이트, 콜라겐 등이 포함된다. Examples of suitable fillers, diluents and / or binders include lactose (eg, spray-dried lactose, α-lactose, ß-lactose, Tabletose)

Pharmatose of various grades

, Microtose

Or Fast-Floc

), Microcrystalline cellulose (various grades of Avicel

, Elcema

, Vivacel

, Ming Tai

Or Solka-Floc

), Hydroxypropylcellulose, L-hydroxypropylcellulose (lower substitution), hydroxypropyl methylcellulose (HPMC) (e.g., Metolose SH, Methocel E, F and K from Shin-Etsu, Ltd, such as 4,000 cps Grade Methocel E and Metolose 60 SH, Grade 4,000 cps Methocel F and Metolose 65 SH, Grade 4,000, 15,000 and 100,000 cps Grade Methocel K; and Grade 4000, 15,000, 39,000 and 100,000 Metolose 90 SH), methylcellulose polymer ( For example, Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrin , Maltodextrin, starch or modified starch (including potato starch, corn starch and rice starch), calcium phosphate (eg, basic calcium phosphate, cal Hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen etc. are included.

Specific examples of diluents include, for example, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextran, dextrin, dextrose, fructose, kaolin , Lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar and the like.

및 Explotab

) 등이 있다. 구체적인 결합제의 예에는, 예를 들어, 아카시아, 알긴산, 아가, 칼슘 카르라기난, 나트륨 카르복시메틸셀룰로오스, 미세결정성 셀룰로오스, 덱스트린, 에틸셀룰로오스, 겔라틴, 액체 글루코오스, 구아 검, 히드록시프로필 메틸셀룰로오스, 메틸셀룰로오스, 펙틴, PEG, 포비돈, 전호화 전분 등이 있다.Specific examples of disintegrants include, for example, alginic acid or alginate, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polyacrylic potassium, sodium starch glycolate, starch Pregelatinized starch, carboxymethyl starch (e.g. Primogel

And Explotab

). Examples of specific binders include, for example, acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose , Methylcellulose, pectin, PEG, povidone, pregelatinized starch and the like.

Glidants and lubricants may also be included in the second composition. Examples include stearic acid, magnesium stearate, calcium stearate or other metallic stearates, talc, waxes and glycerides, light mineral oils, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl Fumarate, polyethylene glycol, alkyl sulfates, sodium benzoate, sodium acetate and the like.

Other excipients that may be included in the compositions or solid dosage forms of the invention include, for example, flavors, colorants, taste masking agents, pH-adjusting agents, buffers, preservatives, stabilizers, antioxidants, wetting agents, humidity regulators, surface-active agents , Suspending agents, absorption enhancers, and agents for modified release.

Other additives in the composition or solid dosage form according to the invention are antioxidants, for example 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, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives and the like. The carrier composition may also include a stabilizer, for example. The concentration of stabilizer and / or antioxidant in the carrier composition is generally from about 0.1% w / w to about 5% w / w.

Compositions or solid dosage agents according to the invention may also comprise one or more surfactants or materials with surface-active properties. The substance is expected to contribute to the improved solubility characteristics of the active substance, as it relates to the wetting of the weakly soluble active substance. Suitable surfactants for use in the compositions or solid dosage agents according to the invention are, for example, surfactants such as hydrophobic and / or hydrophilic surfactants as described in WO 00/50007 (Lipocine, Inc.).

계열; 폴리에틸렌 글리콜 알킬 에테르, 예컨대 PEG 올레일 에테르 및 PEG 라우릴 에테르; 당 에스테르, 예컨대 수크로오스 모노팔미테이트 및 수크로오스 모노라우레이트; 폴리에틸렌 글리콜 알킬 페놀, 예컨대 Triton

X 또는 N 계열; 폴리옥시에틸렌-폴리옥시프로필렌 블록 공중합체, 예컨대 Pluronic

계열, Synperonic

계열, Emkalyx

, Lutrol

, Supronic

등으로부터 선택될 수 있다. 이들 중합체들의 일반 명칭은 "폴록사머" 이고, 본 문맥에서의 관련 예는 플록사머 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 및 407; 소르비탄 지방산 에스테르, 예컨대 Span

계열 또는 Ariacel

계열, 예컨대 소르비난 모노라우레이트, 소르비탄 모노팔미테이트, 소르비탄 모노올레이트, 소르비탄 모노스테아레이트 등; 저급 알코올 지방산 에스테르, 예컨대 올레이트, 이소프로필 미리스테이트, 이소프로필 팔미테이트 등; 양이온성, 음이온성 및 양친매성 계면활성제를 포함하는 이온성 계면활성제, 예컨대 지방산 염, 담즙산염, 인지질, 인산 에스테르, 카르복실레이트, 술페이트 및 술포네이트 등이다Specific examples of suitable surfactants include fatty acid mono or diesters of polyethoxylated fatty acids such as polyethylene glycol or mixtures thereof such as lauric acid, oleic acid, stearic acid, myristic acid, ricinoleic acid and mono- or polyethylene glycol. Diester, polyethylene glycol is 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, ie esters that are previously-mentioned esters, but in the form of glyceryl esters of individual fatty acids; Glycerol, propylene glycol, ethylene glycol, PEG or, for example, sorbitol esters with vegetable oils such as: hydrogenated castor oil, almond oil, palm kernel oil, castor oil, apricot kernel oil, olive oil, peanut oil, Polyglycerided fatty acids such as hydrogenated palm kernel oils, such as polyglycerol stearate, polyglycerol oleate, polyglycerol ricinoleate, polyglycerol linoleate, propylene glycol fatty acid esters such as propylene glycol monolaurate, propylene glycol lysine Mono- and diglycerides such as nolate, such as glyceryl monooleate, glyceryl dioleate, glyceryl mono- and / or dioleate, glyceryl caprylate, glyceryl caprate and the like; Sterols and sterol derivatives; Polyethylene glycol sorbitan fatty acid esters (PEG-sorbitan fatty acid esters) such as esters of PEG with various molecular weights as described above and various Tweens

line; Polyethylene glycol alkyl ethers such as PEG oleyl ether and PEG lauryl ether; Sugar esters such as sucrose monopalmitate and sucrose monolaurate; Polyethylene glycol alkyl phenols such as Triton

X or N series; Polyoxyethylene-polyoxypropylene block copolymers such as Pluronic

Series, Synperonic

Series, Emkalyx

, Lutrol

, Supronic

And the like. The generic names of these polymers are “poloxamers” and related examples in this context 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 as Span

Series or Ariacel

Family such as sorbin 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 surfactants such as fatty acid salts, bile salts, phospholipids, phosphate esters, carboxylates, sulfates and sulfonates, and the like.

If a surfactant or mixture of surfactants is present in the composition or solid dosage agent of the invention, the concentration of surfactant (s) is generally from about 0.1 to 80% w / w, such as from about 0.1 to about 20% w / w. , About 0.1 to about 15% w / w, about 0.5 to about 10% w / w, or alternatively, about 0.10 to about 80% w / w, such as about 10 to about 70% w / w, about 20 To about 60% w / w or about 30 to about 50% w / w.

In certain embodiments of the present invention one or more of the one or more pharmaceutically acceptable excipients may be selected from silica acids or derivatives or salts thereof, including silicates, silicon dioxide and polymers thereof; Magnesium aluminosilicate and / or magnesium aluminomethilicate, bentonite, kaolin, magnesium trisilicate, montmorillonite and / or saponite, Nuesellin ^™ .

Sorption  material

Materials such as those mentioned immediately above are particularly useful as sorption materials for oily materials in pharmaceuticals, cosmetics and / or foodstuffs. In certain embodiments, the material is used as a sorption material for oily materials in pharmaceuticals. Materials that can function as sorption materials for oily materials also mean "oil sorption materials".

In addition, in this context, the term "sorption" is used to mean "sorption" as well as "sorption". Whenever one of the above terms is used, it is to be understood that it is intended to address adsorption as well as absorption. The terms "sorption material" and "oil sorption material" are intended to have the same meaning.

Sorption materials suitable for use in accordance with the present invention are pharmaceutically acceptable solid materials, which, when tested as described herein, are as follows:

i) when tested according to the critical tests disclosed herein, having an oil threshold of at least 10% and the material is used in the compositions of the present invention, which further satisfies one or both of i) and ii):

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

ii) the composition in the form of a tablet comprises at least about 90% w / w of an oil-sorbing material, Ph. Eur. When tested according to the disintegration test, disintegration times of up to 60 minutes are shown.

The materials are particularly useful as sorption materials for pharmaceuticals, cosmetics and / or foodstuffs, especially oily materials in pharmaceuticals.

It is important that the oil sorption material satisfies more than one test. One of the tests is mandatory, i.e. must meet the critical test. This test provides a measure of how much oily material the oil sorbent material can absorb while retaining proper flow properties. Oil sorption materials (with or without absorbed oil) for use in accordance with the present invention have adequate fluidity so that they can be easily mixed with other excipients and / or without major problems associated with, for example, adhesion to related equipment. It is important that it can be further treated with the composition. The test is described in the materials and methods below, and instructions are provided for performing the test. Critical testing involves measuring the fluidity of solid materials loaded with different amounts of oil.

The oil threshold should generally exceed 10% and often oil sorbent materials have an oil threshold of at least about 15%, such as at least about 20%, at least about 25%, at least about 30%, at least about 35%, about 40% It can be seen from the above that it is at least about 45%.

Particularly suitable materials for use according to the invention, Aeropearl 300 has a very high oil threshold of about 60%. Thus, materials having an oil threshold of at least about 50%, such as at least about 55% or at least about 60%, are used in certain embodiments of the present invention.

Moreover, oil sorption materials for use in accordance with the invention must satisfy at least one further test, ie release test and / or disintegration test.

The release test provides a measure of its ability to release the oil absorbed in the material when the oil sorbent material is in contact with water. This ability is particularly important in situations where the active substance is included in the oily material. If the oil sorption material cannot release oil from the material, there is a great risk that only a small amount of active material will be released from the material. Thus, for example, it is expected that a bioavailability problem related to poor absorption or the like will arise in this situation.

The requirements of the release test are that when tested as described herein, the pharmaceutically acceptable solid material may be at least about 30%, such as at least about 35%, at least about 40%, at least about 45%, at least about 50% of the oil. At least about 55% or at least about 60%. As is evident from the examples herein, suitable oil sorption materials such as Aeroperl 300 have a higher degree of release. Thus, in certain embodiments of the invention, the pharmaceutically acceptable solid 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. do.

Disintegration tests are not performed on solid materials in particulate form, but on tablets made of solid materials. When a solid material is included in a solid dosage form, to ensure that it does not impart undesired properties to the dosage form, for example, it does not cause unwanted properties for bioavailability and dissolution of the active substance contained in the dosage form. To ensure that, the requirements related to disintegration are important. In some materials suitable for use in accordance with the invention, it is possible to press-form tablets comprising 100% w / w of the solid material itself. If this is the case, the test is performed on this tablet. However, it is envisaged that there may be a rather difficult situation to make tablets from solid materials alone. In such cases it is possible to add pharmaceutically acceptable excipients which are commonly used in the manufacture of tablets compressed to concentrations up to 10% w / w. Examples of suitable pharmaceutically acceptable excipients include fillers, diluents, binders and lubricants. However, excipients which are usually classified as disintegrants should be avoided.

Thus, solid materials in the form of pharmaceutically acceptable tablets used in accordance with the present invention, when tested as described herein, are obtained by Ph. When tested according to the Eur Disintegration Test, the disintegration time should be less than 1 hour and the tablet should be at least about 90% w / w, such as at least about 92.5% w / w, at least about 95% w / w, about 97.5% at least w / w or about 100% of a pharmaceutically acceptable material.

In further embodiments, the solid material in pharmaceutically acceptable tablet form, when tested as described herein, has a Ph. Has a disintegration time of about 50 minutes or less, such as about 40 minutes or less, about 30 minutes or less, about 20 minutes or less, about 10 minutes or less, or 5 minutes or less when tested according to the Eur disintegration test, and the tablet is about 90% w at least / w, such as at least about 92.5% w / w, at least about 95% w / w, at least about 97.5% w / w, or about 100% of a pharmaceutically acceptable material.

In certain embodiments, the solid material used as the sorption material satisfies all three tests. Accordingly, pharmaceutically acceptable solid materials are as follows when tested as described herein:

i) 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%, about Having an oil threshold of at least 55% or at least about 60%,

ii) at least about 30% of the oil, 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%, Emits at least about 75% or at least about 80%,

iii) in the form of a tablet, Ph. When tested according to the Eur Disintegration Test, the disintegration time is 1 hour or less, such as about 50 minutes or less, about 40 minutes or less, about 30 minutes or less, about 20 minutes or less, about 10 minutes or less, or about 5 minutes or less, and tablets. Comprises at least about 90% w / w, such as at least about 92.5% w / w, at least about 95% w / w, at least about 97.5% w / w or about 100% of a pharmaceutically acceptable material.

Other specific embodiments of the invention, when the pharmaceutical solid material used as a sorption material in the composition according to the invention is tested as described herein,

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

When the pharmaceutical solid material is tested as described herein,

ii) at least about 75% of the oil is released; And / or

When the pharmaceutical solid material is tested as described herein,

iii) in tablet form, Ph. Eur. When tested according to the disintegration test, it has a disintegration time of about 10 minutes or less and the tablet comprises about 97.5% w / w of pharmaceutically acceptable material.

Pharmaceutically acceptable solid materials used as sorbent materials in the compositions according to the invention are usually particulate materials in the form of powders, particles, granules, granules and the like, for example.

Such particulate materials suitable for use as oil sorption materials typically have a bulk density of about 0.15 g / cm ^3. Or at least about 0.20 g / cm ³ or at least about 0.25 g / cm ³ .

Moreover, oil sorption materials typically have an oil absorption value of at least about 100 g oil / 100 g, such as at least about 150 g oil / 100 g, at least about 200 g oil / 100 g, at least about 250 g oil / 100 g, about A pharmaceutically acceptable material that is at least 300 g oil / 100 g, or at least about 400 g oil / 100 g. Oil absorption values are measured as described in the experimental section herein.

We have found that a common feature of some materials suitable for use as oil sorption materials has a relatively large surface area. Thus, pharmaceutically acceptable materials used as oil sorption materials according to the invention have a BET surface area of at least 5 m ² / g, such as at least about 25 m ² / g, at least about 50 m ² / g, at least about 100 m. ^At least ² / g, at least about 150 m ² / g, at least about 200 m ² / g, at least about 250 m ² / g or at least about 275 m ² / g.

As mentioned above, one of the unique features of pharmaceutically acceptable materials for use as oil sorption materials according to the invention is that they retain good flowability even when oily materials are loaded. Thus, at least 25% w / w, such as at least 30% w / w, at least 40% w / w, at least 45% w / w, at least 50% w / w, at least 55% w / w, 60% w / w At least 65% w / w or at least about 70% w / w of the pharmaceutically acceptable material loaded with biscoleo is typically Ph. Eur. Will meet the requirements.

In particular, the oil sorbent material may comprise, as pharmaceutically acceptable excipients, silica acids or derivatives or salts thereof, such as silicon dioxide or polymers thereof. However, depending on the quality utilized, silicon dioxide can be a lubricant, or it can be an oil sorption material. Quality that satisfies the latter function seems to be the most important.

300 에 해당하는 성질을 가진 이산화규소 제품인 약학적으로 허용가능한 부형제를 포함한다.In certain embodiments, the composition or solid dosage form according to the invention is an Aeroperl

And pharmaceutically acceptable excipients which are silicon dioxide products having properties corresponding to 300.

The use of oil sorption materials in compositions or dosage forms according to the invention is very beneficial for the preparation of pharmaceutical, cosmetic, nutritional and / or food compositions, wherein the composition comprises an oily material. One of the advantages is that it is possible to incorporate a relatively large amount of oily material and still have a material that is solid. Thus, by using the oil sorption material according to the present invention, it is possible to produce a solid composition having a relatively high load of oily material. Within the pharmaceutical field, in particular, the active substance is water soluble (e.g. poor water soluble), stability in aqueous medium (i.e. degradation occurs in aqueous medium), oral bioavailability (e.g. low bioavailability) In situations where it does not have adequate properties with respect to, etc., or in situations where it is desirable to modify the release of the active substance from the composition to obtain controlled, delayed, sustained release and / or pulsed delivery of the active substance, a relatively large amount of oily material It is advantageous that it is possible to incorporate into the solid composition. Thus, in certain embodiments, it is used to prepare pharmaceutical compositions.

Oil sorbent materials for use in treating with solid compositions are typically at least about 5% w / w, such as at least about 10% w / w, at least about 15% w / w, at least about 20% w / w, 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 At least about 90% w / w, at least about 95% w / w of oil or oily material, which is still a solid material.

Oily  material

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

In this context, the term “oily material” is used in a very broad sense including oils, waxes, semisolid materials, and materials commonly used as solvents (eg, organic solvents) or as cosolvents within the pharmaceutical industry. The term also includes therapeutically and / or prophylactically active substances in liquid form at room temperature; Moreover, the term includes emulsions and suspensions such as, for example, microemulsions and nanoemulsions. Oils and oily materials that can be absorbed will typically be liquid at room temperature or at elevated temperatures (in practice, the maximum temperature is about 250 ° C.). These may be hydrophilic, lipophilic, hydrophobic and / or amphiphilic materials.

Oily materials suitable for use in the present context are materials or materials having a melting point of at least about 10 ° C. and up to about 250 ° C.

In certain embodiments of the present invention, the melting point of the oily material is at least about 5 ° C, such as at least about 10 ° C, at least about 15 ° C, at least about 20 ° C or at least about 25 ° C.

In a further embodiment of the invention, the melting point of the oily material is at least about 25 ° C, such as at least about 30 ° C, at least about 35 ° C or at least about 40 ° C. Substantially, the melting point is typically not so high that the melting point of the oily material is typically about 300 ° C. or less, such as about 250 ° C. or less, about 200 ° C. or less, about 150 ° C. or less or about 100 ° C. or less. If the melting point is higher, the relatively high temperature may promote the oxidation or other kind of degradation of the active substance, for example when a therapeutic and / or prophylactically active substance is included.

In this context, the melting point is measured by DSC (differential scanning calorimetry). Melting point is measured as the temperature at which the linear increase in the DSC curve intersects the temperature axis (see FIG. 1 for further explanation).

The oily materials of interest are generally the materials used in the preparation of the pharmaceutical products as so-called melt binders or solid solvents (in the form of solid dosage agents) or as co-solvents or ingredients in the pharmaceutical product for topical use. It may be hydrophilic, hydrophobic and / or may have surface-active properties. In general, hydrophilic and / or hydrophobic oily materials may have therapeutic and / or prophylactically active substances with relatively low aqueous solubility and / or when release of the active substance from the pharmaceutical composition is designed to be immediate or non-modified. It is suitable for use in the manufacture of a pharmaceutical composition comprising. Hydrophobic oily materials, on the other hand, are commonly used in the preparation of modified release pharmaceutical compositions. The above considerations are simplified to illustrate the general principles, but the above examples should not limit the invention in any way, as there are many cases where other combinations and other purposes of oily materials are involved.

Typically, suitable hydrophilic oily materials are selected from the group consisting of: polyether glycols such as polyethylene glycol, polypropylene glycol; Polyoxyethylene; Polyoxypropylene; Poloxamer and mixtures thereof, or the group consisting of: 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, other Gelucire types such as Gelucire 44/14, etc., Gelucire 50/10, Gelucire 62/05, Sucro-ester 7, Sucro-ester 11, Sucro-ester 15 , Maltose, mannitol and mixtures thereof.

Suitable hydrophobic oily materials can be selected from the group consisting of: straight chain saturated hydrocarbons, sorbitan esters, paraffins; Fats and oils such as cacao butter, tallow, lard, polyether glycol esters; Higher fatty acids such as stearic acid, myristic acid, palmitic acid, higher alcohols such as cetanol, stearyl alcohol, low melting point waxes such as glyceryl monostearate, glyceryl monooleate, hydrogenated tallow, myristyl Alcohols, stearyl alcohols, substituted and / or unsubstituted monoglycerides, substituted and / or unsubstituted diglycerides, substituted and / or unsubstituted triglycerides, lead, white lead, carnauba wax, castor wax, Wax, acetate monoglycerides; NVP polymers, PVP polymers, acrylic polymers, or mixtures thereof.

In an embodiment of interest, the oily material may be a polyethylene glycol such as polyethylene glycol 1,000, polyethylene glycol 2,000, polyethylene glycol 3,000, polyethylene having an average molecular weight in the range of about 400 to about 35,000, such as about 800 to about 35,000, about 1,000 to about 35,000. 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 certain circumstances, polyethylene glycol having a molecular weight of about 35,000 to about 100,000 may be utilized.

In another embodiment of interest, the oily material has a molecular weight of about 2,000 to about 7,000,000, such as about 2,000 to about 100,000, about 5,000 to about 75,000, about 10,000 to about 60,000, about 15,000 to about 50,000, about 20,000 to about 40,000, Polyethylene oxide that is about 100,000 to about 7,000,000, such as about 100,000 to about 1,000,000, about 100,000 to about 600,000, about 100,000 to about 400,000, or about 100,000 to about 300,000.

및/또는 Tetronic

계열와 같은 에틸렌 옥사이드 및 프로필렌 옥사이드의 기타 블록 공중합체이다. Pluronic

계열의 적합한 블록 공중합체는 분자량이 약 3000 이상, 예컨대 약 4,000 내지 약 20,000 이고/이거나, 점도 (Brookfield) 가 약 200 내지 약 4,000 cps, 예컨대 약 250 내지 약 3,000 cps 인 중합체를 포함한다. 적합한 예에는 Pluronic

F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123, F127, 10R8, 17R8, 25R5, 25R8 등이 포함된다. Tetronic

계열의 적합한 블록 공중합체에는 분자량이 약 8,000 이상, 예컨대 약 9,000 내지 약 35,000 이고/이거나, 점도 (Brookfield) 가 약 500 내지 약 45,000 cps, 예컨대 약 600 내지 약 40,000 cps 인 중합체가 포함된다. 앞서 제공된 점도를 실온에서 페이스트인 물질에 대해서는 60 ℃ 에서 측정하고 실온에서 고체인 물질에 대해서는 77 ℃ 에서 측정한다.In another embodiment, the oily material may be a poloxamer such as poloxamer 188, poloxamer 237, poloxamer 338 or poloxamer 407 or Pluronic

And / or Tetronic

Other block copolymers of ethylene oxide and propylene oxide such as the family. Pluronic

Suitable block copolymers of the family include polymers having a molecular weight of at least about 3000, such as about 4,000 to about 20,000, and / or a viscosity (Brookfield) of about 200 to about 4,000 cps, such as about 250 to about 3,000 cps. Suitable examples include Pluronic

F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123, F127, 10R8, 17R8, 25R5, 25R8 and the like. Tetronic

Suitable block copolymers of the family include polymers having a molecular weight of at least about 8,000, such as about 9,000 to about 35,000, and / or having a viscosity (Brookfield) of about 500 to about 45,000 cps, such as about 600 to about 40,000 cps. The viscosity provided above is measured at 60 ° C. for materials that are pastes at room temperature and at 77 ° C. for materials that are solids at room temperature.

Oily materials are also sorbitan esters such as sorbitan diisostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostea Sorbate, sorbitan sesqui-isostearate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan tri-isostearate, sorbitan trioleate, sorbitan tristearate or mixtures thereof.

The oily material may of course comprise a mixture of several oily materials, such as a mixture of hydrophilic and / or hydrophobic materials. Other suitable oily materials include solvents or semi-solid excipients such as propylene glycol, polyglycolated glycerides including Gelucire 44/14, composite fatty materials of vegetable origin, including: theobroma oil, carnauba wax Vegetable oils such as almond oil, coconut oil, corn oil, cottonseed oil, sesame oil, soy milk, olive oil, castor oil, palm kernel oil, peanut oil, rapeseed oil, grape seed oil and the like, hydrogenated vegetable oils such as hydrogenated peanut oil, hydrogenated Palm kernel oil, hydrogenated cottonseed oil, hydrogenated soymilk, hydrogenated castor oil, hydrogenated coconut oil; Natural fat materials of animal origin comprising: beeswax, lanolin, fatty alcohols comprising: cetyl, stearyl, lauric, myristic, palmitic, stear fatty alcohols; Esters comprising: glycerol stearate, glycol stearate, ethyl oleate, isopropyl myristate; Liquid interesterified semi-synthetic glycerides comprising: Miglycol 810/812; Amides or fatty acid alcoholamides comprising: stearamide ethanol, diethanolamides of fatty coconut acids, acetic acid esters of mono and di-glycerides, citric acid esters of mono and di-glycerides, lactic acid esters of mono and diglycerides , Mono and di-glycerides, poly-glycerol esters of fatty acids, poly-glycerol poly-ricinolates, propylene glycol esters of fatty acids, sorbitan monostearate, sorbitan tristearate, sodium stearoyl lactylate, calcium Stearoyl lactylate, diacetyl tartaric acid esters of mono and di-glycerides, and the like.

A pharmaceutical composition or solid dosage form according to the invention may have a concentration of oily material in said composition or dosage form of at least about 5% w / w, such as at least about 10% w / w, at least about 15% w / w, 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 At least about 85% w / w, at least about 90% w / w or at least about 95% w / w.

In certain embodiments, the concentration of oily material in a composition or solid dosage form of the invention ranges from about 20% to about 80% w / w, such as from about 25% to about 75% w / w.

One of the advantages is that it is possible to incorporate a relatively large amount of oily material and still have a material that is solid. Thus, by using the oil sorption material according to the present invention, it is possible to produce a solid composition having a relatively high load of oily material. Within the pharmaceutical field, in particular, the active substance is water soluble (e.g. poor water soluble), stability in aqueous medium (i.e. degradation occurs in aqueous medium), oral bioavailability (e.g. low bioavailability) In situations where it does not have adequate properties with respect to, etc., or in situations where it is desirable to modify the release of the active material from the composition to obtain controlled, delayed, sustained and / or pulsed delivery of the active material, a relatively large amount of oily material may be used. It is advantageous that it can be incorporated into solid compositions.

A further advantage is that the particulate material obtained is a free-flowing powder and thus can easily be treated with, for example, solid dosage agents such as tablets, capsules or sachets. Typically, the particulate material has properties suitable for preparing tablets by tableting directly without adding a large amount of additional additives. Suitable tests for testing the flowability of particulate material are Ph. Eur. The method described in, is a method of measuring the flow rate of a material through a funnel with a nozzle (orifice) having a diameter of 10.0 mm.

In embodiments of the invention, at least a portion 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 at least 10%, such as at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, such as at least 95% or about 100 of their active substances % w / w is present in the composition in dissolved form.

Solid Medication

The pharmaceutical composition according to the invention is in particulate form and can be utilized as such. However, in many cases, it is in the form of granules, pellets, microspheres, nanoparticles or the like, or tablets, tablets, beads, capsules, granules, pills, granules, granules, powders, pellets, sachets, lozenges, troches It is more convenient to provide the composition in the form of a solid dosage agent, including the like.

The solid dosage agent according to the invention may be a single unit dosage or it may comprise a number of individual units, such as pellets, beads and / or granules, in the form of poly-depot dosages.

In a preferred embodiment of the invention, the solid dosage agent is a tablet.

Solid dosage agents of the invention comprise fenofibrate in amounts of 160 mg, 145 mg, 130 mg, 120 mg, 110 mg, 100 mg, 33 mg, 37 mg, 40 mg, 43 mg, 48 mg and 87 mg.

In a preferred embodiment, the solid dosage agent comprises 145 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 130 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 120 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 110 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 100 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 33 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 37 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 40 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 48 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 43 mg of fenofibrate. In another preferred embodiment, the solid dosage agent comprises 87 mg of fenofibrate.

Typically, a pharmaceutical composition or solid dosage form of the invention is intended for administration via the oral, buccal or sublingual route of administration.

Within the scope of the present invention the composition / solid dosage agent is intended to release the active substance in a rapid release, delayed release or modified release mode.

Solid dosage agents according to the present invention include pharmaceutical compositions in particulate form as previously described. The details disclosed under this main aspect of the invention apply to other aspects of the invention with the necessary modifications. Thus, properties related to the release of one or more fibrates described and / or claimed herein for pharmaceutical compositions in particulate form as well as to increase bioavailability, change in bioavailability parameters, reduction in food adverse effects, etc. Dosage analogs.

Typically, the concentration of the pharmaceutical composition in particulate form is from about 5 to 100% w / w of the dosage agent, 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, about 25% to about 80% w / w, about 30% to about 80% w / w, about 35% to about 80% w / w, about 40% to about 75% w / w , About 45% to about 75% w / w or about 50% to about 70% w / w. In an embodiment of the invention, the concentration of the pharmaceutical composition in particulate form is at least 50% w / w of the dosage agent.

Solid dosage agents of the present invention are very stable. For example, after fibrate is stored for 3 months at a temperature of about 40 ° C. and a relative humidity of about 75%, it is present in an amount of at least 90%, or at least 95% or at least 100% relative to the amount before storage. In addition, the physical stability is very high as can be seen from the following examples.

Solid dosage agents according to the invention are obtained by treating the particulate material according to the invention using techniques known to those skilled in the art. Typically, this involves the addition of one or more of the pharmaceutically acceptable excipients mentioned herein.

If an increase in bioavailability is maintained, the composition or solid dosage agent according to the invention may be designed to release one or more fibrates in any suitable manner. Thus, the active material may be released relatively quickly to obtain enhanced initiation of action, or may be released to follow zero or first order kinetics, or may be released in a controlled or modified manner to obtain a predetermined release pattern. Can be. General formulations are also within the scope of the present invention.

Compositions or solid dosage agents according to the invention may also be coated with film coatings, enteric coatings, modified release coatings, protective coatings, anti-stick coatings and the like.

Solid dosage agents according to the invention can also be coated to obtain suitable properties, for example suitable properties for the release of the active substance. The coating may be applied on a single unit dosage (eg tablets, capsules) or may be applied on a polydepot dosage form or on individual units thereof.

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

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

The pharmaceutical composition or the solid dosage form according to the invention is designed to release the fibrate in a suitable manner. Specific emission patterns are disclosed in the appended claims, to which reference is made. Also provided herein are specific related absorption patterns.

Other of the present invention Embodiment

In further embodiments, fenofibrate is present in the form of a solid dispersion comprising at least partly a solid solution.

In a further embodiment, the present invention relates to a solid pharmaceutical composition in the form of a solid dosage agent or particulate comprising one or more fibrates dissolved in one or more oily materials. In this embodiment, the fibrate is in solid solution form in the particulate composition, and the presence of the solid solution can be tested by the DSC test mentioned herein. In this embodiment, the particulate composition is prepared by dissolving the fibrate in an oily material, optionally at elevated temperatures (optionally after addition of additional active material and / or one or more pharmaceutically acceptable excipients), and The mixture is sprayed on the carrier as described herein. Preferably the concentration of oily material is at least about 10% w / w.

Materials and methods

material

Fenofibrate (supplied by Sigma)

Lactose Monohydrate 200 Mesh (supplied by DMV)

300, (Degussa) Granular Silicium Oxide, Aeroperl

300, (Degussa)

E6000 (BASF 사 공급) Polyethylene Glycol 6000, Pluracol

E6000 (Supplied by BASF)

F-68 (BASF 사 공급) Ploxamer 188, Pluronic

F-68 (supplied by BASF)

MD50, (Danisco Cultor 사 공급), Ph. Eur. Glyceryl Monostearate, Rylo

MD50, (supplied by Danisco Cultor), Ph. Eur.

Avicel PH200 (microcrystalline cellulose) (supplied by FMC)

Magnesium stearate

Tablets, capsules or granules can be used in several types of polymers, such as hydroxypropylmethylcellulose acetate succinate (Aqoat), cellulose acetate phthalate CAP, hydroxypropylmethylcellulose phthalate HPMCP or methacrylic acid copolymers such as Eudragit L30D, Eudragit 100 / S, Eudragit 100 / L may be enteric coated.

Tricor  Tablet formulation

정제는 경구 투여용으로 이용가능한 페노피브레이트-포함 정제이며, 정제 당 54 mg 또는 160 mg 의 미분화 페노피브레이트를 포함한다. 시중에서 구입가능한 이 제형은 현재 FDA 오렌지북에서 제외되었다. 현재 시중에서 구입가능하면서 FDA 오렌지북에 남아있는 TriCor

약물 제형은, 활성 성분으로서 미분화 페노피브레이트를 포함하는 145 mg 및 48 mg 정제이다.TRICOR

Tablets are fenofibrate-comprising tablets available for oral administration and include 54 mg or 160 mg of undifferentiated fenofibrate per tablet. This commercially available formulation is now excluded from the FDA Orange Book. TriCor, now commercially available and remaining in the FDA Orange Book

Drug formulations are 145 mg and 48 mg tablets comprising undifferentiated fenofibrate as active ingredient.

은 지질 조절제로서 지시된다. Tricor

의 권고 투약량은 식품과 함께 섭취하는 54 ~ 160 mg/일 이고, 이내 48 ~ 145 mg 이다. Tricor

정제는 54 및 160 mg 의 강도로 제공되고, 현재 미국에서는 48 및 145 mg 의 강도로 이용가능한 반면, Tricor

캡슐은 67 내지 200 mg 의 강도로 제공된다. 정제는 캡슐보다 생체이용률이 더 높다. 기타 상표명은 Lipanthyl

, Lipantil

또는 Catalip

이다.Tablets include the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, Titanium dioxide, xanthan gum, colorant. Tricor

Is indicated as a lipid modulator. Tricor

The recommended dosage of is 54 to 160 mg / day taken with food, within 48 to 145 mg. Tricor

Tablets are available in strengths of 54 and 160 mg and are currently available in the United States at strengths of 48 and 145 mg, while Tricor

Capsules are provided at a strength of 67 to 200 mg. Tablets have higher bioavailability than capsules. Other brand names are Lipanthyl

, Lipantil

Or Catalip

to be.

Lipanthyl  Formulation

67M 은 페노피브레이트가 고체 표면-활성 성분과 공동-미분화되어 밀접하고 세밀하게 분화된 2 가지 성분의 혼합물을 제공하는 공정으로부터 제공된다.Lipanthyl

67M is provided from a process in which fenofibrate is co-micronized with a solid surface-active component to provide a mixture of two components that are closely and finely differentiated.

Antara ™ Capsule Formulation

Antara ™ capsules are fenofibrate-containing tablets available for oral administration and contain 43 mg or 130 mg of undifferentiated fenofibrate per tablet. This commercially available formulation is included in the FDA Orange Book.

Device

Laboratory Scale Fluidized Bed Apparatus: Strea-1.

The melt injection unit is a prototype consisting of a separation unit, a pressurized tank and an inlet tube for heating the spraying air feed. The granules were sieved manually and mixed with extragranular excipients in a turbula mixer.

Tableting was performed on a single punch press, Diaf ™ 20.

Way

According to the method of the invention, the fenofibrate drug is dissolved into the molten vehicle (s) and applied onto the particulate carrier (s) as follows:

The vehicle (s) were melted in a beaker placed in a microwave oven. The beaker was transferred to a temperature controlled heating plate provided with a magnetic stirrer. Fenofibrate was melted slowly at a temperature of 75 ° C. under magnetic stirring. The hot solution was transferred to a pressurized tank for melt spray application onto the carrier in the fluidized bed. The granular product was emptied from the fluidized bed and manually sieved through a 0.7 mm or 1.0 mm sieve. The sieved product was blended with magnesium stearate in a turbula mixer for 0.5 minutes. If the extragranular phase had to be incorporated, the extragranular phase was premixed with the granules for 3 minutes in a turbulent mixer.

Tableting was performed on a single punch machine Diaf ™ 20.

Critical test

This test measures the flow rate of material through a funnel with a nozzle diameter of 10.0 mm. Eur. It involves the measurement of fluidity according to the method described in.

Bischoleo (medium chain triglycerides MCT; Miglyol 812 N from Condea) was added to 100 g of pharmaceutically acceptable solid material to be tested for use according to the invention and mixed manually. The obtained mixture was sieved through a 0.3 mm sieve to obtain a homogeneous mixture. The oil was added continuously until a flow of 100 g of mixture could not flow through the nozzle. If the material to be tested has a high bulk volume (such as that of the Aeroperl 300, for example), only 50 g of the mixture is used when testing these blends. The maximum concentration of oil through which the material can flow is named the threshold (given in% w / w).

Release test

) 14.3 mg 을 50.0 g 의 비스콜레오 (분획화된 중쇄 트리글리세라이드) 에 용해시켰다.Fat-soluble colorant Sudan II (BDH Gur) from BDH VWR International

14.3 mg) was dissolved in 50.0 g of biscolleo (fractionated heavy chain triglycerides).

10 g of oil were added to 10.0 g of the pharmaceutically acceptable solid material to be tested for use according to the invention and mixed until the oil was completely absorbed by the solid material. The mixture was then sieved through a 0.3 mm sieve to obtain a homogeneous mixture.

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

Disintegration  time

Disintegration time is Ph. Eur. It measured according to the method described in.

Dissolution test

Using the paddle instrument, Ph. The test was carried out according to Eur 2.9.3. Quantification was performed using HPLC with UV-detector.

Medium: 900 ml of water with 0.75% sodium lauryl sulfate (SLS)

Rotational Speed: 50 rpm

Temperature: 37 ℃

Sampling point: 10, 20, 30, 45 and 60 minutes

Acceptance criteria: over 75% in 45 minutes

Determination of Bulk Density

The bulk density was measured by putting 100 g of the present powder into a 250 ml graduated cylinder. Bulk density is provided as tapped bulk density, expressed in g / ml. The measurement is Ph. Eur. (Perspective volume) was performed.

oil Of absorption  Measure

The oil uptake value is determined by adding a quantified amount (10 g) of biscleo to the quantified amount of the pharmaceutically acceptable material (100 g) to be tested. If additional addition of 10 g of oil does not allow the material to have suitable properties in flowability, ie Ph. Eur. The oil absorption value (represented as 100 g of Biscleo / material) is reached when the requirements according to the (liquidity test; see description under critical tests herein) are not satisfied.

BET Surface area  Measure

Applied instrument was Micromertics Gemini 2375. The method applied was according to the USP volume method based on multipoint measurements.

Measurement of liquidity

Flowability is measured by Ph.D., which measures the flow rate of material through a funnel with a nozzle diameter of 10.0 mm. Eur. It measured according to the method described in.

Measurement of weight change

The tablets prepared in the Examples herein were prepared using Ph. Eur. It was applied to the test for the weight change performed according to.

Measurement of Average Tablet Hardness

The tablets prepared in the Examples herein were subjected to testing for tablet hardness using the Schleuniger Model 6D instrument and performed according to the general instructions for the instrument.

Measurement of solid solution

According to the invention, the fibrate was dissolved in the vehicle. To do this, a test using a differential scanning calorimeter is performed. The test is carried out on the particulate composition, solid dosage agent or mixture of vehicle and fibrate (after the solid solution is assumed to have formed). Use a standard DSC device connected to the PC.

Sample size: 10 mg in alu pans

Heating rate: 5 ℃ / min from 27 ℃ to 110 ℃

Evaluation: If no fibrate endothermic peaks are observed and the melting interval does not vary significantly relative to vehicle alone, the fibrate is considered dissolved or amorphous.

Geometric weight average diameter d _gw  of  Measure

Geometric weight average diameter was measured using the laser diffraction method which disperse | distributes the particulate material (or starting material) obtained in air. Measurements were made at 1 bar dispersion pressure in Sympatec Helos apparatus, which records the distribution of the corresponding sphere diameters. Fit this distribution to the log volume-size normal distribution.

As used herein, “geometric weight average diameter” means the average diameter of the log volume-size normal distribution.

beagle On the dog In vivo  Research

의 생체이용률과 관련하여 본 발명의 조성물의 생체이용률을 측정하려는 목적의 생체내 연구 를 비글 도그를 이용해 수행했다.Commercially available fenofibrate tablet formulations, namely Tricor

In vivo studies with the aim of determining the bioavailability of the compositions of the present invention in relation to the bioavailability of were performed using beagle dogs.

Experimental work was carried out in Denmark using four male beagle dogs, each weighing 12-18 kg (starting weight). The study was conducted as an open, non-random, crossover study. Each animal was its own control. Oral dosing of fenofibrate was administered according to the following data. Dogs were fasted overnight (water freely) before dosing and fed 5 hours after dosing (water freely). Each dog received a specific dose of fenofibrate without considering weight.

Blood samples were collected from the external jugular vein at each of the following time points: before dosing, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours after dosing. 4 ml of blood were collected, mixed with EDTA and the sample was frozen (-80 ° C.). Blood samples were analyzed using on-line extracted LC / MS and provided results in mg / mL.

, (Pharsight, California; USA) 를 이용하여 처리하여, 약동학 매개변수를 계산했다. 모든 데이터는, 필요한 경우 투여량에 맞추었다. Pharmacokinetic Software WinNonlin to Measure Whole Blood Concentration Profile of Measured Fenofibrate

, (Pharsight, California; USA) were used to calculate pharmacokinetic parameters. All data were adjusted to the dose if necessary.

The following examples are provided for purposes of illustration of the invention and are not intended to limit the scope of the invention. The pharmaceutical compositions and dosage agents of the invention are illustrated in Examples 1-7. The results of the in vitro dissolution test of the dosage agents of the present invention can be seen in Example 8. The results of the stability test of the dosage agents of the invention can be seen in Example 9. The results of in vivo comparative studies in beagle dogs (blood plasma concentrations) can be seen in Examples 10-12. The results of clinical studies (comparative studies) in human subjects can be seen in Examples 13-15.

Example 1

Immediate release tablets with improved bioavailability

Fenofibrate was dissolved at 75 ° C. at a concentration of 17% in polyethylene glycol 6000 and floxamer 188 (70:30 w / w ratio). 244 g of the molten solution were sprayed onto 200 g lactose in the fluidized bed Strea-1 at 75 ° C. The granular product was sieved through a 0.7 mm sieve and blended with magnesium stearate in a turbula mixer for 0.5 minutes. The mixture was compressed into 10 mm tablets of 50 mg strength (540 mg tablets in the shape of compound cups).

matter  % mg Fenofibrate 9.30 50.00 Lactose 44.78 240.64 PEG 6000 31.80 170.88 Ploxamer 188 13.63 73.24 Magnesium stearate 0.50 2.69 gun 100.00 537.45

Average disintegration time: 26 minutes, hardness 45 N

Example 2

Immediate release tablets with improved bioavailability

A 10 mm tablet (540 mg tablet in the shape of a compound cup) of 50 mg strength, having the following composition, was prepared as described in Example 1:

matter  % mg Fenofibrate 9.30 50.00 Lactose 44.78 240.64 PEG 6000 45.43 244.12 Magnesium stearate 0.50 2.69 gun 100.00 537.45

Average Disintegration Time: 21 minutes, Hardness: 55 N

Example 3

Immediate release tablets with improved bioavailability

A 10 mm tablet (540 mg tablet in the shape of a compound cup) of 50 mg strength, having the following composition, was prepared as described in Example 1:

matter  % mg Fenofibrate 9.30 50.00 Lactose 44.78 240.64 PEG 4000 31.80 170.88 Ploxamer 188 13.63 73.24 Magnesium stearate 0.50 2.69 gun 100.00 537.45

Average Disintegration Time: 22 minutes, Hardness: 48 N

Example 4

Immediate release tablets with improved bioavailability

Fenofibrate was dissolved in polyethylene glycol 4000 at a concentration of 17% at 75 ° C. 244 g of molten solution were sprayed on 200 g lactose in fluidized bed Strea-1 at 75 ° C. The granular product was sieved through a 0.7 mm sieve and blended with magnesium stearate in a turbula mixer for 0.5 minutes. The mixture was compressed into 10 mm tablets (540 mg tablets in compound cup form) of 50 mg strength.

matter  % mg Fenofibrate 9.30 50.00 Lactose 44.78 240.64 PEG 4000 45.43 244.12 Magnesium stearate 0.50 2.69 gun 100.00 537.45

Average Disintegration Time: 21 minutes, Hardness: 55 N

Example 5

Immediate release tablets with improved bioavailability

Fenofibrate was dissolved in polyethylene glycol 4000 at 75 ° C. at a concentration of 17%. 244 g of the molten solution were sprayed onto 190 g lactose as a mixture mixed with 10 g sodium lauryl sulfate (SDS) in fluidized bed Strea-1 at 75 ° C. The granular product was sieved through a 0.7 mm sieve and blended with magnesium stearate in a turbula mixer for 0.5 minutes. The mixture was compressed into 10 mm tablets of 50 mg strength (540 mg tablets in compound cup form).

matter  % 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 gun 100.00 537.45

Average Disintegration Time: 18 minutes, Hardness: 65 N

Example 6

Immediate release tablets with improved bioavailability

Fenofibrate was dissolved at 75 ° C. in 30% concentration in polyethylene glycol 4000 and floxamer 188 (70:30 w / w ratio). 466 g of molten solution were sprayed on 200 g of Aeroperl 300 in fluidized bed Strea-1 at 75 ° C. The granular product was sieved through a 0.7 mm sieve and blended with magnesium stearate in a turbula mixer for 0.5 minutes. The mixture was compressed into 150 mg strength 13.5 mm tablets (720 mg tablets in compound cup form).

matter  % mg Fenofibrate 20.90 150.00 Aeroperl 300 29.85 214.29 PEG 6000 34.13 245.00 Ploxamer 188 14.63 105.00 Mg-Stearate 0.50 3.59 gun 100.00 717.88

Average Disintegration Time: 35 minutes, Hardness: 35 N

Example 7

Formulations of the Invention

Tablets having the following compositions of 33 mg, 37 mg, 40 mg, 43 mg, 48 mg, 50 mg, 100 mg, 110 mg, 120 mg, 130 mg, 145 mg and 160 mg, respectively, were prepared in Examples 1, 4 and Prepared as described in 6:

matter ingredient A mg B mg C mg D mg E mg F mg G mg H mg J mg drug Fenofibrate 160.1 50 50 50.1 160 130 43 48 145 Vehicle 1 PEG 6000 PEG 4000 GMS (Rylo) 208.1-- 171.1-- 124.3-- -244.6- --86.2 169-- 56-- 63-- 189-- Vehicle 2 Ploxamer 188 89.2 73.3 53.3 - - 72 24 25 81 carrier Lactose Aeropearl 300 356.5- 231.9- -63.9 232.0- 163.0- 304- 101- 112- 339- Excipient Mg Stearate Avicel 4.1- 2.7- 1.5- 5.3- 8.3 417.5 1.3- 0.5- 3.2- 9.5- Total (mg) 818 529 293 532 835 676 224 251 764 Hardness N 60 44 44 47 102 62 50 55 70 Disintegration time minute 25 14 30 48 > 55 14 15 14 15 diameter Mm Oval 12 12 10 Oval Oval Oval Oval Oval

matter ingredient K mg L mg M mg N mg P mg R mg drug Fenofibrate 120 110 100 40 37 33 Vehicle 1 PEG 6000 156.4 143.4 130.3 52.1 47.8 43.4 Vehicle 2 Ploxamer 188 67.0 61.4 55.8 22.3 20.5 18.6 carrier Lactose 280.6 257.2 233.8 93.5 85.7 77.9 Excipient Mg Stearate 7.9 7.2 6.6 2.6 2.4 2.2 Total (mg) 632 579 527 211 193 175 Hardness N 70 - - 50 - - Disintegration time minute 18 - - 10 - - diameter Mm Oval Oval Oval Oval Oval Oval

Example 8

Dissolution test

Tablet formulations A (160 mg) and J (145 mg) of the present invention of Example 7 were each subjected to dissolution testing as described in the method and the following results were obtained:

Minutes A (160 mg)% dissolved J (145 mg) Dissolution% 0 0 0 10 28 46 20 56 74 30 74 91 45 88 96 60 97 99

Example 9

Stability test

Samples of the inventive tablet formulation A of Example 7 were each stored under the following conditions and subjected to dissolution (stability) test as described in the method after 1 month and 3 months after storage; Dissolution% is the percentage of fenofibrate dissolved after 45 minutes.

month  Dissolution% 25 ℃ and 60% RH 30 ℃ and 65% RH 40 ℃ and 75% RH 0 88 - - One 99 88 90 3 90 97 90

Samples of the inventive tablet formulation A of Example 7 were each stored under the following conditions and subjected to the fibrate assay to yield the following results:

month Fenofibrate mg 25 ℃ and 60% RH 30 ℃ and 65% RH 40 ℃ and 75% RH 0 163.8 - - One 161.9 160.1 160.8 3 162.6 164.9 164.4

Samples of the inventive tablet formulations A (160 mg), J (145 mg) and K (120 mg) of Example 7 were each stored under the following conditions, and the Ph. Eur. Application to degradation product tests (degradation products A, B, G and unknowns accumulated as total degradation products; HPLC method) yielded the following results:

month Total decomposition products,% w / w, purity 25 ℃ and 60% RH 30 ℃ and 65% RH 40 ℃ and 75% RH 0 <0.05 - - One <0.05 <0.05 <0.05 3 <0.05 <0.05 <0.05

Example 10

In vivo studies in dogs

, 160 mg (배치 번호: 098212E21) 에서와 비교하여 하기의 결과를 도출했다:Conducted in vivo studies of Example 7 Formulation A, 160 mg of beagle dogs of (done as described under the method) the Tricor

, 160 mg (batch number: 098212E21), the following results were obtained:

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

Hour (hr) Formulation

(160 mg)Tricor

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

) 기준의 상대적 생체이용률: 306 %AUC (present invention, A / Tricor

Relative bioavailability of) criteria: 306%

): 356 %Relative c _max (invention, A / Tricor

): 356%

Example 11

In vivo studies in dogs

, 160 mg (배치 번호: 098212E21) 에서와 비교하여, 하기의 결과를 도출했다:Studies conducted both in the second living body of Example 7 Formulation A, 160 mg of beagle dogs of (done as described under the method) the Tricor

, Compared with 160 mg (Batch No .: 098212E21), the following results were obtained:

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

Hour (hr) Formulation

(160 mg)Tricor

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

) 기준의 상대적 생체이용률: 198 %AUC (present invention, A / Tricor

Relative bioavailability of the criterion: 198%

): 238 %Relative c _max (invention, A / Tricor

): 238%

Example 12

In vivo studies in dogs

67M, 2×67 mg (배치 번호: 75641) 에서와 비교하여, 하기의 결과를 도출했다:An exemplary in vivo studies of Example 7 Formulations B, C and D, 2 × 50 mg beagle dogs of (done as described under the method), Lipanthyl

Compared to 67M, 2 × 67 mg (Batch No .: 75641), the following results were obtained:

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

Hour (hr) Formulation

67M (2×67 mg)Lipanthyl

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

67M) 기준의 상대적 생체이용률: 532 %AUC (present invention, B / Lipanthyl

67M) Relative bioavailability as reference: 532%

67M): 548 %Relative c _max (invention, BA / Lipanthyl

67M): 548%

67M) 기준의 상대적 생체이용률: 228 %AUC (present invention, C / Lipanthyl

67M) relative bioavailability: 228%

67M): 161 %Relative c _max (invention, C / Lipanthyl

67M): 161%

67M) 기준의 상대적 생체이용률: 424 %AUC (present invention, D / Lipanthyl

67M) relative bioavailability as reference: 424%

67M): 329 %Relative c _max (invention, D / Lipanthyl

67M): 329%

Example 13

Clinical Trial of Fenofibrate Solid Dosage Agents of the Invention

(Tricor

) 160 mg 정제 (식품과 함께 및 식품 없이 섭취) 와 비교하여 페노피브레이트 (MeltDose

/LCP-Feno 로 명시) 160 mg 정제, 즉 본 발명의 정제 (식품과 함께 및 식품 없이 섭취) 의 약동학 프로파일을 측정하기 위해 임상 시험 연구를 수행했다. 연구는 스위스에서 24 명의 건강한 지원자 [(연령: 27 ~ 55 세; 21 명의 남성 및 3 명의 여성; 체중 > 65 kg); 23 명의 대상이 연구에 끝까지 참여했고, 1 명의 대상은 개인적 이유로 인해 기간 3 후에 빠졌음 (빠진 기간: Lipanthyl 금식)] 를 포함해서 무작위적인 4 방 교차 연구로 수행했다.Commercially available Lipanthyl

(Tricor

Fenofibrate compared to 160 mg tablets (with and without food) (MeltDose)

A clinical trial study was conducted to determine the pharmacokinetic profile of 160 mg tablets, ie tablets of the present invention (with and without food), as indicated by / LCP-Feno. The study included 24 healthy volunteers in Switzerland [age: 27 to 55 years; 21 men and 3 women; weight> 65 kg); Twenty-three subjects participated in the study to the end, and one subject performed a randomized four-way crossover study, including missing period 3 after personal reasons (logging period: Lipanthyl fasting).

The study was conducted as a combination PK and food-effect study in accordance with FDA guidelines.

The objective was to reveal that LCP-Feno (administration after administration) and Lipanthyl (administration administration) and LCP-Feno (administration administration) and LCP-Feno (administration during administration) are biological equivalents. .

Conditions (postprandial conditions) followed industrial guidelines: food-effect bioavailability and postprandial bioequivalence studies; CDER December 2002: fasting overnight (more than 10 hours); High-fat, high-calorie breakfast within 30 minutes; Total 800 to 1000 calories (150 from protein; 250 from carbohydrates; 500 to 600 from fat); 240 ml of blinds in drug administration studies.

Conditions (fasting conditions) were in accordance with industrial guidelines: food-effect bioavailability and postprandial bioequivalence studies; CDER December 2002: fasting overnight (more than 10 hours); Omit breakfast, and omit food intake for 4 hours after drug administration; 240 ml of blinds in drug administration studies.

Result :

The results are shown in FIGS. 1, 2 and 3.

1 shows mean plasma concentration data of Lipanthyl 160 mg (postprandial) and Lipanthyl 160 mg (fasted) (0-96 hours).

2 shows mean plasma concentration data of LCP-feno 160 mg (postprandial) and LCP-feno 160 mg (fasted) (0 to 96 hours).

3 is Lipanthyl (fasting), Lipanthyl (postprandial), LCP-Feno (fasting) and mean AUC _{0 -24 0} and the average AUC for each of the LCP-Feno _{(postprandial)} shows the _infinity:

AUC _{0 -24} (LCP-Feno postprandial) / AUC _{0 -24} (LCP-Feno fasting): 106.9% (Cl 110-114%)

AUC _{0 -24} (after LCP-Feno) / AUC _{0 -24} (after Lipanthyl): 98.0% (Cl 93-103%)

AUC _{0 -infinity} (LCP-Feno postprandial) / AUC _{0 -infinity} (LCP-Feno fasting): 104.9% (Cl 98-111%)

AUC _{0 - infinity} (LCP-Feno postprandial) / AUC _{0 - infinity} (Lipanthyl postprandial): 97.1% (Cl 92 ~ 102%)

AUC _{0 - infinity} (Lipanthyl meals) / AUC _{0 - infinity} (Lipanthyl fasting): 136%

If the AUC _{0 -t} of the new, AUC _{0 -infinity} , C _max is within 80-125% of the reference product (including 90% confidence interval (Cl)), the product is considered to be biologically equivalent to the reference product.

The results show that the bioavailability of LCP-Feno (fasting) is significantly increased compared to Lipanthyl (fasting).

The results showed that the bioequivalence of LCP-Feno (AUC _{0 -t} , AUC _{0 -infinity} , C _max ) under postprandial conditions compared to Lipanthyl and the bioequivalence of LCP-Feno (fasting) compared to LCP-Feno (postprandial) _{0- t} , AUC _{0 -infinity} ).

Thus, it can be concluded that the fenofibrate formulations used in the combination products of the present invention have essentially no food effect.

Example 14

페노피브레이트 정제를 비교하기 위한 생물학적 등가성 연구.Clinical Trials-145 mg LCP fenofibrate tablets and 145 mg TriCor of the invention when ingested with food

Bioequivalence study to compare fenofibrate tablets.

Test drug (active ingredient: fenofibric acid):

정제, 시중에서 구입가능.145 mg TriCor

Tablets, commercially available.

145 mg fenofibrate tablet (LCP) of the present invention, prepared as described in Example 7J.

Study plan and target :

The study was conducted as an open-level, laboratory-blind, one-dose, randomized, two-period cross-biological equivalence study under postprandial conditions, including 12 healthy volunteers in Switzerland, and the minimum washout period between treatments was 7 It was work. Each subject participated in the screening period (28 days), two treatment periods (one single dose each) (site observation period of 24 hours after administration).

Treatment (postprandial condition) :

정제를 240 mL 의 상온의 물과 함께 경구 투여했다.After fasting for at least 10 hours overnight, 30 minutes after the start of a high fat content meal, one 145 mg LCP fenofibrate tablet / 145 mg TriCor

The tablets were orally administered with 240 mL of room temperature water.

Blood sampling point :

Pre-dose, 1 hour, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, 48 hours after dosing , 72 hours and 96 hours (18 samples per pharmacokinetic profile).

Result :

Summary of statistical analysis of single-dose pharmacokinetic parameters for test formulation LCP fenofibrate tablets 145 mg versus reference formulation Tricor® tablets 145 mg (both under postprandial conditions) (each containing 145 mg fenofibrate (n = 12)):

AUC _{0 -infinity} (ng / mlhour): 101.1% (Cl 94% ~ 109%)

AUC _{0 -24} (ng / mlhour): 101.7% (Cl 105%-109%)

C _max (ng / ml): 111.4% (110% to 125%)

If the AUC _{0 -t} , AUC _{0 -infinity} , C _max of the product are within 80 to 125% of the reference product (including 90% confidence interval (Cl)), the product is considered to be biologically equivalent to the reference product.

145mg 페노피브레이트 정제와 비교하여 식후 조건 하에서의 본 발명의 LCP 페노피브레이트 정제 145 mg 의 생물학적 등가성 (AUC_{0 -t}, AUC_{0 -무한대}, C_최대) 을 증명해준다.The result is TriCor

The bioequivalence (AUC _{0 -t} , AUC _{0 -infinity} , C _max ) of 145 mg of LCP fenofibrate tablets of the present invention under post-prandial conditions is demonstrated compared to 145 mg fenofibrate tablets.

Example 15

Clinical Trial-Comparative bioavailability study of 120 mg fenofibrate tablets (LCP) and 130 mg Antara ™ fenofibrate capsules of the present invention with and without food.

Purpose of the study :

To compare the rate and extent of fenofibric acid absorption from a test formulation of a reference 130 mg Antara ™ capsule to 120 mg fenofibrate tablet (LCP) under fasting and postprandial conditions.

Test drug (active ingredient: fenofibric acid):

130 mg Antara ™ Capsule (Lot No. 5ED0026), available commercially.

120 mg fenofibrate tablet (LCP) of the present invention, prepared as described in Example 7K.

Study plan :

The study was conducted as a four-room (four treatment period) crossover, randomized, open-level, single-dose, fasting and postprandial, comparative bioavailability study in Canada.

Subjects : 42 normal, healthy non-smoking male and female subjects.

Treatment A, B, C, D :

Treatment A using 120 mg tablets on an empty stomach: After fasting for at least 10 hours overnight, one 120 mg LCP fenofibrate tablet was administered orally with 240 mL of room temperature water.

Treatment B with 130 mg Capsules on Fasting: After an overnight fast for at least 10 hours, one 130 mg Antara ™ capsule was administered orally with 240 mL of room temperature water.

Treatment C with 120 mg tablets in the postprandial state: After an overnight fast for at least 10 hours, 30 minutes after the start of a high fat content meal, one 120 mg LCP fenofibrate tablet was administered orally with 240 mL of room temperature water.

Treatment D using a 130 mg capsule in a postprandial state: After an overnight fast for at least 10 hours, 30 minutes after the start of a high fat content meal, one 130 mg Antara ™ capsule was administered orally with 240 mL of room temperature water.

Blood collection point :

During each study period, 21 blood samples were collected from each subject at the following time points: 0.0 (pre-dose), 0.5, 1.0, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0, 72.0 and 96.0 hours.

Phenothiazine to about fibric acid pharmacokinetic parameters are standard non-was calculated by dividing method: AUC _{0 -t,} AUC _{0 - infinity,} C _max, T _max, t _1/2.

Result :

The results are shown in FIGS. 4, 5 and 6.

4 shows mean plasma concentration data of Antara ™ 130 mg (postprandial) and Antara 130 mg (fasted) (0-96 hours).

FIG. 5 shows mean plasma concentration data of 120 mg of LCP tablets (postprandial) and 120 mg of LCP tablets (fasting) (0-96 h).

FIG. 6 shows the mean AUC _{0 -24} and mean AUC _{0 -infinity} for Antara ™ 130 mg (fasting), Antara ™ 130 mg (postprandial), LCP tablets 120 mg (fasting) and LCP tablets 120 mg (postprandial), respectively. Shows:

AUC _{0 -24} (LCP postprandial) / AUC _{0 -24} (LCP fasting): 107.7% (Cl 103-112%)

AUC _{0 -24} (LCP postprandial) / AUC _{0 -24} (Antara postprandial): 92.3% (Cl 89-96%)

AUC _{0 -24} (LCP Fasting) / AUC _{0 -24} (Antara Fasting): 112.9% (Cl 109-117%)

AUC _{0 -24} (Antara postprandial) / AUC _{0 -24} (Antara fasting): 131.7% (Cl 127-137%)

AUC _{0 -Infinity} (LCP after meals) / AUC _{0 -Infinity} (LCP Fasting): 106.3% (Cl 102-111%)

AUC _{0 - infinity} (LCP after meals) / AUC _{0 - infinity} (Antara postprandial): 92.2% (Cl 89 ~ 96%)

AUC _{0 - infinity} (LCP fasting) / AUC _{0 - infinity} (Antara fasting): 110.8% (Cl 106 ~ 115%)

AUC _{0 - infinity} (Antara postprandial) / AUC _{0 - infinity} (Antara fasting): 127.7% (Cl 123 ~ 133%)

If the product's AUC _{0 -t} , AUC _{0 -infinity} , C _max (geometric mean ratio) is within 80 to 125% of the reference product (including 90% confidence interval (Cl)), the product is considered to be biologically equivalent to the reference product. I think.

The results demonstrate the bioequivalence (AUC _{0 -t} , AUC _{0 -infinity} , C _max ) of 120 mg of LCP tablets under fasting conditions as well as postprandial compared to Antara ™ 130 mg.

The results show that the bioavailability of 120 mg of LCP tablets (fasting) is significantly increased compared to Antara ™ 130 mg capsules (fasting) (8% lower dose results in 13% higher AUC).

Thus, when compared to commercially available fenofibrate product Antara ™ 130 mg capsules, it can be concluded that the fenofibrate formulations used in the products of the present invention have essentially no food effect, i.e. can be administered with or without food. .

Claims (30)

Solid dispersion of fibrate selected from the group consisting of active metabolites and analogs thereof, including any related fibric acid such as gemfibrozil, fenofibrate, bezafibrate, clofibrate, cipropibrate, and fenofibric acid A tablet comprising water or a solid solution in a hydrophobic, hydrophilic or water-miscible vehicle, wherein the therapeutic effect in the patient of the tablet is essentially independent of whether the tablet is administered to a patient in a postprandial or fasting state refine. The tablet of claim 1, wherein the fibrate is fenofibrate or an analog thereof. The tablet of claim 1, wherein the fibrate is a solid solution in the vehicle of fenofibrate. 3. The fenofibrate of claim 2 wherein the fenofibrate is selected from the group consisting of 160 mg, 145 mg, 130 mg, 120 mg, 110 mg, 100 mg, 33 mg, 37 mg, 40 mg, 43 mg, 48 mg and 87 mg of fenofibrate Present in quantities that become. The tablet according to claim 2, wherein the fibrate is present in an amount of 145 mg. The tablet according to claim 2, wherein the fibrate is present in an amount of 130 mg. The tablet according to claim 2, wherein the fibrate is present in an amount of 120 mg. The tablet according to claim 2, wherein the fibrate is present in an amount of 110 mg. The tablet according to claim 2, wherein the fibrate is present in an amount of 100 mg. The tablet of claim 1, wherein when administered orally to a patient in need thereof, the AUC _fasting value for the AUC _postprandial value is at least about 0.85 and at least 0.75 at a confidence limit of less than 90%. The tablet of claim 1, wherein the AUC _fasting value for the AUC _postprandial value is at least about 0.9 when orally administered to a patient in need thereof. The tablet of claim 1, wherein when administered orally to a fasting patient in need thereof, a bioavailability of less than about 15% is obtained that is lower than the bioavailability after administration to a patient in a postprandial state. The process of claim 1, wherein the vehicle has a melting point of about 250 ° C. or less, the vehicle is hydrophobic, a straight chain saturated hydrocarbon, paraffin; Fats and oils such as cacao butter, tallow and lair; Higher fatty acids such as stearic acid, myristic acid, palmitic acid; Or may be selected from the group consisting of hydrogenated tallow, substituted and / or unsubstituted triglycerides, lead, white lead, carnauba wax, castor wax, wax and mixtures thereof; Or vehicles are preferably sorbitan esters, polyether glycol esters; Higher alcohols such as cetanol, stearyl alcohol; Water-miscible polar lipids selected from the group consisting of glyceryl monooleate, substituted and / or unsubstituted monoglycerides, substituted and / or unsubstituted diglycerides, and mixtures thereof; Or the vehicle is hydrophilic or water-miscible, polyethylene glycol, polyoxyethylene oxide, poloxamer, polyoxyethylene stearate, poly-epsilon caprolactone and mixtures thereof, polyglycolated glycerides, Gelucire

, Polyvinylpyrrolidone, polyvinyl-polyvinylacetate copolymer (PVP-PVA), polyvinyl alcohol (PVA), PVP polymer, acrylic polymer, polymethacrylic polymer (Eudragit RS; Eudragit RL, Eudragit NE, Eudragit E ), Myristyl alcohol, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethylcellulose, cellulose derivatives including hydroxyethyl cellulose, pectin, cyclodextrin, galactomannan, Tablets selected from the group consisting of alginates, carrageates, xanthan gum and mixtures thereof. The tablet of claim 1, wherein the vehicle comprises polyethylene glycol (PEG) having an average molecular weight of 3000 or greater. The process according to claim 1, wherein the vehicle is comprised of 1: 3 to 10: 1, preferably 1: 1 to 5: 1, more preferably 3: 2 to 4: 1, especially 2: 1 to 1, of polyethylene glycol and fluoroxamer. Tablets consisting of a mixture in a weight ratio of 3: 1, in particular about 7: 3. The tablet of claim 15, wherein the poloxamer is poloxamer 188. The tablet of claim 15 wherein the polyethylene glycol has an average molecular weight (PEG6000) of about 6000. The tablet of claim 1, wherein at least 90% w / w fibrate is dissolved in the vehicle. The tablet of claim 1 further comprising one or more pharmaceutically acceptable excipients selected from the group consisting of fillers, diluents, disintegrants, binders, glidants and lubricants. The tablet of claim 1 coated with a coating selected from the group consisting of film coatings, modified release coatings, enteric coatings, protective coatings and anti-stick coatings. 4. A tablet according to claim 3 which is biologically equivalent to any commercially available drug product recorded in the Orange Book, comprising as active ingredient the same amount of fenofibrate as in the tablet. 4. The composition of claim 3 comprising 120 mg of fenofibrate and, on an empty stomach, the AUC value is provided at about 1.1 or more compared to the AUC value of a commercially available Antara ™ 130 mg capsule, wherein the AUC value is measured under similar conditions. Tablet. A hydrophobic solution of fibrate selected from the group consisting of active metabolites and analogs thereof, including any related fibric acid such as gemfibrozil, fenofibrate, bezafibrate, clofibrate, cipropibrate, and fenofibric acid A pharmaceutical composition comprising in a hydrophilic or water-miscible vehicle, wherein the therapeutic effect in the patient of the composition is essentially independent of whether the composition is administered to a patient in a postprandial or fasting state. The composition of claim 23, wherein the fibrate is fenofibrate dissolved in polyethylene glycol. The composition of claim 23 in the form of particles, ie in the form of particulates. A process for preparing a tablet of claim 3 comprising the following steps: i) taking the vehicle in liquid form, if applicable, ii) maintaining the liquid vehicle at a temperature below the melting point of the fibrate, iii) dissolving the desired amount of fibrate in the vehicle, iv) spraying the resulting solution onto a solid carrier having a temperature below the melting point of the vehicle, v) mechanically manipulating the resulting composition to obtain particles, ie particulate material, and vi) applying the particulate material to a conventional tablet preparation method. Use of the composition of claim 24 in the manufacture of a medicament for the treatment of hyperlipidemia, hypercholesterolemia, type II diabetes, metabolic syndrome or microalbuminuria. A method of treating hyperlipidemia comprising administering to a patient a therapeutically-effective amount of the composition of claim 24. A method of treating type II diabetes, metabolic syndrome or microalbuminuria comprising administering to a patient a therapeutically-effective amount of the composition of claim 24. A method for enhancing oral bioavailability of fenofibrate comprising administering to a patient a therapeutically-effective amount of the composition of claim 24.

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