MXPA00010649A - Pellets having a core coated with a lipid lowering agent and a polymer - Google Patents

Abstract

The present invention is concerned with pellets comprising a 250-1180&mgr;m (16-60 mesh) sugar sphere, a coating film of a water-soluble polymer and a sparingly soluble lipid lowering agent, and a seal coating layer;pharmaceutical dosage forms comprising said pellets and a method of preparing said pellets.

Description

PELLETS THAT HAVE A COATED NUCLEUS WITH A REDUCING AGENT OF LIPIDS AND A POLYMER The present invention relates to pellets comprising a sugar sphere of 250-1180 μm (16-60 mesh), a coating film of a water soluble polymer and a barely soluble lipid reducing agent, and a coating layer of seal; the pharmaceutical dosage forms comprise said pellets and a method for preparing said pellets. The lipid reducing agents can be administered to a mammal suffering from hyperlipidemia, obesity or atherosclerosis by means of which a single dosage form can be administered once a day daily. The development of effective pharmaceutical compositions of lipid reducing agents as previously described in WO-96/13499 is made considerably difficult by the fact that said lipid reducing agents are hardly soluble in water. The lipid reducing agents described above in WO-96/13499 have the formula the ? oxides, one or more stereochemically isomeric forms, and the pharmaceutically acceptable acid addition salts thereof, wherein A and B taken together form a bivalent radical of the formula: -N = CH- (a), -CH = CH- (d), -CH = N- (b), -C (= 0) -CH2- (e), -CH2-CH2- (c), -CH2-C (= 0) - (f), wherein in the bivalent radicals of formula (a) and (b) the hydrogen atom can be replaced by C? .6 alkyl; and wherein in the bivalent radicals of formula (c), (d), (e), (f), one or two hydrogen atoms can be replaced by C 1 -β alkyl; R1 is hydrogen, C1-6 alkyl or halogen; R2 is hydrogen or halogen; R3 is hydrogen; Ci-β alkyl; C3.6 cycloalkyl; or C 1-8 alkyl substituted with hydroxy, oxo, C 3-6 cycloalkyl or aplo; Het is a heterocycle selected from the group consisting of pyridine; pyridine substituted with one or more substituents selected from C1.6alkyl, hydroxy, C1-6alkyloxy, triahalonomethyl, amino, mono- or di (alkylamino or aryl; pyrimidine; pyrimidine substituted with one or two substituents selected from alkyl of C1.6, hydroxy, C1-6alkyloxy, trihalogenomethyl, amino, mono- or di (C6-6 alkyl) -amino or aryl; tetrazole; tetrazole substituted with C1-6alkyl or aryl; triazole; triazole; substituted with one or two substituents selected from C 1-6 alkyl, hydroxy, C 1-6 alkyloxy, trihalomomethyl, amino, mono- or di (C? -6 alkyl) -amino; thiadiazole; thiadiazole; substituted with one or two substituents selected from Ci-e alkyl, hydroxy, Ci-e alkyloxy, triahalonomethyl, amino, mono- or di (Ci-6 alkyl) amino; oxadiazole substituted with one or two substituents selected from C 1-6 alkyl, hydroxy, C-? 6 alkyloxy, trihalomomethyl, amino, mono- or di (C? -6) alkyl amino; imidazole; imidazole substituted with one or two substituents selected from C 1-6 alkyl, hydroxy, C 1-6 alkyloxy, trihalogenomethyl, amino, mono- or di (C? 6 alkyl) -amino; thiazole; thiazole substituted with one or two substituents selected from C-α-6 alkyl, hydroxy, C 1-6 alkyloxy, trihalomomethyl, amino, mono- or di (C-i-e alkyl) amino; oxazole; oxazole substituted with one or two substituents selected from C 1-6 alkyl, hydroxy, C-? 6 alkyloxy, trihalomomethyl, amino, mono- or di (C? -6) alkyl amino; and aryl is phenyl or phenyl substituted with C 1-6 alkyl or halogen. The compounds of formula (I) and their salts have very limited aqueous solubility (< 0.5 mg / ml at pH 3 [10"3 N HCl]) and hardly dissolve when in crystalline form. of formula (I) have sufficient bioavailability, can be dissolved in water in the presence of a solubilizing agent such as a cyclodextrin derivative, for example, 2-hydroxypropyl-beta -cloclodextrin.The present invention provides an alternative that does not require the use of a solubilizing agent and provides a dosage form that has sufficient bioavailability.

In the compounds of formula (I) which are described below, the heterocyclic radical "Het" is attached to the sulfur atom by a carbon atom. As used in the above definitions halogen is generic to fluorine, chlorine, bromine and iodine; C1.6 alkyl defines saturated straight and branched chain hydrocarbon radicals having from 1 to 6 carbon atoms such, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 2-methylpropyl and the like; C 1-8 alkyl defines C 1-6 alkyl and higher homologs thereof containing 7 or 8 carbon atoms such, for example, heptyl or octyl and the branched isomers thereof. C3-6cycloalkyl defines saturated cyclic hydrocarbon radicals having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Het can be in particular a radical of formula (9) (h) (¡) w wherein: R 4 is hydrogen or C 1 -β alkyl; i "- - ^ -. ^.

R5 and R6 are hydrogen, C1-6 alkyl or amino; R7 is hydrogen or C-? 6 alkyl; each R8 is independently hydrogen or C1-6alkyl; each R9 is independently hydrogen, C-i-β alkyl, trifluoromethyl, amino or hydroxy; R10 and R11 are each independently hydrogen or alkyl R13 is hydrogen or C6.6 alkyl; R 14 is hydrogen, C 1-6 alkyl or hydroxy; R15 is hydrogen or C? -6 alkyl, The pharmaceutically acceptable acid addition salts as mentioned above refer to comprising the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are capable of forming . The latter can be obtained conveniently by treating the base form with an appropriate acid. Suitable acids comprise, for example, inorganic acids such as halohydric acids, for example, hydrochloric or hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid and similar acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, p-aminosalicylic, pamoic and the like. The term "addition salt" as used above also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are capable of forming. Such solvates are for example hydrates, alcoholates and the like. Conversely, the salt form can be converted by alkali treatment to the free base form. The term "stereochemically isomeric forms" as used below defines all possible stereoisomeric forms in which the compounds of formula (I) may exist, therefore, also including all enantiomers, enantiomeric mixtures and diastereomeric mixtures. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. The same applies to the intermediates as described herein, used to prepare final products of formula (I). The pure enantiomeric forms of the compounds of formula (I) are defined as enantiomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds. The asymmetric centers have the R- or S- configuration. The terms "cis" and "trans" are used herein in accordance with the nomenclature "Abstracts" of Chemistry and refer to the position of the substituents in a ring portion, more particularly to the dioxolane ring in the compounds of formula (I). In the second case, when establishing the cis or trans configuration, the substituent with the highest priority at the carbon atom at the 2-position of the dioxolane ring, and the substituent with the highest priority at the carbon atom at the 4-position of the dioxolane ring are considered (the priority of a substituent being determined according to the Cahn-Ingold-Prelog sequence rules). When said two substituents with higher priority are on the same side of the ring then the configuration is designated cis, if not, the configuration is designated trans. The compounds of formula (I) wherein the stereogenic carbon atom in the 2- position of the dioxolane portion has the S- configuration are particularly preferred. The compounds of formula (I) may also exist in their tautomeric forms. For example, heterocycles such as, for example, pyridine, pyrimidine, triazole, thiadiazole, oxadiazole, imidazole, thiazole and oxazole, which are substituted with hydroxy, amino or alkylamino of Ci-β may exist in their tautomeric form. It is intended that such forms, although not explicitly indicated in the above formula, be included within the scope of the present invention. The? / -oxide forms of the compounds of formula (I) refer to those compounds of formula (I) wherein one or more nitrogen atoms are oxidized by calling? -xldo, particularly those? / - oxides where one or more of the piperazine nitrogens are / V-oxidized.

Interesting compounds are those compounds of formula (I) wherein R 1 is chlorine or fluorine, especially chlorine. £ __ifeí.-__ a_3__ Other interesting compounds are those compounds of formula (I) wherein R 1 is C 1-6 alkyl, especially methyl. Other interesting compounds are those compounds of formula (I) wherein R 2 is hydrogen, chlorine or fluorine, preferably hydrogen. Another group of interesting compounds of formula (I) are those compounds in which the bivalent radical -AB- is -CH = CH-, -N = CH- or -CH = N-, especially -CH = N- or -N = CH-. In said bivalent radicals, the hydrogen atom can be replaced by C1.6 alkyl, especially methyl. A group of particular compounds comprises those compounds wherein R 3 is C 1 - β alkyl or C 1 cycloalkyl, preferably butyl, pentyl or cyclopentyl. A group of preferred compounds of formula (I) comprises those compounds wherein Het is a triazole, substituted triazole, imidazole, substituted imidazole, thiazole, or substituted thiazole. More preferred compounds of formula (I) are those Interesting or particular compounds wherein Het is 2-thiazolyl, 4-methyl-4H-1, 2,4-triazol-3-yl, 4H-1, 2,4-triazole- 3-yl, 2-methyl-2H-1, 2,4-triazol-3-yl or 2H-1, 2,4-trlazol-3-yl. The most preferred compounds are: c / s-4- [4- [4- [4 - [[2- (4-chlorophenyl) -2 - [[(4-methyl-4H-1, 2,4-tr! azol-3-yl) thio] methyl] -1, 3-dioxolan-4-yl] methoxyl] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methyl-propyl) ) -3H-1, 2,4-triazol-3-one; more in particular the diestereoisomer (-) - [2S- [2a, 4a (S *)]] compound 40 in Table 3, hereinafter referred to as Compound A; c / s-2- [4- [4- [4 - [[2- (4-chlorophenyl) -2 - [[(4-methyl-4H-1, 2,4-triazol-3-yl) thio] methyl] -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] pheny] -2,4-dihydro-4- (1-methyl-propyl) -3H-1, 2,4-triazol-3-one; c? s-2- [4- [4-t4 - [[2- (4-fluorophenyl) -2 - [[(4-methyl-4H-1, 2,4-triazol-3-yl) thio] methyl] ] -1, 3-d-oxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -4-cyclopentyl-2,4-dihydro-3H-1, 2,4-triazol-3-one; c / s-2- [4- [4- [4 - [[2- (4-chlorophenyl) -2 - [[(4-methyl-4H-1, 2,4-triazol-3-yl) thio] methyl] -1, 3-d-oxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-4-pentyl-3H-1, 2,4-triazol-3-one; c / s-4- (1-ethylpropyl) -2- [4- [4- [4 - [[2- (4-fluorophenyl) -2 - [[(4-methyl-4H-1, 2,4- triazol-3-yl) thio] methyl] -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-3H-1, 2,4-triazole-3 -one; a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof. In view of its apolipoprotein B inhibiting activity and concomitant lipid reducing activity, the compounds herein are useful as a medicine especially in a method for treating patients suffering from hyperlipidemia, obesity or atherosclerosis. In particular, the compounds of the present invention can be used for the manufacture of a medicine for treating disorders caused by an excess of very low density lipoproteins (VLDL) or low density lipoproteins (LDL), and in particular disorders caused by the related cholesterol. with said VLDL and LDL.

A large number of genetic and acquired diseases can result in hyperlipidemia. They can be classified into primary and secondary hyperlipidemic states. The most common causes of secondary hyperlipidemia are diabetes mellitus, alcohol abuse, drugs, hypothyroidism, chronic renal failure, nephrotic syndrome, cholestasis and bulimia. Primary hyperlipidemias are common hypercholesterolemia, familial combined hyperlipidemia, familial hypercholesterolemia, remnant hyperlipidemia, chylomicronemia syndrome, familial hypertriglyceridemia. The compounds of the present invention can also be used to prevent or treat patients suffering from obesity or atherosclerosis, especially coronary atherosclerosis and more generally disorders that are related to atherosclerosis, such as ischemic heart disease, peripheral vascular disease, cerebral vascular disease. . The compounds of the present invention can cause regression of atherosclerosis and inhibit the clinical consequences of atherosclerosis., in particular morbidity and mortality. The dosage depends on the particular compound of formula (I) used and its formulation, the particular condition being treated and the severity thereof, the age, weight and general physical condition of the patient and whether the patient is fasting or is fed, as well as other medication that the patient may be taking, as is well known to those skilled in the art. Likewise, it is evident that said effective daily amount can be decreased or increased depending on the response of the treated patient and / or depending on the evaluation of the physician prescribing the compounds of the present invention. The effective daily amount ranges mentioned herein are therefore only guidelines. Experts in the treatment of hyperlipidemia, obesity or atherosclerosis can determine an effective daily amount of compound A from the test results presented below. In general, a therapeutically effective dose will vary from 0.01 mg / kg to 5 mg / kg of body weight, most preferably from 0.1 mg / kg to 3 mg / kg of body weight. It suffices to administer a single dose orally once a day. Said dose once a day is preferably formulated as a unit dosage form, for example, containing 25 mg to 200 mg, and in particular 100 to 150 mg of compound A per unit dosage form. As already mentioned, the compounds of formula (I) and their salts have a very limited aqueous solubility and hardly dissolve when they are in crystalline form. They can be dissolved in water in the presence of a solubilizing agent such as a cyclodextrin derivative. However, it is very convenient to have solid pharmaceutical dosage forms of the compounds of formula (I) in addition to liquid formulations. Dosage forms with a high drug content, a unit of which contains the required daily dose of the active ingredient instead of two or more of said units, are another convenient goal in pharmaceutical development. Ideally, the bioavailability of dosage forms should be independent of the food ingested by the patient or fasting thereof so that the drug can be administered to the patient - or as to that, to any mammal - at any time of the day, in particular that can be administered to patients (mammals) in a state of fasting. The present invention provides a once-a-day solid dosage form (o.d.) of a compound of formula (I) that has almost equal bioavailability in fasted and fed volunteers. At this stage, it can be seen that the therapeutically effective plasma levels of the lipid reducing agent or active metabolites thereof are easily maintained for at least 24 hours. The main condition is that the lipid-lowering agent must reach the plasma. The absorption of the dissolved lipid-reducing agent from the stomach does not in itself constitute a problem. Accordingly, there is no need for a sustained release dosage form of the compound of formula (I), an immediate release form will serve well. In other words, the main problem with the administration of a lipid-lowering agent in therapeutically effective amounts relates firstly to ensuring that a sufficient amount of the lipid-lowering agent remains in solution long enough to allow it to enter the circulation, and that it does not become a form that is not readily bioavailable, in particular in crystalline lipid reducing agent (which is formed, for example, when the lipid-lowering agent is precipitated in an aqueous medium).

The present invention provides pharmaceutical compositions of a lipid-lowering agent and a water-soluble polymer that can be administered to a mammal, in particular a human, suffering from hyperlipidemia, obesity or atherosclerosis by means of which a single dosage form is You can administer once a day. The bioavailability of the drug from these dosage forms in fasting and fed mammals is comparable. The dosage forms comprise a therapeutically effective amount of pellets as described in detail below. In order to achieve the desired lipid lowering effect, it is essential that therapeutically effective plasma levels of the agent can be maintained. Since the agent is practically insoluble, effective formulations must be designed in such a manner that the drug is readily bioavailable. In other words, the main problem with the administration of the agent in therapeutically effective amounts refers to ensuring that a sufficient quantity of the agent remains in solution long enough to allow it to enter the circulation, and does not become a form that is not readily bioavailable, in particular crystalline agent (which is formed, for example, when the agent is precipitated in an aqueous medium). For this purpose, the agent is preferably ingested during or at the end of a meal. This, however, limits the ease with which patients can comply with their prescribed therapy.; For example, some patients can not eat normally or swallow drugs easily due to disease, nausea, or due to opportunistic infections of the esophagus. Accordingly, it would be very convenient to have pharmaceutical dosage forms that can be administered to a patient at any time of day regardless of the food ingested, ie, dosage forms that can be administered to patients in a fasting state. Unexpectedly, it has now been found that pellets with good bioavailability of a lipid reducing agent can be manufactured conveniently. A therapeutically effective amount of novel pellets as described in detail below can be introduced into capsules or can be processed in tablet form. In particular, the present invention relates to pellets comprising (a) a central, rounded or spherical core, (b) a coating film of a water-soluble polymer and a lipid-lowering agent and optionally (c) a layer of polymer coating seal, and in Wherein the core has a diameter of from about 250 to about 1180 μm (16-60 mesh), preferably from about 300 to about 1000 μm (18-50 mesh), most preferably from about 355 to about 850 μm (20- mesh) 45), and optimally from about 600 to about 710 μm (25-30 mesh). The pellets, spheres or cores of the dimensions mentioned herein can be obtained by sieving through nominal standard test sieves as described in the CRC Manual, edition 64, page F-114. The nominal standard sieves are characterized by the mesh / hole width (μm), DIN 4188 (mm), ASTM E 11-70 (No), Tyier® (mesh) or standard values BS 410 (mesh). Throughout this description and the claims, the particle sizes are designated by reference to the mesh / hole width in μm and the corresponding screen No. in the ASTM E11-70 standard. Suitable materials for use as cores in the pellets according to the present invention are varied, as long as said materials are pharmaceutically acceptable and have appropriate dimensions (approximately 16-60 mesh) and firmness. Examples of such materials are polymers, for example, plastic resins; inorganic substances, for example, silica, glass, hydroxyapatite, salts (sodium or potassium chloride, calcium or magnesium carbonate) and the like; organic substances, for example, activated carbon, acids (citric, fumaric, tartaric, ascorbic and the like), and saccharides and derivatives thereof. Particularly suitable materials are saccharides such as sugars, oligosaccharides, polysaccharides and their derivatives, for example, glucose, rhamnose, galactose, lactose, sucrose, mannitol, sorbitol, dextrin, maltodextrin, cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, starches (corn, rice, potato, wheat, tapioca) and similar saccharides. A particularly preferred material suitable for use as cores in the pellets according to the present invention is represented by 25-30 mesh sugar spheres (USP 22 / NF XVII, P. 1989) which consist of 62.5% - 91.5% (w / w) of sucrose, the rest being starch and possibly also dextrins, and which are pharmaceutically inert or neutral. Accordingly, these cores are also known in the art as neutral pellets. The pellets that can be obtained from 25-30 mesh sugar cores comprise approximately, by we based on the total we of the pellet: (a) 20 to 60 percent core material; (b) 25 to 50 percent water soluble polymer; (c) 10 to 25 percent lipid reducing agent; and (d) 2 to 5 percent of seal coating polymer. The water soluble polymer in the pellets according to the present invention is a polymer having an apparent viscosity of 1 to 100 mPa when dissolved in a 2% aqueous solution at 20 ° C. For example, the water soluble polymer can be selected from the group comprising - alkyl celluloses such as methyl cellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose, hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose, carboxyalkylcelluloses such as carboxymethylcellulose, alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose, carboxyalkylalkylcelluloses such as carboxymethylethylcellulose, carboxyalkyl cellulose esters, starches, pectins such as sodium carboxymethylammopectin, chitin derivatives such as chitosan, polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar , gum arabic, guar gums and xanthan gums, - polyacrylic acids and salts thereof, - polymethacrylic acids and salts thereof, copolymers of methacrylate, - polyvinyl alcohol, - polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide. The non-listed polymers that are pharmaceutically acceptable and have appropriate physicochemical properties as defined below are equally suitable for preparing pellets according to the present invention. The drug coating layer preferably comprises a water soluble polymer such as hydroxypropylmethylcellulose (Methocel®, Pharmacoat®), methacrylate (Eudragit E®), hydroxypropylcellulose (Klucel®), or a polyvidone. The preferred water-soluble polymers are hydroxypropylmethylcelluloses or HPMC. Said HPMC contains sufficient hydroxypropyl and methoxy groups to make it soluble in water. HPMC having a methoxy degree of substitution of about 0.8 to about 2.5 and a molar hydroxypropyl substitution of about 0.05 to about 3.0 are generally soluble in water. The methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. The molar substitution of hydroxypropyl refers to the average number of moles of propylene oxide that have reacted with each anhydroglucose unit of the cellulose molecule. Hydroxypropylmethylcellulose is the name adopted in the United States for hypromellose (see Martindale, The Extra Pharmacopoeia, edition 29, page 1435). Preferably the hydroxypropylmethylcellulose with low viscosity, ie about 5 mPa., Is used, for example hydroxypropylmethylcellulose 2910 5 mPa. In the four-digit number "2910", the first two digits represent the approximate percentage of methoxyl groups and the third and fourth digits represent the approximate percentage composition of hydroxypropoxyl groups. 5 mPa is a value that indicates the apparent viscosity of a 2% aqueous solution at 20 ° C. Suitable HPMCs include those having a viscosity of about 1 to about 100 mPa, in particular about 3 to about 15 mPa, preferably about 5 mPa. The most preferred type of HPMC having a viscosity of 5 mPa is commercially available HPMC 2910 5 mPa.

PVP-VA 64 is a vinylpyrrolidone-vinyl acetate copolymer that is soluble in both water and alcohol, and is commercially available as Kollidon® VA 64 from BASF. The copolymer is derived from 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6: 4 by mass, and is designated CAS nr 25086-89-9. The copolymer is particularly suitable for use as a matrix material for fast release formulations and can be easily melted and extruded with drugs having relatively poor bioavailability to form rapidly dissolving dispersions. The weight-to-weight ratio of (a) :( b) is in the scale from 1: 1 to 1: 35, preferably 1: 1 to 1: 5. In the case of (compound A): (HPMC 2910 5 mPa.), Said ratio can vary from about 1: 1 to about 1: 3, and optimally is about 2: 3. The weight-for-weight ratio of the lipid-lowering agent to other water-soluble polymers can be determined by a person skilled in the art by simple experimentation. The lower limit is determined by practical considerations. Indeed, given the therapeutically effective amount of the lipid reducing agent (from about 25 mg to about 200 mg, preferably 150 mg per day), the lower limit of the ratio is determined by the maximum amount of mixture that can be processed in a practical size dosage form. When the relative amount of water soluble polymer is too high, the absolute amount of mixture necessary to reach the therapeutic level will be too high to be processed in one capsule or tablet. The tablets, for example, have a maximum weight of about 1 g, and the extrusion product may represent at most about 90% (w / w) thereof. Accordingly, the lower limit of the amount of the lipid reducing agent on the water soluble polymer will be about 1: 35 (25 mg of lipid reducing agent + 875 mg of water soluble polymer). On the other hand, if the ratio is too high, this means that the amount of lipid-lowering agent is relatively high compared to the amount of the water-soluble polymer, then there is a risk that the lipid-lowering agent does not dissolve. sufficient in the water soluble polymer, and therefore, the required bioavailability will not be obtained. The degree to which a compound has dissolved in a water-soluble polymer can often be checked visually: if the extrudate is clear then it is very likely that the compound has completely dissolved in the water-soluble polymer. The upper 1: 1 limit is determined by the fact that above said ratio it was observed that the extrusion product resulting from extruding the lipid reducing agent with HPMC 2910 mPa forms a solid solution, but appears to partially crystallize during grinding . It will be understood that the upper limit of 1: 1 can be underestimated by particular water-soluble polymers. Because this can be easily established except for the time of experimentation involved, it is also intended that solid dispersions wherein the ratio (a) :( b) is greater than 1: 1 are within the scope of the present invention. The drug coating layer of the pellets as described above may also comprise one or more pharmaceutically acceptable excipients, such as, for example, plasticizers, flavors, colorants, preservatives and the like. Said excipients must be inert, in other words, they must not show any degradation or decomposition under the manufacturing conditions. In the formulations of compound A: HPMC 2910 5mPa hereof, the amount of plasticizer is preferably small, in the order of 0% to 15% (w / w), preferably less than 5% (w / w), very preferably 0% (w / w). However, with other water-soluble polymers plasticizers can be used in different, often higher amounts. Suitable plasticizers are pharmaceutically acceptable and include low molecular weight polyalcohols such as ethylene glycol, propylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol; polyethylene glycols such as diethylene glycol, triethylene glycol, tetraethylene glycol; other polyethylene glycols having a molecular weight of less than 1,000 g / mol; polypropylene glycols having a molecular weight less than 200 g / mol; glycol ethers such as monopropylene glycol monoisopropyl ether; propylene glycol monoethyl ether; diethylene glycol monoethyl ether, ester type plasticizers such as sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, allyl glycolate; and amines such as monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine; triethylenetetramine, 2-amino-2-methyl-1,3-propanediol and the like. Of these, low molecular weight polyethylene glycols, ethylene glycol, low molecular weight polypropylene glycols and especially propylene glycol are preferred. A seal coating polymer layer is applied to the drug coated cores to prevent the pellets from sticking which would have in effect undesirable a concomitant decrease in dissolution rate and bioavailability. Preferably, a thin layer of polyethylene glycol (PEG), in particular polyethylene glycol 20000 (Macrogol 20000) is used as a layer of seal coating polymer. Preferred pellets comprise approximately: (a) 41 to 44 percent sugar spheres; (b) 32 to 33 percent hydroxypropylmethylcellulose 2910 5 mPa; (c) 21 to 24 percent of compound A; and (d) 3 to 4 percent polyethylene glycol 20,000. In addition, the pellets according to the present invention can also contain various additives such as thickening agents, lubricants, surfactants, preservatives, complexing agents and chelating agents, electrolytes or other active ingredients, for example, anti-inflammatory, antibacterial, disinfectant or vitamin agents. The pellets according to the present invention are conveniently prepared in the following manner. A drug coating solution is prepared by dissolving appropriate quantities of a lipid-lowering agent and a soluble polymer in a suitable solvent system. in water A suitable solvent system comprises a mixture of methylene chloride and an alcohol, preferably ethanol which can be denatured, for example, with butanone. Such a mixture should comprise at least 50% by weight of methylene chloride acting as a solution for the drug substance. Since hydroxypropylmethylcellulose does not dissolve completely in methylene chloride, at least 10% alcohol must be added. Preferably a relatively low methylene chloride / alcohol ratio is used in the coating solution, for example a methylene chloride / ethanol ratio ranging from 75/25 (w / w) to 45/55 (w / w), in particular approximately 50/50 (w / w). The amounts of solids, ie, lipid-lowering agent and water-soluble polymer, in the drug coating solution can vary from 7 to 10% (w / w) and is preferably about 8.3-8.5%. The drug coating process (on an industrial scale) is conveniently carried out in a fluidized bed granulator (e.g., Glatt WSG-30 or GPCG-30 type) equipped with a Wurster lower spray insert (e.g. a Wurster insert of 45.7 cm). The development of the laboratory-scale procedure can be carried out in a Glatt WSG-1 type with a lower Wurster insert of 15.2 cm. Obviously the procedure parameters depend on the equipment used. The spray speed must be carefully regulated. Too low a spray speed can cause some spray drying of the drug coating solution and result in a Product loss A too high sprinkling speed will cause excessive wetting with subsequent agglomeration. With agglomeration to the more serious problem, lower spraying speeds can be used initially, to be increased as the coating process continues and the pellets grow. The atomization air pressure with which the drug coating solution is applied also influences the performance of the coating. A low atomization air pressure results in the formation of larger droplets and an increased tendency towards agglomeration. A high atomization air pressure could conceivably carry the risk of spray drying of the drug solution, but it was found that this is not a problem. Consequently, the atomizing air pressure must be adjusted to near maximum levels. The volume of fluidisation air can be monitored by operating the exhaust air valve of the apparatus and must be adjusted in such a way as to obtain optimum circulation of pellets. Too low a volume of air will cause insufficient fluidization of the pellets; too high a volume of air will interfere with the circulation of pellets due to the countercurrent air currents that develop in the apparatus. In the present process optimum conditions were obtained by opening the exhaust air valve to approximately 50% of its maximum and gradually increasing the opening thereof by approximately 60% of the maximum as the coating process continued.

The coating process is carried out favorably using an inlet air temperature ranging from about 50 ° C to about 55 ° C. Higher temperatures may accelerate the process but have the disadvantage that evaporation of the solvent is so rapid that the coating liquid does not spread uniformly over the surface of the pellets resulting in the formation of a drug coating layer with high porosity As the overall volume of the coated pellets increases, the dissolution of the drug can decrease significantly to unacceptable levels. Obviously, the optimum process temperature will also depend on the equipment used, the nature of the core and the lipid reducing agent, the batch volume, the solvent and the spray speed.

Parameter settings for optimal coating results are described in more detail in the example below. It was found that performing the coating procedure under these conditions produced very reproducible results. In order to decrease the levels of residual solvent in the drug coating layer, the drug-coated cores can be conveniently dried in any suitable drying apparatus. Good results can be obtained by using a vacuum stirrer-dryer operated at a temperature from about 60 ° C to about 90 ° C, preferably about 80 ° C, a reduced pressure ranging from about 150-400 mbar (15-40 kPa) ), from preferably 200-300 mbar (20-30 kPa), for at least 24 hours, preferably about 36 hours. The vacuum stirrer-dryer is rotated conveniently at its minimum speed, for example 2 to 3 rpm. After drying, the drug coated cores can be screened. The seal coating polymer layer is applied to the drug coated cores in the fluidized bed granulator with Wurster bottom spray insert. The seal coating solution can be prepared by dissolving an appropriate amount of a seal coating polymer in a suitable solvent system. Said system is, for example, a mixture of methylene chloride and an alcohol, preferably ethanol. The methylene chloride / alcohol ratio used can be similar to the ratio used in the drug coating process and can therefore vary from about 75/25 (w / w) to about 45/55 (w / w) and in particular is approximately 50/50 (w / w). The amount of seal coating polymer in the seal coating spray solution can vary from 7 to 12% (w / w) and is preferably approximately 10-11%. The seal coating spray solution is favorably agitated during the seal coating process. The parameter setting to perform this last step is essentially similar to that used in the drug coating process. Appropriate conditions are described in more detail in the example below.

Another drying step may be required after applying the seal coating polymer layer. Excess solvents could be easily removed while operating the apparatus at the parameter settings used for approximately 5 to 15 minutes after the sprinkling had been completed. Both the drug coating process and the preferred seal coating process are carried out under an inert atmosphere of, for example, nitrogen. The coating equipment should preferably be connected to ground and should be provided with a system of adequate solvent recovery that contains an efficient condensation system. The pellets of the present invention can be formulated into pharmaceutical dosage forms comprising a therapeutically effective amount of pellets. Although, in the first place, the pharmaceutical dosage forms for oral administration such as tablets and capsules, the pellets of the present invention can also be used to prepare pharmaceutical dosage forms, for example, for rectal administration. Preferably, the pellets are filled into hard gelatin capsules so that the amount of, for example, 100 to 200 mg of the active ingredient is available per dosage form. For example, size 0 hard gelatin capsules are suitable for formulating pellets comprising 21 to 22 weight percent of agent lipid reducer, equivalent to approximately 100 mg of active ingredient. Drug-coated and seal-coated pellets can be filled into hard gelatin capsules using standard automatic capsule filling machines. A suitable earth connection and deionization equipment can favorably prevent the development of electrostatic charges. The capsule filling speed can influence the weight distribution and should be monitored. Good results are obtained when operating the equipment at approximately 75% to 85% of the maximum speed and in many cases when operating at full speed. Using the procedure parameters described above, a reproducible manufacturing method can be obtained for preparing pellets comprising a 25-30 mesh core, a drug coating layer of a lipid reducing agent and a water soluble polymer and a thin seal coating polymer layer . Pharmacokinetic studies showed that the pellets thus obtained have excellent dissolution and bioavailability properties.

Tablet Formulations Other dosage forms are those adapted for oral administration in the form of a tablet. They can be produced from the aforementioned pellets (coated with seal, but preferably without coating) by conventional tableting techniques with conventional ingredients or excipients and with conventional tableting machines. In addition, they can be produced at low cost. As mentioned above, an effective daily dose of the lipid reducing agent such as compound A ranges from about 25 mg to about 200 mg o.d., and preferably is about 100 to about 150 mg o.d. The shape of the tablets can be round, oval or oblong. In order for a patient to be allowed to swallow large dosage forms, it is favorable to give the tablets an appropriate form. The tablets that can be swallowed comfortably are therefore preferably in the form of a start instead of a round one. Especially preferred tablets are biconvex oblate tablets. As described later in more detail, a film coating on the tablet also contributes to the ease with which it can be swallowed. Tablets that give an immediate release of the lipid-lowering agent during oral Ingestion and that have good bioavailability are designed in such a way that the tablets disintegrate rapidly in the stomach (immediate release) and that the pellets that are released thus stay away one of the other so that they do not come together, provide the local high concentrations of the lipid-lowering agent and the possibility that the drug will precipitate (bioavailability). The desired effect can be obtained by distributing said pellets in a homogeneous manner throughout the mixture of a disintegrant and a diluent.

Suitable disintegrants are those that have a large coefficient of expansion. Examples thereof are hydrophilic, insoluble or poorly water soluble crosslinked polymers such as crospovidone (crosslinked polyvinylpyrrolidone) and croscarmellose (crosslinked sodium carboxymethylcellulose). The amount of immediate-release tablet disintegrant according to the present invention can conveniently range from about 3 to about 15% (w / w) and preferably is from about 7 to 9%, particularly about 8.5% (w / w). p). This amount tends to be larger than usual in tablets in order to ensure that the pellets are spread over a large volume of stomach contents during ingestion. Because disintegrants by their nature produce sustained-release formulations when used in bulk, it is favorable to dilute them with an inert substance called a diluent or filler. A variety of materials can be used as diluents or fillers. Some examples are lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (e.g., Avicel ™ microcrystalline cellulose) spray-dried or anhydrous, calcium phosphate dibasic dihydrate or anhydrous, and others known in the art, and mixtures thereof. same. A commercial spray-dried mixture of lactose monohydrate (75%) with microcrystalline cellulose (25%) which is commercially available as Microcelac ™ is preferred. The amount of diluent or filler in the tablets can conveniently range from about 20% to about 40% (w / w) and preferably ranges from about 25% to about 32% (w / w). The tablet may include a variety of one or more conventional excipients such as binders, pH regulating agents, lubricants, slipping agents, thickening agents, sweetening agents, flavors, colors. Some excipients may serve multiple purposes. Lubricants and sliders can be used in the manufacture of certain dosage forms, and will usually be employed in producing tablets. Examples of lubricants and sliders are hydrogenated vegetable oils, for example, hydrogenated cottonseed oil, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, talc, mixtures thereof, and others known in the art. Lubricants and slippery agents Interesting are magnesium stearate, and mixtures of magnesium stearate with colloidal silica. A preferred lubricant is hydrogenated vegetable oil type I (micronized), most preferably hydrogenated and deodorized cottonseed oil (commercially available from Karishamns as Akofine NT ™ (formerly called Sterotex ™). Lubricants and sliders generally comprise 0.2 to 7.0 % of the total weight of the tablet Other excipients such as coloring agents and pigments can also be added to the tablets of the present invention Colorants and pigments include titanium dioxide and colorants suitable for food A coloring agent is an optional ingredient on the tablet of the present invention, but when the coloring agent is used it may be present in an amount of up to 3.5% based on the total weight of the tablet. The flavors are optional in the composition and can be chosen from synthetic flavor oils and flavoring aromatic substances or natural oils, extracts from leaves of plants, flowers, fruits, etc. and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oil, bay oil, anise oil, eucalyptus, thyme oil, vanilla, citrus oil, including lemon, orange, grape, lime, etc. and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. The amount of flavor may depend on a number of factors including the desired organoleptic effect. the flavor will be present in an amount of from about 0% to about 3% (w / w) As is known in the art, the tablet mixes can be dry-granulated or wet-granulated prior to tableting. it is otherwise standard and is easily practiced by forming a tablet from the desired combination or mixture of ingredients with the appropriate shape, using a conventional tablet press. cleaves the tablets of the present invention to improve taste, to provide ease of swallowing and elegant appearance. Many suitable polymeric film coating materials are known in the art. A preferred film coating material is hydroxypropylmethylcellulose HPMC, especially HPMC 2910 at 5 mPa.s. Other suitable film-forming polymers, including hydroxypropylcellulose and acrylic-methacrylate copolymers, can also be used herein. In addition to a film-forming polymer, the film layer may further comprise a plasticizer (for example propylene glycol) and optionally a pigment (for example titanium dioxide). The film coating suspension can also contain talc as an anti-adhesive. In the immediate release tablets according to the invention, the film layer is small and in terms of weight calculation by less than about 3.5% (w / w) of the total weight of the tablet. Preferred dosage forms are those in which the weight of the pellets varies from 40% to 60% of total weight of the total dosage form, the diluent varies from 20 to 40% and the disintegrant varies from 3 to 10%, the remainder being considered by one or more of the excipients described hereinabove. Preferred alternative dosage forms according to the present invention are those of which at least 40% of the available lipid reducing agent is dissolved within 60 minutes, when such a dosage form is tested as provided by the invention. USP test < 711 > in a USP-2 dissolution apparatus under conditions at least as stringent as the following: 900 ml of HCl at 0.1 N, at 37 ° C, with the paddles rotating at 50 rpm. It can be said that tablets that meet the above definition have Q > 40% (60 '). Preferably, the tablets according to the present invention dissolve more rapidly and have Q > 75% (60 '), more preferably Q > 75% (45 '). It is another object of the invention to provide a method of preparing a pharmaceutical dosage form as described hereinabove, characterized by the combination of a therapeutically effective amount of pellets as described above in a, with pharmaceutically acceptable excipients and the compression of said combination forming tablets. Furthermore, this invention relates to pellets as described hereinabove, for use in the preparation of a pharmaceutical dosage form for oral administration to a mammal suffering from hyperlipidemia., obesity or atherosclerosis, wherein only one such dosage form can be administered once a day to said mammal. The invention also relates to pellets as described hereinabove, for use in the preparation of a pharmaceutical dosage form for oral administration to a mammal suffering from hyperlipidemia, obesity or atherosclerosis, wherein said form can be administered. of dosing at any time of day regardless of the food ingested by said mammal.

The present invention also relates to the use of pellets as described hereinabove, for the preparation of a pharmaceutical dosage form for oral administration to a mammal suffering from hyperlipidemia, obesity or atherosclerosis, wherein only one can be administered. of such dosage forms once a day to said mammal. The invention also relates to the use of pellets as described hereinabove, for use in the preparation of a pharmaceutical dosage form for oral administration to a mammal suffering from hyperlipidemia, obesity or atherosclerosis, where it can be administered said dosage form at any time of day independently of food ingested by said mammal. The invention also relates to a method of treating hyperlipidemia, obesity or atherosclerosis in a mammal, which comprises administering to said mammal an effective amount of said lipid-lowering agent in a single oral dosage form that can be administered once a day. The invention also relates to a method of treating hyperlipidemia, obesity or atherosclerosis in a mammal, which comprises administering to said mammal an effective amount of said lipid-lowering agent in a single oral dosage form that can be administered at any time of day independently of the food ingested by said mammal.

The invention also relates to a pharmaceutical package suitable for commercial sale comprising a container, an oral dosage form of lipid reducing agent as described hereinabove and, associated with said package, printed material not limited as to if you can take the dosage form with or without food.

Experimental part The following tables show the formulas of the compounds of the formula I, their physical data and references to the examples in WO-96/13499 according to which the compounds in question can be prepared. In the pharmacological example, the lipid-lowering effect of the compounds of the formula I is illustrated. Examples which demonstrate how compound A (compound 40) can be pelletized and formulated as capsules having good bioavailability are then followed.

TABLE 1 TABLE 2 Co. Ex. Physical data No. No. 10 22 CH (CH3) CH2CH3 P.f. 176.9 ° C / c / s 23 CH2CH (CH3) 2 G? P.f. 192.9 ° C / c? S 24 Cycle (C5H9) P.f. 210.2 ° C / c / s 25 CH2CH (CH3) 2 P.f. 180.6 ° C / c / s 26 (CH2) 3CH3 77 P.f. 194.1 ° C / c / s 27 (CH2) 2CH3 P.f. 187.3 ° C / c / s 28 CH (CH3) CH2CH3 P.f. 157.5 ° C / c / s \ I 29 CH (CH3) CH2CH3 G? P.f. 146.4 ° C / c / s 30 CH2-CH3 r ~ \ P.f. 195.5 ° C / c / s 31 CH3 P.f. 161.2 ° C / c / s 32 (CH2) 4CH3 P.f. 191.7 ° C / c / s 33 CH (CH3) 2 G? P.f 157.2 ° C / c / s 34 CH2-CH (OH) -C (CH3) 3 G? P.f. 189.9 ° C / c / s 35 Cycle (C5H9) G? P.f. 198.2 ° C / c / s 36 CH (CH3) CH2CH3 P.f. 180.7 ° C / c / s TABLE 2 (CONTINUED) TABLE 3 TABLE 4 TABLE 6 TABLE 7 TABLE 8 TABLE 9 TABLE 10 TABLE 11 Pharmacology EXAMPLE 1 Apolipoprotein B inhibition test (apoB) Cultured human liver cells (Hep G2 cells) that synthesize and secrete low density lipoproteins were incubated overnight at 37 ° C in a liquid medium containing radioactively labeled leucine. Thus, radiolabelled leucine was incorporated into apolipoprotein B. The liquid medium was decanted and apolipoprotein B was isolated. by means of double immunoprecipitation, i.e., an antibody specific for apolipoprotein B (antibody-i) was first added to the liquid medium and a second antibody (antibody?) which specifically binds to the apoB-antibody-i complex was subsequently added. . The apoB-antibody? -antibody2 complex thus formed was precipitated and smoothed with a centrifuge. The quantification of the amount of apolipoprotein B synthesized during the night resulted from measuring the radioactivity of the isolated complex. To measure the inhibition activity of the test compound, that test compound was added to the liquid medium at different concentrations and a concentration of apolipoprotein B synthesized in the presence of a test compound (apoB concentration (after)) was compared to the concentration of apollipoprotein B that was synthesized in the absence of the compound of test (concentration of apoB (control)). For each experiment, the inhibition of apolipoprotein B formation was expressed as 1 - apoB concentration (after)% inhibition = 100 x apoB concentration (control) When more experiments had been carried out for the same concentration, the mean value of the inhibition calculated for these experiments was calculated. IC 50 values were also calculated (concentration of the drug needed to reduce apoB secretion at 50% control).

Table 12 lists the IC50 values for some of the exemplified compounds of formula I. Compounds of formula II that are not listed in table 12 and for which data are available, have an IC50 value of 1 x 10 ' 6 M or more.

TABLE 12 Example of composition EXAMPLE 2 to the spraying solution of compound A A stainless steel vessel was charged with methylene chloride (141 kg) and denatured ethanol (153 kg) through a filter (5 μ). Compound A (10.75 kg) and hydroxypropylmethylcellulose 2910 were added at 5 mPa.s (16.13 kg) while stirring. Stirring was continued until a complete solution was obtained. b) Seal coating spraying solution A stainless steel vessel was charged with methylene chloride (7.95 kg) and polyethylene glycol 20000 (Macrogol 20000) (1935 kg), while stirring. Denatured ethanol (8.622 kg) was added and the solution was stirred until homogeneous. c) Drug coating process A fluidized bed granulator (GPCG 30) equipped with a 45.72 cm Wurster insert was loaded with 25-30 mesh (600-700 μm) sugar spheres. The spheres were heated with dry air of 50 ° -55 ° C. The fluidizing air volume was controlled by opening the air exhaust valve approximately 50% of its maximum at the start, increasing to 60% at the end of the spray procedure. The previously prepared compound A spraying solution was then sprayed onto the spheres moving in the apparatus. The solution was sprayed at an initial delivery rate of approximately 600 to 700 g.min'1 at an atomization air pressure of approximately 3.5 kg / cm2 (0.343 MPa). After the supply of approximately 30% of the spray solution, the supply speed was increased to 700-800 g / min. When the spraying procedure was completed, the coated spheres were dried by again supplying dry air of 50 ° -55 ° C for about 10 minutes. The coated spheres were allowed to cool in the apparatus, supplying dry air of 20-25 ° C for about 10 to 20 minutes. The apparatus was emptied and the coated spheres were collected. d) Intermediate drying In order to minimize residual solvent levels, the coated spheres were then subjected to a drying step. The coated spheres were placed in a vacuum mixer-dryer and dried for at least 24 hours, preferably about 36 hours, at a temperature of about 80 ° C at a pressure of about 200-300 mbar (20-30 kPa ). The mixer-dryer was operated at its minimum rotation speed (2 to 3 rpm). The dried coated spheres were sieved with a sieve (Sweco S24C, sieve mesh width of 1.14 mm). e ^ > Seal coating process The dried coated spheres were again introduced into the fluidized bed slot, equipped with Wurster insert and heated with dry air of 50-55 ° C. The spray coating solution previously prepared on the coated spheres moving in the apparatus was then sprayed. The solution was sprayed at a delivery rate of about 400 to 500 g.min, at an atomizing air pressure of about 2.5 bar (0.25 MPa). When the spraying procedure was completed, the beads were dried by again supplying dry air of 50-55 ° C for 10 min. The coated beads were then allowed to dry in the apparatus, supplying dry air at 20 ° -25 ° C for about 5 to 15 minutes. The globules were removed from the apparatus and stored in suitable containers. • f) Capsule filling The drug coated pellets were introduced into the hard gelatine capsules (460 mg pellets equivalent to 100 mg of active ingredient in number of size 0) (115 mg pellets equivalent to 25 mg of active ingredient in number of size 4), using conventional automatic capsule filling machines (eg model GFK-1500, Höffliger and Karg, Germany). In order to obtain capsules with good weight distribution, the filling speed of capsules was reduced to approximately 75-85% of the maximum speed. Using the parameters of the process described above, hard gelatin capsules of 100 mg of compound A were obtained which satisfied all the requirements, in particular the dissolution specifications.

EXAMPLE 3 Comparative bioavailability of the capsule filled with pellets with respect to the oral solution and the influence of the food In a three-way, open, randomized, and open-group crossover experiment, the oral bioavailability of the capsule comprising 100 mg of compound A was compared with that of an aqueous oral solution. The aqueous oral solution comprised 0.63 mg / ml of compound A, 100 mg / ml of 2-hydroxypropylcyclodextrin, 2.5 μl of HCl (12 N) and NaOH to give a final pH of 2.0 ± 0.1. Three groups of six healthy male volunteers took a single oral dose of 100 mg of compound A in capsule formation under fasting conditions, directly after conditional breakfast and as an oral solution under fasting conditions. The pharmacokinetic products were evaluated for the unaltered drug only and are summarized in the following table in the present.

*: Fasting with capsule with respect to fasting with solution. #: food with capsule with respect to fasting with capsule.

Claims (20)

NOVELTY OF THE INVENTION CLAIMS

1. - A pellet comprising: a) a central, rounded or spherical core having a diameter of about 250 to about 1180 μm (18-60 mesh); b) a coating film of a water soluble polymer and a lipid reducing agent of the formula II, and optionally c) a layer of seal coater polymer, characterized in that said lipid reducing agent has the formula an N-oxide, a stereochemically isomeric form, a mixture of two or more such forms, or a pharmaceutically acceptable acid addition salt thereof, wherein A and B taken together form a bivalent radical the formula: -N = CH - (a), -CH = N- (b), -CH2-CH2- (c), -CH = CH- (d), -C (= 0) -CH2- (e), -CH2-C ( = 0) - (f), whereby the bivalent radicals of formula (a) and (b) can be replaced by the hydrogen atom by Ci-β alkyl; in the bivalent radicals of formulas (c), (d), (e), (f), one or two hydrogen atoms may be replaced by Ci-e alkyl; R1 is hydrogen, C-i-β alkyl or halogen; R2 it is hydrogen or halogen; R3 is hydrogen; Ci-β alkyl; C3-6 cycloalkyl; or alkyl of C-i-s substituted with hydroxy, oxo, C3-6 cycloalkyl or aryl; Het is a heterocycle selected from the group consisting of pyridine; pyridine substituted with one or more substituents selected from C 1-6 alkyl, hydroxy, C 1-6 alkyloxy, trihalogenomethyl, amino, mono- or di (Ci-β) -amino alkyl or aryl; pyrimidine; pyrimidine substituted with one or two substituents selected from C 1-6 alkyl, hydroxy, C 1-6 alkyloxy, trihalogenomethyl, amino, mono- or di (C 1-6 alkyl) -amino or aryl; tetrazole; tetrazole substituted with C 1-6 alkyl or aryl; triazole; triazole substituted with one or two substituents selected from C 1 -C 6 alkyl, hydroxy, C 1-6 alkyloxy, trihalogenomethyl, amino, mono- or di (C 6 alkyl) amino; thiadiazole, substituted with one or two substituents selected from Ci-Cβ alkyl, hydroxy, C 1-6 alkyloxy, trihalogenomethyl, amino, mono- or di (C-rß alkyl) -amino; oxadiazole substituted with one or two substituents selected from C 1 -C 6 alkyl, hydroxy, C 1-6 alkyloxy, trihalogenomethyl, amino, mono- or di (C 6 alkyl) -amino; imidazole; imidazole substituted with one or two substituents selected from Ci-Cß alkyl, hydroxy, d-β alkyloxy, trihalogenomethyl, amino, mono- or di (Cr6 alkyl) -amino; thiazole: thiazole substituted with one or two substituents selected from C 1 -C 7 alkyl, hydroxy, C 1-6 alkyloxy, trihalogenomethyl, amino, mono- or di (C-rß alkyl) -amino; oxazole; oxazole substituted with one or two substituents selected from d-Cß alkyl, hydroxy, Ci-β alkyloxy, trihalogenomethyl, amino, mono- or dl (C? -β) -amino alkyl; and aryl is phenyl or phenyl substituted with C 1-6 alkyl or halogen.

2. A pellet according to claim 1, further characterized in that the water-soluble polymer is a polymer having an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2% aqueous solution at 20 ° C.

3. A pellet according to claim 2, further characterized in that the water soluble polymer is selected from the group comprising: alkyl celluloses such as methyl cellulose; hydroxyalkyl celluloses such as hydroxymethyl cellulose; hydroxyethylcellulose; hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose; carboxyalkylcelluloses such as carboxymethylcellulose; alkali metal salts of carboxyalkylcelluloses such as carboxymethylcellulose; carboxyalkylalkylcelluloses such as carboxymethylethylcellulose; esters of carboxyalkylcellulose; starches; pectins such as sodium carboxymethylammycin; chitin derivatives such as chitosan; polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic, guar gum and xanthan gum; polyacrylic acids and the salts thereof; polymethacrylic acids and the salts thereof; methacrylate copolymers; polyvinyl alcohol, polyvinylpyrrolldone, copolymers of polyvinylpyrrolidone with vinyl acetate; oxides of polyalkylene such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.

4. A pellet according to claim 3, further characterized in that the water-soluble polymer is HPMC 2910 hydroxypropylmethylcellulose at 5 mPa.s.

5. A pellet according to claim 1, further characterized in that the weight-to-weight ratio of lipid-reducing agent: water-soluble polymer is from 1: 1 to 2: 3.

6. A pellet according to claim 1, further characterized in that the seal coating polymer is polyethylene glycol.

7. A pellet according to claim 1, comprising by weight based on the total weight of the pellet: a) 20 to 60 percent core material; b) 25 to 50 percent soluble polymer in 15 water; c) from 10 to 25 percent lipid reducing agent; and d) from 2 to 5 percent of seal coater polymer.

8. A pellet according to claim 7, comprising approximately: a) from 41 to 44 percent sugar spheres b) from 32 to 33 percent hydrophoxypropylmethylcellulose 2910 at 5 mPa.s .; c) from 20 21 to 22 percent c / s - (-) - [2S- [2alpha, 4alpha (S *)]] - 4- [4- [4- [4 - [[2- (4- chlorophenyl) -2- [[(4-methyl-4H-1, 2,4-triazol-3-yl) thio] methyl] -1, 3-d-oxolan-4-yl] methoxy] phenyl] -1 -piperazinyl] phenyl] -2,4-dihydro-2- (1-methoxypropyl) -3H-1, 2,4-triazol-3-one; and d) from 3 to 4 percent polyethylene glycol 20,000. _ ^^

9. - A pellet according to any of the preceding claims, further characterized in that the core material is a sugar sphere of 600-710 μm (25-30 mesh).

10. A pellet according to the preceding claims, further characterized in that the lipid reducing agent is c / s - (-) - [2S- [2alpha, 4alpha (S *)]] - 4- [4- [4 - [4 - [[2- (4-chlorophenyl) -2 - [[(4-methyl-4H-1, 2,4-triazol-3-yl) thio] methyl] -1,3-dioxolan-4 -yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methoxypropyl) -3H-1, 2,4-triazol-3-one.

11. A process for preparing pellets according to claims 1 to 10, further characterized by: a) coating of 250-1180 μm (18-60 mesh) of sugar spheres sprinkled on them a solution of a lipid-lowering agent and a water soluble polymer in an organic solvent consisting of methyl chloride and an alcohol in a fluidized bed granulator, equipped with a Wurster insert (bottom spray); (b) drying the resulting coated cores; and (c) seal coating of the dry cores by sprinkling on them a solution of a Wurster seal coater (bottom spray) from an organic solvent.

12. Pellet-coated pellets obtainable by a process according to claim 11.

13. A pharmaceutical dosage form, comprising a lipid-reducing effective amount of pellets according to any of claims 1 to 10.

14. - A dosage form according to claim 13, further characterized in that the dosage form is a hard gelatin capsule.

15. A dosage form according to claim 13, from which at least 40% of the available lipid reducing agent is dissolved within 60 minutes when said dosage form is tested as set forth in the USP test < 711 > in a USP-2 dissolution apparatus under conditions at least as stringent as the following: 900 ml of 0.1 N HCl, pH 6.0, at 37 ° C with the paddles rotating at 50 rpm.

16. Pellets according to any of claims 1 to 10, for use in the preparation of a pharmaceutical dosage form for oral administration to a mammal suffering from hyperllpidemia, obesity or atherosclerosis, characterized in that it can be administered a alone of such dosage forms once a day to said mammal.

17. Pellets according to any of claims 1 to 10, for use in the preparation of a pharmaceutical dosage form for oral administration to a mammal suffering from hyperlipidemia, obesity or atherosclerosis, further characterized because any order of the day regardless of the food ingested by said mammal.

18. - Pellets according to any of claims 1 to 10, for use in the preparation of a pharmaceutical dosage form for oral administration to a mammal suffering from hyperlipidemia, obesity or atherosclerosis, characterized in that it can be administered only one of such dosage forms once a day to said mammal.

19. Pellas according to any of claims 1 to 10, for use in the preparation of a pharmaceutical dosage form for oral administration to a mammal suffering from hyperlipidemia, obesity or atherosclerosis, characterized in that it can be administered to any order of the day regardless of the food ingested by said mammal.

20. A pharmaceutical package suitable for commercial sale, comprising a container, an oral dosage form of lipid reducing agent according to any of claims 13 to 15, and, associated with said package, printed material not limited as to whether the dosage form can be taken with or without food.