JP2002544118A - Pellet having a core coated with a lipid-lowering agent and a polymer - Google Patents

Abstract

  (57) [Summary] The present invention provides a sugar sphere of 250 to 1180 μm (16 to 60 mesh), a coating film of a water-soluble polymer and a slightly soluble lipid-lowering agent, a pellet comprising a seal coating layer, and a drug administration comprising the pellet. The present invention relates to a form and a method for producing the pellet.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a sugar spher of 250 to about 1180 μm (16 to 60 mesh).
e), a coating film of a water-soluble polymer and a sparingly soluble lipid-lowering agent, and a pellet comprising a seal-coating layer, a drug-containing form comprising the pellet, and a method for producing the pellet About. The lipid-lowering agent can be administered to a mammal suffering from hyperlipidemia, obesity or atherosclerosis,
A single such dosage form can then be administered once a day.

[0002] The development of effective pharmaceutical compositions of lipid-lowering agents, such as those previously disclosed in WO-96 / 13499, has been significantly hindered by the fact that the lipid-lowering agents are very slightly soluble in water. I have.

[0003] The lipid-lowering agents previously disclosed in WO-96 / 13499 are of the formula

[0004]

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Wherein A and B together form the formula: —N 式 CH— (a), —CH ＝ CH— (d), —CH ＝ N— (b), —C (＝ O) -CH_Two-(E), -CH_Two-CH_Two-(C), -CH_Two—C (＝ O) — forms a divalent group of the formula (a) wherein the hydrogen atom in the divalent group of the formulas (a) and (b)
Is C_1-6Optionally substituted by alkyl, wherein the compounds of formulas (c), (d)
, (E) and (f) have one or two hydrogen atoms as C_1-6Al
May be substituted by a kill, R¹Is hydrogen, C_1-6Alkyl or halo; R^TwoIs hydrogen or halo; R^ThreeIs hydrogen; C_1-8Alkyl; C_3-6Cycloalkyl; or hydroxy, oxo
, C_3-6C substituted with cycloalkyl or aryl_1-8Het is pyridine; C_1-6Alkyl, hydroxy, C_1-6Alkyloxy, triha
Romethyl, amino, mono- or di (C_1-6Alkyl) amino or aryl
Pyridine substituted with one or two substituents selected from: pyrimidine;
C_1-6Alkyl, hydroxy, C_1-6Alkyloxy, trihalomethyl, amino,
Mono- or di (C_1-61 selected from alkyl) -amino or aryl
Pyrimidine substituted with one or two substituents; tetrazole; C_1-6Archi
Or triaryl-substituted tetrazole; triazole; C_1-6Alkyl,
Hydroxy, C_1-6Alkyloxy, trihalomethyl, amino, mono- or
Di (C_1-6Substituted with one or two substituents selected from alkyl) -amino
Triazole; thiadiazole; C_1-6Alkyl, hydroxy, C_1-6Al
Killoxy, trihalomethyl, amino, mono- or di (C_1-6Alkyl)
Thiadiazole substituted with one or two substituents selected from mino; C _1-6 Alkyl, hydroxy, C_1-6Alkyloxy, trihalomethyl, amino, mo
No or di (C_1-6One or two positions selected from alkyl) amino
Oxadiazole substituted with a substituent; imidazole; C_1-6Alkyl, hydroxy
Si, C_1-6Alkyloxy, trihalomethyl, amino, mono- or di (C_1-6 Imida substituted with one or two substituents selected from alkyl) amino
Sol; thiazole; C_1-6Alkyl, hydroxy, C_1-6Alkyloxy, tri
Halomethyl, amino, mono- or di (C_1-6Alkyl) amino
Thiazole substituted by one or two substituents; oxazole; C_1-6A
Alkyl, hydroxy, C_1-6Alkyloxy, trihalomethyl, amino, mono-
Or di (C_1-6One or two substituents selected from alkyl) amino
Is a heterocyclic ring selected from the group consisting of oxazoles substituted with_1-6With phenyl substituted by alkyl or halo
The N-oxides, one or more stereochemically isomeric forms thereof, and drugs
It has a pharmaceutically acceptable acid addition salt.

The compounds of formula (I) and their salts have very limited aqueous solubility (pH 3 [1
0 In ^-3 N HCl] have <0.5 mg / ml) and hardly dissolves during crystal form. To ensure that the compounds of formula (I) have sufficient bioavailability, they may be dissolved in water in the presence of a solubilizing agent, such as a cyclodextrin derivative, such as 2-hydroxypropyl-beta-cyclodextrin. Can be done. The present invention provides an alternative that provides a dosage form that does not require the use of a lysing agent and has sufficient bioavailability.

In the compounds of formula (I) as defined above, the heterocyclic group “Het” is linked to the sulfur atom via a carbon atom.

The halo used in the above definition is a generic term for fluoro, chloro, bromo and iodo, and C _1-6 alkyl is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, For example, define methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 2-methylpropyl, etc., wherein C _1-8 alkyl is C _1-6 alkyl and higher homologues thereof having 7 or 8 carbon atoms. Are defined, for example heptyl or octyl, as well as their branched isomers. C _3-6 cycloalkyl has 3 carbon atoms
Define from 6 to 6 saturated cyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0009] Het is especially of the formula

[0010]

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Wherein R ⁴ is hydrogen or C _1-6 alkyl; R ⁵ and R ⁶ are hydrogen, C _1-6 alkyl or amino; R ⁷ is hydrogen or C _1-6 alkyl Each R ⁸ is independently hydrogen or C _1-6 alkyl; each R ⁹ is independently hydrogen, C _1-6 alkyl, trifluoromethyl, amino or hydroxy; and R ¹⁰ and R ¹¹ are each Independently hydrogen or C _1-6 alkyl; R ¹³ is hydrogen or C _1-6 alkyl; R ¹⁴ is hydrogen, C _1-6 alkyl or hydroxy; R ¹⁵ is hydrogen or C _1-6 Alkyl].

The pharmaceutically acceptable acid addition salts mentioned above are meant to comprise the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) can form. The latter can be conveniently obtained by treating the base form with such a suitable acid. Suitable acids are, for example, inorganic acids such as hydrohalic acids, such as hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and similar acids, or organic acids, such as acetic acid,
Propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfone Acids, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and similar acids. The term addition salt as used above also comprises solvates from which the compounds of formula (I) can be formed, as well as their salts. Such solvates are for example hydrates, alcoholates and the like. Conversely, the salt form can be converted to the free base form by treatment with an alkali.

The term “stereochemically isomeric forms” as used above defines all possible stereoisomeric forms in which the compounds of formula (I) can exist, and thus all mirror image forms Includes isomers, enantiomeric mixtures and diastereomeric mixtures. Unless otherwise stated or indicated, chemical representations of compounds indicate mixtures of all possible stereochemically isomeric forms, which mixtures contain all diastereomers and enantiomers of the basic molecular structure . The same applies to the intermediates described here which are used to prepare the final product of formula (I).

A pure enantiomer of a compound of formula (I) is defined as an enantiomer substantially free of other enantiomers or diastereomeric forms of the same basic molecular structure of the compound.

[0015] The asymmetric center has either the R- or S-configuration. The terms cis and trans are used herein according to Chemical Abstracts nomenclature and refer to the position of a substituent on a ring moiety in a compound of formula (I), more particularly on a dioxolane compound. In the latter case, when establishing the cis or trans configuration, the substituent with the highest priority on the carbon atom at the 2-position of the dioxolane ring and the highest priority on the carbon atom at the 4-position of the dioxolane ring are assigned. The substituent may be included (the priority of the substituent is determined according to the Cahn-Ingold-Prelog sequence rule). If these two substituents with the highest priority are on the same side of the ring, the configuration is designated as cis, otherwise the configuration is designated as trans.

Compounds of formula (I) in which the 2-position stereogenic carbon atom of the dioxolane moiety has the S-configuration are particularly preferred.

The compounds of the formula (I) can also exist in their tautomeric form. For example, heterocycles substituted with hydroxy, amino or C _1-6 alkylamino, such as pyridine, pyrimidine, triazole, thiadiazole, oxadiazole,
Imidazole, thiazole and oxazole can exist in their tautomeric form. Such forms are not explicitly shown in the above formula, but are intended to be included within the scope of the present invention.

The N-oxide forms of the compounds of the formula (I) are compounds of the formula (I) in which one or several nitrogen atoms have been oxidized to so-called N-oxides, in particular one of the piperazine nitrogen.
Means one or more comprises an N-oxide that is N-oxidized.

Compounds of interest are those of formula (I) wherein R ¹ is chloro or fluoro, especially chloro.
Is a compound of

Another compound of interest is a compound of formula (I) wherein R ¹ is C _1-6 alkyl, especially methyl.

Other compounds of interest are compounds of formula (I), wherein R ² is hydrogen, chloro or fluoro, preferably hydrogen.

Yet another group of compounds of interest of formula (I) is that the divalent group -AB- is -CH =
CH-, -N = CH- or -CH = N-, especially -CH = N- or -N = CH
-, Is a compound. In the divalent group, a hydrogen atom may be substituted by C _1-6 alkyl, especially methyl.

A special group of compounds comprises those compounds wherein R ³ is C _1-8 -alkyl or C _3-6 cycloalkyl, preferably butyl, pentyl or cyclopentyl.

A group of preferred compounds of the formula (I) comprises those compounds wherein Het is a triazole, a substituted triazole, an imidazole, a substituted imidazole, a thiazole, or a substituted thiazole.

More preferred compounds of formula (I) are those wherein Het is 2-thiazolyl, 4-methyl-4
H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-3-
Yl, 2-methyl-2H-1,2,4-triazol-3-yl or 2H-1,
An interesting or special compound that is 2,4-triazol-3-yl.

The most preferred compound is cis-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-methylpropyl) -3H-1,2,4-triazol-3-one, more particularly the diastereomer (-)-[2S- [2α,
4α (S *)]] compound 40, cis-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] phenyl] -2,4-dihydro-4- ( 1-methylpropyl) -3H-1,2,4-triazol-3-one, cis-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] -4-cyclopentyl-2, 4-dihydro-3H-1,2,4-triazol-3-one, cis-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] phenyl] -2,4-dihydro-4-pentyl -3H-1,2,4-triazol-3-one, cis-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-triazol-3-one, their pharmaceutical properties In the form of an acid addition salt or a stereochemically isomeric form.

In view of their apolipoprotein B inhibitory activity and concomitant lipid-lowering activity, the compounds are particularly useful as medicaments in methods of treating patients suffering from hyperlipidemia, obesity or atherosclerosis. . In particular, the compounds are useful for treating disorders caused by very low density lipoprotein (VLDL) or excess of low density lipoprotein (LDL), and especially disorders caused by cholesterol associated with said VLDL and LDL. Can be used for the manufacture of medicines.

[0028] A number of genetic and acquired diseases can cause hyperlipidemia. They can be classified into primary and secondary hyperlipidemic stages. The most common causes of second-stage hyperlipidemia are diabetes mellitus, alcohol abuse, drugs, hypothyroidism, chronic renal failure,
Nephrotic syndrome, hepatic secretion arrest and pathological starvation. Primary hyperlipidemia is normal hypercholesterolemia, familial complex hyperlipidemia, familial hypercholesterolemia, remnant hyperlipidemia, chylemic syndrome, familial hypertriglyceride Is bloody. The compounds may prevent or prevent patients suffering from obesity or atherosclerosis, especially coronary atherosclerosis, and more generally disorders associated with atherosclerosis, such as ischemic heart disease, peripheral vascular disease, cerebrovascular disease. It can also be used to treat. The compounds can cause atherosclerosis regression and suppress the clinical symptoms of atherosclerosis, especially morbidity and mortality.

As is known to those skilled in the art, the dosage will depend on the particular compound of formula (I) used and its formulation, the particular condition to be treated and its severity, the age, weight and overall It depends on the physical condition and whether the patient is fasting or eating, as well as other medications the patient is receiving. It is further evident that this effective daily dose can be reduced or increased by the response of the treated patient and / or by the evaluation of the physician indicating the compound of the invention. The effective daily dose ranges listed below are therefore merely guidelines.

The skilled person in the treatment of hyperlipidemia, obesity or atherosclerosis can determine the effective daily dose of Compound A from the test results presented below. Generally, a therapeutically effective dose will be from 0.01 mg / kg to 5 mg / kg body weight, more preferably 0.1 mg / kg.
It will range from mg / kg to 3 mg / kg body weight. It is sufficient to administer a single dose orally once a day. This once daily dose is preferably for example 25 mg to 200 mg, and especially 100 to 150 mg of compound A per unit dosage form
Is formulated as a unit dosage form containing

As mentioned above, the compounds of formula (I) and their salts have very limited aqueous solubility and are poorly soluble when in crystalline form. They can be dissolved in water in the presence of a solubilizer, for example, cyclodextrin. However, it is highly desirable to have a solid pharmaceutical dosage form of the compound of formula (I) in addition to a liquid formulation. Dosage forms having a high drug content, one unit instead of the required daily dose of the active ingredient in two or more units, are another desirable goal in drug development. Ideally, in order for a drug to be able to be administered to a patient-or indeed to any mammal-at any time of the day, especially if it is administered to a fasting patient (
In order to be able to administer to a mammal, the bioavailability of the dosage form must be independent of the food or fasting consumed by the patient. The present invention provides a once-daily (od) solid dosage form of a compound of formula (I) having approximately equal bioavailability in fasting and ingesting volunteers.

At this stage it is noteworthy that therapeutically effective plasma levels of lipid-lowering agents 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. Gastric absorption of dissolved lipid-lowering agents is not a problem per se. Therefore, a sustained release dosage form of the compound of formula (I) is not required, and an immediate release form would be justified. In other words,
The main problem with administering a lipid-lowering agent in a therapeutically effective amount is first of all that a sufficient amount of the lipid-lowering agent remains in solution long enough to allow it to circulate, and It is concerned with ensuring that it is not converted to a non-available form, especially a crystalline lipid-lowering agent, which is formed, for example, when the lipid-lowering agent precipitates in an aqueous medium.

The present invention can be administered to mammals, especially humans, suffering from hyperlipidemia, obesity or atherosclerosis, whereby a single such dosage form is administered once daily. And a pharmaceutical composition of a lipid-lowering agent and a water-soluble polymer. The bioavailability of drugs from these dosage forms in fasted and fed mammals is substantial. The dosage form comprises a therapeutically effective amount of a pellet as described in detail below.

In order to achieve the desired lipid-lowering effect, it is essential that the therapeutically effective plasma level of the reagent be maintained. Since the reagents are virtually insoluble, an effective formulation should be designed in such a way that the drug is readily bioavailable. In other words, the main problem with administering a reagent in a therapeutically effective amount is that a sufficient amount of the reagent remains long enough to allow it to circulate and that it is not readily bioavailable, especially in crystalline forms. Relating to ensuring that the lipid-lowering agent is not converted to a lipid-lowering agent, which is formed, for example, when the lipid-lowering agent precipitates in an aqueous medium. For this purpose, the reagent is preferably taken during or at the end of a meal. However, this limits patients' compliance with their prescribed therapy, for example, some patients eat or swallow the drug normally due to illness, vomiting or opportunistic infections of the esophagus Can not do. Therefore, it is highly desirable to have a drug dosage form that can be administered at any time of the day independently of the food taken by the patient, ie, a dosage form that can be administered to a fasted patient. There will be.

Unexpectedly, it has now been found that pellets with good bioavailability of lipid-lowering agents can be conveniently prepared. A therapeutically effective amount of the novel pellets described in detail below can be filled into capsules or processed into tablets.

In particular, the invention comprises (a) a central round or spherical core, (b) a water-soluble polymer and a lipid-lowering agent coating film, and optionally (c) a seal-coating polymer layer. For pellets, where the core is from about 250 to about 1
180 μm (16 to 60 mesh), preferably about 300 to about 1000 μm (1
8 to 50 mesh), more preferably about 355 to about 850 μm (20 to 45 mesh), and optimally about 600 to about 710 μm (25 to 30 mesh).

The pellets, beads or cores of the dimensions given here can be obtained by sieving through a nominal standard test sieve as described in the CRC Handbook, 64 ^th ed., Page F-114. it can. Nominal standard sieve is mesh / pore width (μm
), DIN 4188 (mm), ASTM E 11-70 (No), Tyler (Tyl
er) Identified by ^R (mesh) or BS 410 (mesh) standard.

Throughout this description and the claims, the particle size is indicated by pore size in mesh / μm and the corresponding sieve number in the ASTM E 11-70 standard.

Materials suitable for use as a core in pellets according to the present invention can vary as long as the material is pharmaceutically acceptable and has appropriate dimensions (about 16-60 mesh) and firmness. Over. Examples of such materials are polymers, such as plastic resins, inorganic substances such as silica, glass, hydroxyapatite, organic substances such as salts (sodium or potassium chloride, calcium or magnesium carbonate),
For example, activated carbon, acids (citric, fumaric, tartaric, ascorbic and similar acids), and their saccharides and derivatives. Particularly suitable materials are sugars, such as sugars, oligosaccharides, polysaccharides and derivatives thereof, such as glucose, rhamnose, galactose, lactose, sucrose, mannitol, sorbitol, dextrin, maltodextrin, cellulose, microcrystalline cellulose, Sodium carboxymethylcellulose, starch (corn, rice, potato, barley, tapioca) and similar sugars.

A particularly preferred material suitable for use as a core in a pellet according to the invention is 6
25-30 mesh sugar spheres (USP 22) containing 2.5% -91.5% (w / w) sucrose, the balance being starch and possibly dextrin, and pharmaceutically inert or neutral / NF XVII, p. 1989). Accordingly, these wicks are also known in the art as neutral pellets.

The pellets obtainable from a 25-30 mesh sugar core are generally (a) 20-60% core material, (b) 25 by weight, based on the total weight of the pellets.
５０50% water soluble polymer, (c) 10-25% lipid lowering agent, and (d)
5% of the 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 · s when dissolved in a 2% aqueous solution at 20 ° C. For example,
Water-soluble polymers include -alkyl celluloses, such as methyl cellulose, -hydroxyalkyl celluloses, such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose, -hydroxyalkyl alkyl celluloses, such as hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose, -carboxyalkyl Celluloses such as carboxymethylcellulose, alkali metal salts of carboxyalkylcellulose such as sodium carboxymethylcellulose, carboxyalkylalkylcellulose such as carboxymethylethylcellulose, carboxyalkylcellulose esters, starch, pectins such as sodium carboxylate -Methylamylopectin,-chitin derivatives, such as chitosan,-polysaccharides, such as alginic acid, its alkali metal and ammonium salts, carrageenans, galactomannans, tragacanth, agar, acacia, guar gum and xanthan gum,-polyacrylic acids and their Salts, polymethacrylic acids and salts thereof, methacrylate copolymers, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone and vinyl acetate, polyalkylene oxides such as polyethylene oxide and polypropylene oxide, and ethylene oxide and propylene oxide Can be selected from the group consisting of: Unlisted polymers which are pharmaceutically acceptable and have the appropriate physicochemical properties defined above are equally suitable for the preparation of pellets according to the invention.

The drug-coating layer is preferably a water-soluble polymer, such as hydroxypropylmethylcellulose (Methocel ^™ , Pharmacoat ^™ ), methacrylate (Eudragit E ^™ ), hydroxypropylcellulose (Kurcell® Klucel ^TM), or comprise a polyvidone. preferred water-soluble polymers are hydroxypropyl methylcellulose i.e. HPMC. the HPM
C contains enough hydroxypropyl and methoxy groups to make it water-soluble. HPMC having a degree of methoxy substitution of about 0.8 to about 2.5 and a hydroxypropyl molar substitution of about 0.05 to about 3.0 are generally water-soluble. The degree of methoxy substitution refers to the average number of methyl ether groups present per unit of anhydroglucose in a cellulose molecule. Hydroxypropyl molar substitution refers to the average number of moles of propylene oxide reacted with one unit of anhydroglucose of the cellulose molecule. Hydroxypropyl methylcellulose is the US recognized name for hypromellose (Martindale, The Extra Pharmacopoeia, 29th edit
ion, page 1435). Preferably, hydroxypropyl methylcellulose having a low viscosity, ie about 5 mPa.s, is used, for example hydroxypropyl methylcellulose 2910 5 mPa.s. 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. 5mPa.s is 20 ° C of 2% aqueous solution
It is a value indicating the apparent viscosity at.

Suitable HPMCs include those having a viscosity of about 1 to about 100 mPa.s, especially about 3 to about 15 mPa.s, preferably about 5 mPa.s. The most preferred type of HPMC having a viscosity of 5 mPa.s is the commercially available HPMC 2910 5 mPa.s.

PVP-VA 64 is a vinylpyrrolidone-vinyl acetate copolymer that is soluble in both water and alcohol, and from BASF Kollidon ^™ V
It is commercially available as A64. This copolymer had a 6: 4 mass ratio of 1-vinyl-2.
-Derived from pyrrolidone and vinyl acetate, and CAS nr 25086-
89-9 is displayed. This copolymer is particularly suitable for use as a matrix material for rapid release formulations and can be melted and extruded with a drug having relatively poor bioavailability to form a rapidly dissolving dispersion. .

The weight-to-weight ratio of (a) :( b) is 1: 1 to 1:35, preferably 1: 1 to 1:
5 is within the range. In the case of (Compound A) :( HPMC 2910 5 mPa.s), the ratio ranges from about 1: 1 to about 1: 3, and optimally is about 2: 3. The weight to weight ratio of lipid lowering agent to other water-soluble polymer can be determined by one of ordinary skill in the art by direct experiment. The lower limit is determined by practical considerations. In fact, a therapeutically effective amount of a lipid lowering agent (from about 25 mg to about 200 mg per day, preferably about 15 mg
0 mg), the lower limit of the ratio is determined by the maximum amount of mixture that can be processed in a single dosage form of practical size. If the relative amount of water-soluble polymer is too high, the absolute amount of the mixture required to reach therapeutic levels will be too high to be processed in a single capsule or tablet. Tablets have, for example, a maximum weight of about 1 g and the extrudate is considered to be up to about 90% (w / w). Thus, the lower limit on the amount of lipid-lowering agent to water-soluble polymer would be about 1:35 (25 mg lipid-lowering agent + 875 mg water-soluble polymer).

On the other hand, if the ratio is too high, meaning that the amount of lipid-lowering agent is relatively high compared to the amount of water-soluble polymer, the lipid-lowering agent will not dissolve sufficiently in the water-soluble polymer. There is a risk and consequent lack of the required bioavailability. The extent to which the compound has dissolved in the water-soluble polymer can often be visually inspected, and if the extrudate is clear, it appears that the compound has completely dissolved in the water-soluble polymer. The upper limit of 1: 1 was observed above that ratio where the extrudate resulting from extrusion of the lipid-lowering agent with HPMC 29105 mPa.s formed a solid solution but appeared to crystallize partially during milling. Determined by facts. It will be appreciated that the 1: 1 upper limit may be underestimated for certain water-soluble polymers. This can be easily set without any relevant experimental time, so (a):
Solid dispersions in which the ratio of (b) is greater than 1: 1 are also meant to be within the scope of the present invention.

[0048] The drug-coating layer of the above pellets further comprises one or more pharmaceutically acceptable excipients, such as plasticizers, fragrances, coloring agents, preservatives, and the like. Is also good. The excipients must be inert; in other words, they must not show degradation or degradation under the conditions of manufacture.

In the current Compound A: HPMC 2910 5 mPa.s formulation, the amount of plasticizer is preferably low, on the order of 0% to 15% (ww), preferably less than 5% (w / w), Preferably, it is 0% (w / w). In other water-soluble polymers, the plasticizer can be used in other amounts, often in higher amounts. Suitable plasticizers are pharmaceutically acceptable and 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 lower than 1,000 g / mol; 2
Polypropylene glycols having a molecular weight lower than 00 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; triethylenetetraamine, 2-amino-2-methyl-1,3-propanediol and the like. Among these, low molecular weight polyethylene glycols, ethylene glycol, low molecular weight polypropylene glycols, and especially propylene glycol are preferred.

A seal-coated polymer layer is applied to the drug-coated core to prevent sticking of pellets, which would have the undesirable effect of simultaneously reducing dissolution rate and bioavailability. Preferably, polyethylene glycol (
PEG), especially polyethylene glycol 20000 (Macrogel 20)
000) is used as the seal coating polymer layer.

Preferred pellets are generally (a) 41-44% sugar spheres, (b) 32-33%
Of hydroxymethylcellulose 2910 5 mPa.s, (c) 21 to 24% of compound A, and (d) 3 to 4% of polyethylene glycol 20,000.

In addition, the pellets according to the invention may contain various additives, such as thickeners, lubricants, surfactants, preservatives, complexing agents and chelating agents, electrolytes or other active ingredients, such as antimicrobial agents. It may further contain inflammatory agents, antibacterial agents, disinfectants or vitamins.

The pellets according to the present invention are easily produced by the following method. A drug-coating solution is prepared by dissolving an appropriate amount of a lipid-lowering agent and a water-soluble polymer in an appropriate solvent system. A suitable solvent system comprises a mixture of methylene chloride and an alcohol, preferably ethanol, which may be modified, for example, with butanone. The mixture must contain at least 50% by weight of methylene chloride acting as a solvent for the drug substance. Since hydroxypropyl methylcellulose does not dissolve completely in methylene chloride, at least 10% alcohol must be added. Preferably a relatively low ratio of methylene chloride / alcohol, for example 75 /
25 (w / w) to 45/55 (w / w), especially about 50/50 (w / w);
Of methylene chloride / ethanol is used in the coating solution. The amount of solids in the drug-coating solution, ie, lipid-lowering agent and water-soluble polymer, is 7-10%
(W / w) and is preferably about 8.3-8.5%.

The chemical coating method (industrial scale) is conveniently a fluid bed granulator (eg Glatt type WSG-30 equipped with a Wurster bottom spray insert (eg an 18 inch Wurster insert). Or GPCG-30). Development of a laboratory-scale method can be performed on a Glatt-type WSG-1 with a 6-inch Wurster insert. Obviously, the parameters of the method depend on the equipment used.

The spray speed should be carefully controlled. Spray speeds that are too low can cause some spray drying of the drug-coating solution and can result in product loss. Spray rates that are too high will cause over-wetting with subsequent bulk agglomeration. Since agglomeration is the most serious problem, a relatively low spray rate is used initially and is increased as the coating process proceeds and as the pellets grow larger.

The spray air pressure at which the chemical coating solution is applied also affects the coating performance.
Low atomizing air pressure results in the formation of relatively large droplets and an increasing tendency for clumping. High spray air pressures will likely carry the risk of spray drying of the chemical solution, but this has been found to be not a problem. Therefore, the spray air pressure can be set near the maximum level.

The amount of flowing air can be monitored by operating the exhaust valve of the apparatus and should be set in such a way that optimal pellet circulation is obtained. An air volume that is too low will cause insufficient fluidization of the pellets, and an air volume that is too high will prevent circulation of the pellets due to convective airflow generated in the apparatus. In the present process, optimum conditions were obtained by opening the exhaust valve to about 50% of its maximum and gradually increasing its opening to about 60% of the maximum as the coating process proceeded.

The coating method is advantageously carried out by using an inlet air temperature in the range from about 50 ° C. to about 55 ° C. A relatively high temperature accelerates the process, but has the disadvantage that the solvent evaporation is too rapid and the coating liquid does not spread evenly on the surface of the pellets, producing a highly porous drug coating layer. As the bulk volume of the coated pellet increases, the dissolution of the drug decreases significantly to unacceptable levels. Obviously, the optimal process temperature will further depend on the equipment used, the nature of the wick and lipid lowering agent, the batch volume, the solvent and the spray rate.

The parameter settings for optimal coating results are described in more detail in the examples below. It has been found that performing the coating step under these conditions produces very reproducible results.

To reduce the level of residual solvent in the drug-coated layer, the drug-coated core can be conveniently dried in a suitable drying device. About 60 ° C to about 90 ° C,
Preferably at a temperature of about 80C, about 150-400 mbar (15-40 kPa
Good results are obtained with a vacuum stir-dryer operated at reduced pressure, preferably in the range from 200 to 300 mbar (20 to 30 kPa), for at least 24 hours, preferably for about 36 hours. The vacuum stir-dryer is conveniently rotated at its lowest speed, for example at 2-3 rpm. After drying, the drug-coated core may be sieved.

The seal-coated polymer layer is applied to the drug-coated wick in a fluid bed granulator with a Wurster bottom spray insert. The seal coating solution can be prepared by dissolving an appropriate amount of the seal coating polymer in a suitable solvent system.
Such a system is, for example, a mixture of methylene chloride and an alcohol, preferably ethanol. The methylene chloride / alcohol ratio may be similar to the ratio used in the drug coating process, and is therefore about 75/25 (w / w) to about 45/55 (
w / w) and especially about 50/50 (w / w). The amount of seal coating polymer in the seal coating spray solution is 7-12% (w / w)
And preferably about 10-11%. The seal coating spray solution is advantageously agitated during the seal coating process. The parameter settings for performing this final step are essentially the same as those used during the drug coating process. Suitable conditions are described in further detail in the Examples below.

An additional drying step may be required after applying the seal coating polymer layer. Excess solvent could be easily removed after the spraying was completed, operating at the parameter settings using the apparatus, for about 5-15 minutes.

Both the chemical and seal coating steps are preferably performed under an inert atmosphere of, for example, nitrogen. The coating equipment should preferably be grounded and equipped with a suitable recovery system containing an efficient liquefaction system.

The pellets of the present invention can be formulated in a pharmaceutical dosage form comprising a therapeutically effective amount of the pellets. In the first example, drug dosage forms for oral administration such as tablets and capsules are recommended, but the pellets of the invention can also be used, for example, to produce drug dosage forms for topical administration. Preferably, the pellets are filled into hard-gelatin capsules such that an amount of 100 or 200 mg of active ingredient per dosage form is available. For example, a hard-gelatin capsule of size 0 is suitable for preparing a pellet comprising 21-22% by weight of a lipid-lowering agent, corresponding to about 100 mg of active ingredient.

The drug-coated and seal-coated pellets can be filled into hard-gelatin capsules using a standard automatic capsule filling machine. Appropriate grounding and deionization devices can advantageously prevent the generation of static charges.

The capsule filling rate can affect the weight distribution and should be monitored. Good results have been obtained when operating the device at about 75% to 85% of maximum speed and often at maximum speed.

Using the above process parameters, a simple and convenient method for producing pellets comprising a 25-30 mesh core, a lipid-lowering agent and a drug-coated layer of a water-soluble polymer and a thin seal-coating polymer layer. And a reproducible manufacturing method can be obtained. Pharmacokinetic studies have shown that the pellets thus obtained have excellent dissolution and bioavailability properties. Tablet Formulation Another dosage form is adapted for oral administration, formed as a tablet. They can be obtained from the above-mentioned pellets (sealed-coated, but preferably uncoated) by means of universal tableting techniques using universal ingredients or excipients and using universal tableting machines. Can be manufactured. further,
They can be manufactured at low prices. As noted above, an effective daily dose of a lipid lowering agent such as Compound A will range from about 25 mg to about 200 mg once a day, and preferably from about 100 to about 150 mg once a day. . The shape of the tablet can be round, oval or oval. It is advantageous to give the tablets a suitable shape in order to facilitate swallowing by the patient in large dosage forms. Tablets that are comfortable to swallow are therefore preferably elongated rather than round in shape. Biconvex oblate tablets are particularly preferred. As discussed in more detail below, the film coat on the tablet further contributes to its swallowability.

Tablets that provide immediate release of the lipid-lowering agent upon oral ingestion and have good bioavailability are those in which the tablet disintegrates rapidly in the stomach (immediate release) and the released pellets Designed in such a way that they are kept apart, they do not aggregate, local high concentrations of lipid-lowering agents and do not give the drug a chance to precipitate (bioavailability). Desirable results can be obtained by homogeneously distributing the pellets throughout the mixture of disintegrant and diluent.

[0069] Suitable disintegrants are those having a high coefficient of expansion. Examples thereof are hydrophilic, insoluble or slightly water-soluble cross-linked polymers such as crospovidone.
one) (cross-linked polyvinyl pyrrolidone) and croscarmellose (croscar
mellose) (crosslinked sodium carboxymethylcellulose). The amount of disintegrant in an immediate release tablet according to the invention can conveniently range from about 3 to about 15% (w / w) and preferably is about 7 to 9%, especially about 8.5% (w / w). w / w)
It is. This amount tends to be higher than is typical in tablets to ensure that the pellets spread over the bulk of the stomach contents upon ingestion. Since disintegrants by their very nature produce a sustained release formulation when used in bulk, it is advantageous to dilute them with inert substances called diluents or fillers.

Various substances can be used as diluents or fillers. Examples are spray drying
Dried or anhydrous lactose, sucrose, dextrose, mannitol
Sorbitol, starch, cellulose (eg, microcrystalline cellulose Avicel (Avice
l)^TM), Dihydrated or anhydrous dibasic calcium phosphate, and
And mixtures thereof. Microcelac ^TM Lactose monohydrate (75%) commercially available as Microcrystalline Cellulose (
25%) of a commercial spray-dried mixture is preferred. Diluent or filler in tablets
The amount of filler can conveniently range from about 20% to about 40% (w / w).
And preferably in the range of about 25% to about 32% (w / w).

Tablets contain various one or more other common excipients, for example, binders, buffers, lubricants, lubricants, thickeners, sweeteners, flavors, and coloring agents. be able to. Some excipients may serve multiple purposes.

Lubricants and slip agents can be used in the manufacture of certain dosage forms,
And will generally be used in making tablets. Examples of lubricants and slip agents are hydrogenated vegetable oils, such as hydrogenated cottonseed oil, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, talc, mixtures thereof, and the like. Other known. Lubricants and slip agents of interest are magnesium stearate and mixtures of magnesium stearate and colloidal silica. A preferred lubricant is hydrogenated vegetable oil type I (finely powdered), most preferably hydrogenated deodorized cottonseed oil (from Karlshamns to Akofin NF ^™ (official name Sterotex ^™ ) )). Lubricants and slip agents preferably comprise from 0.2 to 7.0% of the total tablet weight.

Other excipients such as, for example, colorants and pigments, may be added to the tablets of the present invention. Coloring agents and pigments include titanium dioxide and food grade dyes. The colorant is an optional ingredient in the tablets of the present invention, but when used, the colorant can be present in amounts up to 3.5% based on total tablet weight.

The fragrance is optional in the composition and is selected from synthetic fragrance oils and scented aromatic or natural oils, extracts from plant leaves, flowers, fruits and the like, and mixtures thereof. These include cinnamon oil, lime oil, peppermint oil, menstrual oil, anise oil, eucalyptus, thyme oil. Citrus oils including vanilla, lemon, orange, grape, lime and grapefruit, fruit essences including apples, bananas, pears, peaches, strawberries, raspberries, cherries, plums, pineapples, apricots and the like are also useful as flavors. The amount of perfume depends on many factors, including the desired sensory effect. Generally, the perfume will be present in an amount from about 0% to about 3% (w / w).

As is known in the art, tablet formulations may be dried-granulated or wet-formed prior to tablet formation.
Can be granulated. The tableting process itself is otherwise standard and is easily accomplished by molding the tablet from the desired blend or mixture of ingredients into a suitable shape using a conventional tablet press.

The tablets of the present invention can also be film-coated to improve taste, impart ease of swallowing, and provide an elegant appearance. Many suitable polymeric film-coating materials are known in the art. Preferred film-coating materials are hydroxypropylmethylcellulose HPMC, especially HPMC 291
It is 0.5 mPa.s. Hydroxypropylcellulose and acrylate-
Other suitable film-forming polymers, including methacrylate copolymers, can also be used. In addition to the film-forming polymer, the film coat may further comprise a plasticizer (eg, propylene glycol) and optionally a pigment (eg, titanium dioxide). The film-coating suspension may contain talc as an anti-adhesive. In the immediate release tablets according to the invention, the film coat is small and accounts for about 3.5% (w / w) of the total tablet weight by weight.

[0077] Preferred dosage forms are those in which the weight of the pellets is 40% to 60% of the total weight of all dosage forms.
%, The weight of the diluent ranges from 20 to 40%, and the weight of the disintegrant ranges from 3 to 10%, with the balance being occupied by one or more of the above-mentioned excipients. It is something that can be done.

Another preferred dosage form according to the invention is a dosage form as shown in USP Test <711> in a USP-2 dissolution apparatus with at least the following stringent conditions: 900 ml At least 40% of the effective lipid lowering agent is dissolved within 60 minutes using a paddle rotating at 50 rpm at 0.1 N HCl, 37 ° C. Tablets according to the above definition can be said to have Q> 40% (60 '). Preferably, the tablet according to the invention dissolves more rapidly and has a Q
> 75% (60 ′), more preferably Q> 75% (45 ′).

Another object of the invention is characterized in that a therapeutically effective amount of the above-mentioned pellets is compounded with a pharmaceutically acceptable excipient and the mixture is compressed into tablets. An object of the present invention is to provide a method for producing the above-mentioned drug administration form.

Further, the present invention provides a pharmaceutical dosage form for oral administration to mammals that can administer a single dosage form once daily to a mammal suffering from hyperlipidemia, obesity or atherosclerosis. The present invention also relates to the above-mentioned pellets for use in preparing.

The present invention also provides a method of administering to a mammal suffering from hyperlipidemia, obesity or atherosclerosis, the dosage form may be administered at any time of the day independently of the food consumed by the mammal. It also relates to a pellet as described above for use in preparing a pharmaceutical dosage form for oral administration to an animal.

The present invention also relates to the manufacture of a pharmaceutical dosage form for oral administration to a mammal, wherein a single dosage form can be administered once daily to a mammal suffering from hyperlipidemia, obesity or atherosclerosis. The present invention also relates to the use of the above-mentioned pellets.

The present invention also provides a method for administering to a mammal suffering from hyperlipidemia, obesity or atherosclerosis, the dosage form may be administered at any time of the day independently of the food consumed by the mammal. It also relates to the use of a pellet as described above for the manufacture of a pharmaceutical dosage form for oral administration to an animal.

The present invention also relates to administering hyperlipidemia, obesity or atherosclerosis in a mammal comprising administering to the mammal an effective amount of a lipid-lowering agent in a single oral dosage form that can be administered once daily. It also relates to a method of treating the disease.

The present invention also includes administering to a mammal an effective amount of a lipid-lowering agent in a single oral dosage form that can be administered at any time of the day independently of the food consumed by the mammal. The invention also relates to a method of treating hyperlipidemia, obesity or atherosclerosis in a mammal.

The present invention also comprises a container, an oral dosage form of a lipid-lowering agent as described above, and a commercial product in which the package contains instructions that are not limited as to whether the dosage form can be taken with or without food. It also relates to drug packages suitable for sale. EXPERIMENTAL SECTION The table below shows the formulas of the compounds of formula (I), their physical data and citations of the examples in WO-96 / 13499 in which the compounds can be prepared accordingly.
The pharmacological examples show the lipid-lowering effect of the compounds of formula (I). This is followed by an example showing how compound A (compound 40) can be converted to an implant and formulated into a capsule with good bioavailability.

[0087]

[Table 1]

[0088]

[Table 2]

[0089]

[Table 3]

[0090]

[Table 4]

[0091]

[Table 5]

[0092]

[Table 6]

[0093]

[Table 7]

[0094]

[Table 8]

[0095]

[Table 9]

[0096]

[Table 10]

[0097]

[Table 11]

[0098]

[Table 12]

Pharmacological Example 1: Apolipoprotein (apo B) Inhibition Assay Cultured human hepatocytes that synthesize and secrete low-density lipoprotein (Hep
G2-cells) were incubated overnight at 37 ° C. in liquid medium containing radiolabeled leucine. Therefore, radioactively labeled leucine was introduced into apolipoprotein B. The liquid medium is decanted and apolipoprotein B is isolated by double immunoprecipitation, i.e. first apolipoprotein B-specific antibody (antibody 1) is added to the liquid medium and subsequently specific for the apoB-antibody 1-complex. A second antibody (antibody 2) that binds to was added. The apoB-antibody1-antibody2-complex thus formed precipitated and was isolated by centrifugation. Quantification of the amount of apolipoprotein B synthesized at night resulted from measurement of the radioactivity of the isolated complex. To determine the inhibitory activity of the test compound, the test compound is added to the liquid medium at different concentrations and the concentration of apolipoprotein B synthesized in the presence of the test compound (concentration apoB (later)) is determined by the test compound Concentration of apolipoprotein B synthesized in the presence (concentration apoB
(Control)). For each experiment, suppression of apolipoprotein-B production was

[0100]

(Equation 1)

It was displayed as.

If further experiments were performed at the same concentration, the mean inhibition calculated for these experiments was median. IC ₅₀ -value (Apo B secretion was 5
The concentration of the drug needed to reduce it to 0%) was also calculated.

Table 12 shows the ICs for some of the exemplified compounds of formula (I)₅₀-Indicates a value. Table 12
An exemplary compound of formula (I) that is not protected and for which data is available is 1 × 10 ^-6 M or larger IC₅₀-Has a value.

[0104]

[Table 13]

Composition Examples Example 2 a) Compound A spray solution Into a stainless steel container methylene chloride (141 kg) and denatured ethanol (15
3 kg) was filled through a filter (5μ). Compound A (10.75 kg)
And hydroxypropyl methylcellulose 2910 5 mPa.s (16.13
kg) was added with stirring. Stirring was continued until complete dissolution was obtained. b) Seal- Coated Spray Solution To a stainless steel vessel was added, with stirring, methylene chloride (7.95 kg) and polyethylene glycol 20000 (Macrogol) (1.935 kg). Denatured ethanol (8.622 kg) was added and the solution was stirred until homogeneous. c) Pharmaceutical coating process Fluid bed granulator (GPC) equipped with an 18 inch Ulster (bottom spray) insert
F30) 25-30 mesh (600-700 μm) sugar spheres (20.64 k
g) was charged. The bulb was warmed with dry air at 50-55 ° C. The fluidized bed volume was adjusted by first opening the exhaust valve to about 50% of its maximum and increasing it to 60% at the end of the spraying process. The pre-made Compound A spray solution was then sprayed onto a sphere moving through the apparatus. The solution about the initial distribution rate of about 600～700G. Min ^-1 3.5 kg /
and spraying air pressure of cm ² (0.343MPa). After dispensing about 30% of the spray solution, the dispensing rate was increased to 700-800 g / min. When the spraying process is completed, 5
The coated spheres were dried by further supplying dry air at 0 ° -55 ° C. for about 10 minutes. The coated spheres are then placed in an apparatus at 20-25 ° C.
Was allowed to cool by supplying about 10-20 minutes of dry air. The apparatus was emptied and the coated balls were collected. d) Intermediate drying The coated spheres were then subjected to a drying step to minimize residual solvent levels. The coated spheres are introduced into a vacuum stir-dryer and at a temperature of about 80 ° C for about 200-300 for at least 24 hours, preferably about 36 hours.
Dry at a pressure of millibar (20-30 kPa). The stir-dryer was operated at its lowest rotational speed (2-3 rpm). The dried coated spheres were sieved using a sieve (Sweco S24C, sieve mesh width 1.14 mm). e) Seal-coating step The dried coated balls were again introduced into a fluid bed granulator equipped with a Wurster insert and warmed with dry air at 50-55 ° C. Pre-manufactured seal
The coated spray solution was then sprayed onto the coated spheres moving through the apparatus. The solution was dispensed at about 2.5 bar (0.25 MPa) at a distribution rate of about 400-500 g.min- ¹ .
) Was sprayed at the spray air pressure. When the spraying step was completed, the beads were dried by further supplying dry air at 50-55 ° C for 10 minutes. The coated spheres were then allowed to cool in the apparatus by supplying dry air at 20 ° -25 ° C. for about 5-15 minutes. The beads were removed from the device and stored in a suitable container. f) Capsule Filling The drug coated beads are transferred to a standard automatic capsule filling machine (eg, Model G).
Hard-gelatin capsules (460 mg of pellets corresponding to 100 mg of active ingredient in size no. 0) using FK-1500, Hoeffliger and Karg, Germany (25 mg in size no. 4) (115 mg of pellets corresponding to the active ingredient). To obtain capsules with good weight distribution, the capsule filling rate was reduced to about 75-85% of the maximum rate.
Using the above process parameters, 100 mg hard-gelatin capsules of Compound A were obtained which met all the conditions, especially the dissolution specifications. Example 3 Comparative Bioavailability of Pellet-Filled Capsules vs. Oral Solution and Food Influence.

In an uncontrolled, randomized, parallel group, three-way crossover test, a 100 m
The oral bioavailability of a capsule comprising g of Compound A was compared to that of an aqueous oral solution. Oral aqueous solution is 0.63 mg / ml Compound A, 100m
g / ml 2-hydroxypropylcyclodextrin, 2.5 μl HCl (
12N) and NaOH to give a final pH of 2.0 ± 0.1. Three groups of six healthy male volunteers received a single oral dose of 100 mg of Compound A in a capsule formulation under fasting conditions, immediately after a standard breakfast, and as an oral solution under fasting conditions. did. The pharmacokinetics were evaluated only for the unchanged drug and are summarized in the table below.

[0107]

[Table 14]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 3/06 A61P 3/06 9/10 9/10 C07D 405/12 C07D 405/12 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA ( AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK , LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor De Conde, Valentein Florent Victor Belgium B-2340 Bierce Touln Houtsebeek 30 Janssen Pharma Syutika Nahmrose Huennaught Shajap (72) Inventor Gillis, Paul Marie Victor Belgian Bee-2340 Beerse Touln Houtsebeek 30 Ka Nahmrose Fuennaut Shyaup (72) Inventor Puttmann, Peter Belgian B-2340 Biersee Touln Houtsebeek 30, Jyansen Fumar Shujika Nahmrose Huennaut Shajap F-term (Reference) 4C063 AA01 AA03 BB03 BB07 CC81 DD AA61 BB01 CC11 CC21 DD67 EE06 EE09 EE11 EE16 EE23H EE31 EE32 EE36 EE37 EE38 EE48 FF04 FF05 FF21 4C086 AA01 AA02 BC38 BC60 GA02 GA07 MA03 MA05 MA07 MA37 MA38 MA52 NA11 ZA45 ZA70 ZC33

Claims (20)

[Claims] 1. a) a central round or spherical core having a diameter of about 250 to about 1180 μm (18 to 60 mesh); b) a coating film of a water-soluble polymer and a lipid-lowering agent of formula (I); Optionally, c) a pellet comprising a seal-coating polymer layer, wherein the lipid-lowering agent has the formula Wherein, A and B together formula: -N = CH- (a), -CH = N- (b), -CH 2 -CH 2 - (c), -CH = CH- (d ), -C (= O) -CH 2 - (e), -CH 2 -C (= O) - ( forming a divalent group f), 2 here formula (a) and (b) In the valence group, the hydrogen atom may be substituted by C _1-6 alkyl, and the formulas (c), (d), (e), (
In the divalent group of f), one or two hydrogen atoms may be substituted by C _1-6 alkyl, R ¹ is hydrogen, C _1-6 alkyl or halo, R ² is hydrogen or R ³ is hydrogen; C _1-8 alkyl; C _3-6 cycloalkyl; or C _1-8 alkyl substituted with hydroxy, oxo, C _3-6 cycloalkyl or aryl; Het is pyridine Substituted with one or two substituents selected from C _1-6 alkyl, hydroxy, C _1-6 alkyloxy, trihalomethyl, amino, mono- or di (C _1-6 alkyl) amino or aryl; Pyridine; pyrimidine;
C _1-6 alkyl, hydroxy, C _1-6 alkyloxy, trihalomethyl, amino,
Pyrimidine substituted with one or two substituents selected from mono- or di (C _1-6 alkyl) amino or aryl; tetrazole; tetrazole substituted with C _1-6 alkyl or aryl; triazole; Triazoles substituted with one or two substituents selected from _1-6 alkyl, hydroxy, C _1-6 alkyloxy, trihalomethyl, amino, mono- or di (C _1-6 alkyl) amino; thiadiazole A thiadiazole substituted with one or two substituents selected from C _1-6 alkyl, hydroxy, C _1-6 alkyloxy, trihalomethyl, amino, mono- or di (C _1-6 alkyl) amino C _1-6
Oxadiazole substituted with one or two substituents selected from alkyl, hydroxy, C _1-6 alkyloxy, trihalomethyl, amino, mono- or di (C _1-6 alkyl) amino; imidazole; Imidazole substituted with one or two substituents selected from C _1-6 alkyl, hydroxy, C _1-6 alkyloxy, trihalomethyl, amino, mono- or di (C _1-6 alkyl) amino; Thiazole; substituted by one or two substituents selected from C _1-6 alkyl, hydroxy, C _1-6 alkyloxy, trihalomethyl, amino, mono- or di (C _1-6 alkyl) amino thiazole; oxazole; C _1-6 alkyl, hydroxy, C _1-6 alkyloxy, trihalomethyl, amino, mono- - or di (C _1-6 alkyl) A A heterocycle selected from one or two group consisting been oxazole substituted with a substituent selected from Roh, and aryl is phenyl substituted with phenyl or C _1-6 alkyl or halo A pellet characterized in that it has its N-oxide, stereochemically isomeric form, a mixture of two or more such forms, or a pharmaceutically acceptable acid addition salt. 2. The pellet according to claim 1, wherein 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 a temperature of 20 ° C. 3. The water-soluble polymer comprises:-an alkylcellulose such as methylcellulose;-a hydroxyalkylcellulose such as hydroxymethylcellulose, hydroxyethylcellulose,-hydroxypropylcellulose and hydroxybutylcellulose, Propylmethylcellulose, -carboxyalkylcellulose, for example, carboxymethylcellulose, -alkali metal salts of carboxyalkylcellulose, for example, sodium carboxymethylcellulose, -carboxyalkylalkylcellulose, for example, carboxymethylethylcellulose, -carboxyalkylcellulose ester, -starch, -pectins, For example, Lium carboxymethyl amylopectin,-chitin derivatives such as chitosan, polysaccharides such as alginic acid, its alkali metal and ammonium salts, carrageenans, galactomannans, tragacanth, agar, acacia, guar and xanthan gum,-polyacrylic acids and Polymethacrylic acids and their salts, methacrylate copolymers, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone and vinyl acetate, polyalkylene oxides, such as polyethylene oxide and polypropylene oxide and ethylene oxide. The pellet according to claim 2, which is selected from the group comprising a copolymer of propylene oxide. 4. The method according to claim 1, wherein the water-soluble polymer is hydroxypropylmethylcellulose HPM.
The pellet according to claim 3, having a C 2910 5 mPa.s. 5. A weight-to-weight ratio of lipid-lowering agent: water-soluble polymer of 1: 1 to 1: 3.
The pellet according to claim 1, which is: 6. The pellet according to claim 1, wherein the seal-coating polymer is polyethylene glycol. 7. By weight based on the total weight of the pellets: a) 20-60% core material; b) 25-50% water-soluble polymer; c) 10-25% lipid lowering agent; A pellet according to claim 1, comprising d) 2-5% of a seal-coating polymer. 8. In general, a) 41-44% sugar spheres, b) 32-33% hydroxypropylmethylcellulose 2910 5 mPa.s
C) 21-22% cis-(-)-[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-
The pellet according to claim 7, comprising (1-methylpropyl) -3H-1,2,4-triazol-3-one, and d) 3 to 4% of polyethylene glycol 20,000. 9. The pellet according to claim 1, wherein the core material is a sugar sphere of 600 to 710 μm (25 to 30 mesh). 10. The lipid-lowering agent is cis-(-)-[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-
The pellet according to any of the preceding claims, which is dihydro-2- (1-methylpropyl) -3H-1,2,4-triazol-3-one. 11. A) In a fluidized bed granulator equipped with a Wurster (bottom spray) insert, sugar spheres of 250-1180 μm (18-60 mesh) are treated with organic methylene chloride and alcohol. Coating them by spraying a solution of a lipid-lowering agent and a water-soluble polymer in a solvent; b) drying the resulting coated wick; and c) fluidized bed equipped with a Wurster (bottom spray) insert. among the granulator, the dry core, in an organic solvent consisting of methylene chloride and an alcohol seals - them by solution sprayed of the coating polymer seal - of claims 1 to 10, characterized in that coating A method for producing a pellet as claimed in any of the above. 12. Pharmaceutical-coated pellets obtainable by the method according to claim 11. 13. A drug dosage form comprising a lipid-lowering effective amount of a pellet as claimed in any of claims 1 to 10. 14. The dosage form according to claim 13, wherein the dosage form is a hard-gelatin capsule. 15. The dosage form as indicated in USP test <711> in a USP-2 dissolution apparatus at least as strict as possible:
14. The dosage form according to claim 13, wherein at least 40% of the active lipid-lowering agent dissolves within 60 minutes when tested with 00 ml of 0.1N HCl, pH 6.0, paddle rotating at 50 rpm at 37 [deg.] C. 16. Such a dosage form for a mammal suffering from hyperlipidemia, obesity or atherosclerosis, wherein a single dosage form for oral administration can be administered once a day to the mammal. A pellet according to any of claims 1 to 10 for use in manufacturing. 17. A pharmaceutical dosage form for oral administration which can be administered at any time of day independently of a food consumed by a mammal suffering from hyperlipidemia, obesity or atherosclerosis. A pellet according to any of claims 1 to 10 for use in preparing said dosage form for mammals. 18. A method of administering such a dosage form to a mammal suffering from hyperlipidemia, obesity or atherosclerosis, wherein the single dosage form for oral administration can be administered once daily to a mammal suffering from hyperlipidemia, obesity or atherosclerosis. Use of a pellet according to any of claims 1 to 10 for production. 19. The pharmaceutical dosage form for oral administration can be administered at any time of the day independently of a food taken by a mammal suffering from hyperlipidemia, obesity or atherosclerosis. Claim 1 for the manufacture of said dosage form for a mammal.
Use of the pellet according to any one of to 10 to 10. 20. A container, comprising an oral dosage form of a lipid-lowering agent as claimed in any of claims 13 to 15, and limitations on whether the dosage form can be taken with or without food in a package. Drug package suitable for commercial sale with instructions not to be given.