Patent Description:
The compound ezetimibe belongs to a class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related phytosterols.

It is reported that ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds, such as HMG-CoA reductase inhibitors, bile acid sequestrants (resins), fibric acid derivatives, and plant stanols. Ezetimibe reportedly does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. Instead, it appears that ezetimibe localizes and acts at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. The result is a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. Such a mechanism is complementary to that of HMG-CoA reductase inhibitors.

Ezetimibe is sold in the US under the brand name Zetia®, which is available as a tablet for oral administration containing <NUM> of ezetimibe and the following inactive ingredients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, povidone USP, and sodium lauryl sulfate NF.

<CIT> describes ezetimibe polymorphs and processes for preparing same. In particular, this reference describes processes for preparing crystalline forms of ezetimibe, such as ezetimibe form A or form B by precipitating ezetimibe from selected solvents. The micronized ezetimibe particles of <CIT> have a small particle size and a high specific surface area.

<CIT> describes a specific composition comprising <NUM> % ezetimibe, <NUM> % lactose monohydrate, <NUM> % microcrystalline cellulose NF, <NUM> % povidone USP, <NUM> % croscarmellose sodium NF, <NUM> % sodium lauryl sulfate and <NUM> % magnesium stearate. The composition of <CIT> does not contain starch and does not contain starch paste.

<CIT> and <CIT> disclose substituted acetidinone compounds useful as hypocholesterolemic agents. Both documents disclose a composition comprising active compound, lactose, corn starch as a <NUM> % paste in purified water, corn starch and magnesium stearate. However, the amount of active compound in the compositions of these documents is greater than <NUM> wt-%, and the concentration of lactose is less than <NUM> %.

<CIT> discloses pharmaceutical compositions comprising micronized particles of ezetimibe.

<CIT> discloses compositions containing milled ezetimibe to which a hydrophilic excipient, such as a saccharide or polysaccharide, e.g. starch, is added in order to improve solubility of ezetimibe.

It is desirable that the ezetimibe containing pharmaceutical compositions show a rather fast dissolution and optionally quick disintegration. It is an object of this invention to provide ezetimibe containing compositions having favourable properties.

The present invention is set out in the appended set of claims, wherein claim <NUM> relates to the use of a pharmaceutical composition comprising:.

Preferred embodiments of the use according to claim <NUM> are defined in claims <NUM> to <NUM>.

Another aspect of the invention is defined in claim <NUM>, which relates to a method for the preparation of a pharmaceutical composition for use according to claim <NUM>, the method comprising:.

Preferred embodiments of the method according to claim <NUM> are defined in claims <NUM> to <NUM>.

The chemical name of ezetimibe is <NUM>-(<NUM>-fluorophenyl)-<NUM>(R)-[<NUM>-(<NUM>-fluorophenyl)-<NUM>(S)-hydroxypropyl]-<NUM>(S)-(<NUM>-hydroxyphenyl)-<NUM>-azetidinone. The structural formula is:
<CHM>.

The term "ezetimibe", as used herein, includes any pharmaceutically acceptable salts and solvates of the above compound.

The ezetimibe in accordance with the present invention is characterized by a specific particle size distribution, wherein the ezetimibe has a particle size distribution of d(<NUM>) of <NUM> to <NUM> and d(<NUM>) of <NUM> to <NUM>, wherein the particle size is determined by laser diffraction using the "wet powder method".

Preferably, the ezetimibe that is used for manufacturing the pharmaceutical composition of the invention and/or that is present in said pharmaceutical composition has a d(<NUM>) value of at least <NUM>. The upper limit of the d(<NUM>) value is <NUM>. The d(<NUM>) value is preferably at least <NUM>, and most preferably at least <NUM>. The upper limit of the d(<NUM>) value is <NUM>. The terms "d(<NUM>)" and "d(<NUM>)" as used herein denote that <NUM> % and <NUM> %, respectively, of the particles in a population of particles are smaller than the specified size.

The size of a particle is determined by the "Wet powder method" as described in Example <NUM> b).

The ezetimibe in accordance with the invention preferably has a specific surface area of less than <NUM><NUM>/g, more preferably less than <NUM><NUM>/g, more preferably less than <NUM><NUM>/g. The specific surface area of the ezetimibe particles of the invention may range from <NUM> - <NUM><NUM>/g, preferably from <NUM> - <NUM><NUM>/g, more preferably from <NUM> - <NUM><NUM>/g, most preferably it will be in the range of from <NUM> - <NUM><NUM>/g.

The specific surface area is determined by Coulter instrument using BET calculation.

One advantage of the pharmaceutical composition of the present invention is that it has a favourable dissolution profile. The dissolution profile is determined as described in Example <NUM>, i.e. using a USP standard apparatus in <NUM> of <NUM> % sodium lauryl sulfate in pH <NUM> phosphate buffer at <NUM> rpm.

The pharmaceutical formulation shows an in vitro release of at least <NUM> %, preferably of at least <NUM> %, most preferably of at least <NUM> % of ezetimibe within <NUM> minutes.

The pharmaceutical composition of this invention may further show favourable disintegration properties. For example, the disintegration time of the composition (preferably a tablet) may be less than <NUM> seconds, preferably less than <NUM> seconds, most preferably less than <NUM> seconds, e.g. <NUM> to <NUM> seconds.

The pharmaceutical composition of this invention may be a tablet. The tablet hardness may range from about <NUM> N to about <NUM> N, preferably from about <NUM> N to about <NUM> N, more preferably from about <NUM> N to about <NUM> N, even more preferably from about <NUM> N to about <NUM> N and most preferably from about <NUM> N to about <NUM> N.

Pharmaceutical compositions of the present invention can optionally be mixed with other forms of ezetimibe and/or other active ingredients such as HMG-CoA reductase inhibitors. In addition, pharmaceutical compositions of the present invention can contain inactive ingredients such as diluents, carriers, fillers, bulking agents, binders, disintegrants, disintegration inhibitors, absorption accelerators, wetting agents, lubricants, glidants, surface active agents, flavoring agents, solubility enhancers and the like. The pharmaceutical compositions of the present invention can further comprise one or more pharmaceutical acceptable carriers, one or more excipients and/or one or more additives. The amount of excipient or additive can range from about <NUM> to about <NUM> wt-%, preferably from about <NUM> to about <NUM> wt-% of the total weight of the composition or therapeutic combination. One skilled in the art would understand that the amount of carrier(s), excipients and additives can vary.

The pharmaceutical composition of the invention comprises <NUM> to <NUM> % by weight, preferably about <NUM> to about <NUM> % of diluent. Diluents increase the bulk of a solid pharmaceutical composition and can make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents include cellulose derivatives, sugar derivatives, starch derivatives, calcium phosphate, oxides/ corbonates/ sulfates/ chlorides of magnesium or calcium or sodium etc. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), Microcelac® (<NUM>% lactose monohydrate and <NUM>% microcrystalline cellulose), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, lactose monohydrate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, spray dried lactose, sodium chloride, sorbitol and talc.

Carriers for use in the pharmaceutical compositions may include, but are not limited to, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like.

The pharmaceutical composition of the invention comprises <NUM> to <NUM> wt-%, preferably <NUM> to <NUM> % of binder. Binders help bind the active ingredient and other excipients together after compression. Binders include cellulose derivatives, sugar derivatives, starch derivatives, gelatin, guar gum, magnesium aluminium silicate, sodium alginate, stearic acid, hydrophylic or hydrophobic polymers etc. Binders for solid pharmaceutical compositions include for example acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, copovidone (Plasdone® S-<NUM>), dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, polyvinyl pyrrolidone (PVP), pregelatinized starch, sodium alginate and starch.

The pharmaceutical composition of the invention comprises <NUM> to <NUM> wt-%, preferably about <NUM> to about <NUM> wt-% of disintegrant. Disintegrants can increase dissolution. Disintegrants include cellulose derivatives, hydrophilic polymers, calcium phosphate, alginic acid, colloidal silicon dioxide, starch, sodium starch glycolate, aluminium silicates, guar gum etc. Disintegrants include, for example, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrillin potassium, polyvinyl polypyrrolidone (PVPP, crosslinked polyvinyl pyrrolidone, Polyplasdon® XL <NUM>), powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch.

The pharmaceutical composition of the invention comprises <NUM> to <NUM> wt-% of solubility enhancer. Solubility enhancers increase solubility of Ezetimibe. Solubility enhancers may include, but are not limited to sodium lauryl sulphate, alkalizing agents such as meglumine (D-(-)-N-methylglucamine) and the like.

Disintegration inhibitors may include, but are not limited to, white sugar, stearin, coconut butter, hydrogenated oils, and the like.

Absorption accelerators may include, but are not limited to, quaternary ammonium base and the like. Wetting agents may include, but are not limited to, glycerin, starch, and the like. Adsorbing agents used include, but are not limited to, starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like.

The pharmaceutical composition of the invention comprises <NUM> to <NUM> wt-% of lubricant. A lubricant can be added to the composition to reduce adhesion and ease release of the product from a punch or dye during tableting. Lubricants include glyceryl derivatives, oils, sodium or magnesium stearyl fumarate, stearic acid, calcium or magnesium stearate, talc etc. Lubricants include for example magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, stearic acid, talc and zinc stearate. Glidants can be added to improve the flowability of non-compacted solid composition and improve the accuracy of dosing. Excipients that can function as glidants include for example colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present invention include for example maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Tablets can be further coated with commonly known coating materials such as sugar coated tablets, gelatin film coated tablets, tablets coated with enteric coatings, tablets coated with films, double layered tablets, and multi-layered tablets. Capsules can be coated with shell made, for example, from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention, the ezetimibe forms described herein and any other solid ingredients are dissolved or suspended in a liquid carrier, such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin. Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention can also contain viscosity enhancing agents to improve the mouth- feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include for example acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethy[iota]cellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar can be added to improve the taste. Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid can be added at safe levels to improve storage stability.

A liquid composition according to the present invention can also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.

A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, which causes the powders to clump up into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate can then be tableted or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.

A tableting composition can be prepared conventionally by dry blending. For instance, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can be compressed subsequently into a tablet.

As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well-suited to direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting. A capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described with reference to tableting, only they are not subjected to a final tableting step.

A specific aspect of this invention is a method for preparing a pharmaceutical formulation as defined in claim <NUM>, said method comprising dispersing corn starch in cold water (e.g. <NUM> - <NUM>), heating the mixture to form a paste, cooling the mixture to about <NUM> - <NUM> (e.g. <NUM>) to form a first composition; mixing ezetimibe, lactose monohydrate and corn starch to form a second composition; granulating said first composition together with said second composition, screening and/or milling the granules if necessary, drying the granules, screening the dried granules through an appropriate mesh if necessary, mixing the resulting composition with magnesium stearate, compressing the blend to appropriate size and weight on a suitable tabletting machine or filling into suitable capsules.

When preparing a composition comprising starch paste, <NUM> part of corn starch may be dispersed in about <NUM> to about <NUM> parts of cold water, preferably in about <NUM> to about <NUM> parts of cold water, more preferably in about <NUM> to about <NUM> parts of cold water, most preferably in about <NUM> to about <NUM> parts of cold water, e.g. in about <NUM> parts of cold water. It has been found that the dissolution characteristics are improved when less than <NUM> parts of cold water are used for preparing the corn starch paste.

It is therefore an aspect of this invention to use corn starch paste for the manufacture of a pharmaceutical composition as described herein, wherein said corn starch paste has a concentration of more than <NUM> % by weight, preferably in water. Preferably, the concentration of corn starch in the paste is <NUM> wt-% to <NUM> wt-%, more preferably <NUM> wt-% to <NUM> wt-%, most preferably <NUM> wt-% to <NUM> wt-%.

The compositions and therapeutic combinations of the present invention can be administered to a mammal in need of such treatment in a therapeutically effective amount to treat one or more conditions, for example vascular conditions such as atherosclerosis, hyperlipidaemia (including but not limited to hypercholesterolemia, hypertriglyceridaemia, sitosterolemia), vascular inflammation, stroke, diabetes, obesity, and/or reduce the level of sterol (s) in the plasma. The compositions and treatments can be administered by any suitable means which produce contact of these compounds with the site of action in the body, for example in the plasma, liver or small intestine of a mammal or human.

The compositions of the present invention can be administered in any conventional dosage form, preferably an oral dosage form such as a capsule, tablet, powder, cachet, suspension or solution. The formulations and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable and conventional techniques. Several examples of preparation of dosage formulations are provided below. The pharmaceutical compositions can be administered, for example, as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injection preparations (solutions and suspensions), and the like.

The dosage of a pharmaceutical composition for reducing cholesterol according to the present invention will depend on the method of use, the age, sex, weight and condition of the patient. Typically, about <NUM> to <NUM> of ezetimibe may be contained in an administration unit form, preferably a <NUM> tablet. The daily dosage for the various compositions and therapeutic combinations described above can be administered to a patient in a single dose or in multiple subdoses, as desired. Subdoses can be administered <NUM> to <NUM> times per day, for example. Preferably, the pharmaceutical composition of the invention is administered once per day.

Method of manufacture:
Mix item No. <NUM> and <NUM> in suitable mixture for <NUM>-<NUM> minutes. Granulate the mixture with item No. <NUM>. Mill the damp granules through a coarce screen (e.g., <NUM>/<NUM>", <NUM>) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with item No.<NUM> and mix for <NUM>-<NUM> minutes. Add item No. <NUM> and mix for <NUM>-<NUM> minutes. Compress the mixture to appropriate size and weight on a suitable tablet machine.

Method of manufacture:
Corn starch was dispersed in cold water (<NUM> part corn starch to <NUM> parts water). The mixture was heated to about <NUM> form paste and cooled to about <NUM>. Ezetimibe lactose and cornstarch were mixed and granulated using corn starch paste. Wet granules were dried at about <NUM>, passed through #<NUM> mesh screen and blended with magnesium stearate. the blend was compressed to appropriate size (Punch size <NUM> X <NUM>) and weight on a suitable tablet machine.

Formulations were prepared with the different samples of ezetimibe described in Example <NUM> infra.

Method of manufacture:
Item No.<NUM> disperse in cold water (<NUM> part corn starch to <NUM> parts water). Heat the mixture to about <NUM> to form paste and cool to about <NUM>. Mix item No. <NUM>, <NUM> and <NUM> in suitable mixer for <NUM> to <NUM> minutes and granulate with corn starch paste. Mill the damp granules from coarce screen if necessary. Dry the damp granules. Screen the dried granules through appropriate mesh (#<NUM> mesh) if necessary and mix with item No. <NUM> for <NUM>-<NUM> minutes. Compress the blend to appropriate size and weight on suitable tablet machine or filled into suitable hard gelatine capsules on suitable encapsulating machine.

Dissolution rate at <NUM> minutes of the example <NUM> tablets showed more than <NUM>% drug release therefore by increase in paste quantity and reducing the water quantity as state of art can be used to improve processes related issues without affecting the drug release.

Method of manufacture:
Item No. <NUM> disperse in cold water (<NUM> part corn starch to <NUM> parts water). Heat the mixture to about <NUM> to form paste and cool to about <NUM>. Mix item No. <NUM>, <NUM>, <NUM> and <NUM> in suitable mixer for <NUM> to <NUM> minutes and granulate with corn starch paste. Mill the damp granules from coarce screen if necessary. dry the damp granules. Screen the dried granules through appropriate mesh (#<NUM> mesh) if necessary and mix with item No. <NUM> for <NUM>-<NUM> minutes. Compress the blend to appropriate size and weight on suitable tablet machine or filled into suitable hard gelatine capsules on suitable encapsulating machine.

Procedure : Pour the small volume sample in Drypowder Sampler unit. Set the feed rate & air pressure with the help of adjustable knob. And start the measurement until to get the obscuration between <NUM> and <NUM>. Pass the laser beam through the sample cell to measure the particle size distribution and record the data into a histogram then report the results at <NUM>%, <NUM>% and <NUM> % level of particles size distribution. Note : Ensure the Laser power should be more than <NUM> %.

Particle sizes determined for the ezetimibe used in Examples <NUM>, <NUM> and <NUM>:.

A Malvern Laser Diffraction instrument was used to characterize the particle size distribution of ezetimibe. A Mastersizer S model equipped with a small cell dispersion unit MSI with a digital dispersion unit controller was used. The measurement was done using range lens 300RF (working range <NUM>-<NUM> mem), beam length: <NUM> and presentation 3NHE. In this case, a solution of dioctyl sulfosuccinate sodium salt in n- hexane was used as a dilution medium. The measurement was started after <NUM> minute of recirculation after suspension addition into measurement cell at speed rate <NUM> +- <NUM> rpm. The suspension was prepared of ~<NUM> sample in solution <NUM>% dioctyl sulfosuccinate sodium salt in n-hexane by vortex for <NUM> seconds and by sonication for <NUM> seconds. According to the accepted rules of Good Manufacture Procedures, the sample of ezetimibe is preferably measured after a successful blank measurement (% obscuration NMT <NUM>%) is performed. Results are given below.

Particle sizes determined for the ezetimibe used in Example <NUM>:.

Particle sizes of further ezetimibe samples according to the invention, measured according to the "Wet method":.

Specific surface area is measured by using the following Parameters:.

<NUM> of example 5b) of known weight is taken in the sample transparent U shape glass tube. The sample is preheated to remove all atmosphere at liquid nitrogen temperature (-<NUM>). This is achieved by passing nitrogen through the sample tube, which is placed in a liquid nitrogen bath (-<NUM>). The value divided by the weight of the catalyst/sample taken in the tube gives the surface area of the sample.

Surface area determination is an important factor in determining the catalyst performance, a method of assessing the efficiency of the catalyst support and promoter. The surface area measurement can be used to predict catalyst poisoning and provide reasons for the deactivation of the catalyst either due to poisoning or due to sintering. The BET (Brunner, Emmett and Teller) equation is based on the extension of Langmuir theory to multilayer. The basic equation to find the surface area is follows <MAT> Where.

According to BET method a plot of <MAT> Is a straight line (in the range of P / P<NUM>:<NUM>-<NUM>) with slope (C-<NUM>) / (VmC) and intercept <NUM> / VmC. By knowing these intercept and slope values calculated and further specific surface area can be calculated as follows <MAT> Where, Vm = monolayer volume in ml at STP.

Specific surface area of ezetimibe is <NUM><NUM>/ gram.

Further formulations according to the present invention.

Claim 1:
Use of a pharmaceutical composition comprising:

<TAB>

wherein the ezetimibe has a particle size distribution of d(<NUM>) of <NUM> to <NUM> and d(<NUM>) of <NUM> to <NUM>, wherein the particle size is determined by laser diffraction using the "wet powder method",
for obtaining a dissolution profile such that at least <NUM> % of ezetimibe are released within <NUM> minutes, wherein the dissolution profile is determined using a USP standard apparatus in <NUM> of <NUM> % sodium lauryl sulfate in pH <NUM> phosphate buffer at <NUM> rpm.