Patent Description:
<CIT> discloses a ferric iron composition for use in a method of treating hyperphosphatemia, wherein the ferric iron composition is a solid ligand-modified poly oxo-hydroxy metal ion material represented by the formula (MxLy(OH)n), wherein M one or more metal ions that comprise Fe3+ ions, L represents one or more ligands that comprise a carboxylic acid ligand, or an ionised form thereof, and OH represents oxo or hydroxy groups and wherein the material has a polymeric structure in which the ligands L are substantially randomly substituted for the oxo or hydroxy groups and wherein the solid ligand-modified poly oxo-hydroxy metal ion material having one or more reproducible physico-chemical properties. While this document mentions certain particle sizes of the solid ligand-modified poly oxo-hydroxy metal ion material, it does not disclose any particle size distribution for a particular pharmaceutical composition, but only a particle size distribution of the freshly prepared phosphate binder materials. Accordingly this document does not teach anything about the relevance of the particle size distribution to be used for a pharmaceutical composition. <CIT> does not contain any example of a specific pharmaceutical composition.

<CIT> relates to a process for the selective reduction of the amount of inorganic phosphate in an aqueous liquid feed containing protein, in addition to said inorganic phosphate, without significantly adversely affecting said protein, which comprises: contacting an aqueous liquid feed, containing phosphate ions and protein, with an adsorbent composition comprising; at least one polynuclear metal oxyhydroxide covalently bound to an adsorbent base material. It mentions some particle sizes of the adsorbent base or support material (e.g. silicate, silicon dioxide, glyceryl modified silicagel, a glyceryl modified glass, and a polymer), but not for the phosphate adsorbent and the polynuclear metal oxyhydroxide. In the examples the phosphate binder is used in an extracorporeal treatment. There is no disclosure of a specific administrable pharmaceutical composition except for known soluble metal oxyhydroxide/polyol complexes.

This invention relates to compressed tablets for oral administration, especially to chewable tablets, mini-tablets (micro-tablets) formed with and without prior processing like wet granulation or dry granulation (e. g roller compaction), granulate and tablets especially formed by direct compression of a certain phosphate binder compound (hereinafter phosphate binder). The term "starch" as used herein includes any conventionally used starch products (such as potato starch, corn starch, rice starch, tapioca starch) in native, pregelatinized, degraded, modified, and derivatized forms, preferably suitable for direct compression, and mixtures thereof. Most preferred products include native and pregelatinized starch, such as in a mixture having a ratio (native-pregelatinized) in the weight-range of <NUM> : <NUM> to <NUM> : <NUM>, preferably in the range of <NUM> : <NUM> to <NUM> : <NUM> more preferably in the range of <NUM>: <NUM> to <NUM> : <NUM>.

The phosphate binder is sucroferric oxyhydroxide (USAN name) or defined by the WHO under the ATC code as V03AE05, or also known as PA21, which is a mixture of iron(III) oxyhydroxide, sucrose, starches.

The phosphate binder comprises polynuclear iron(III)-oxyhydroxide stabilized by sucrose, and starches (known as sucroferric oxyhydroxide or PA21 (PA21-<NUM> or PA21-<NUM>)) or a polynuclear β-iron(III)-oxyhydroxide stabilized by sucrose, and starches (known as sucroferric oxyhydroxide or PA21 (PA21-<NUM> or PA21-<NUM>)). A particularly preferred mixture of iron(III) oxyhydroxide, sucrose and starches comprises about <NUM> to <NUM> wt-% iron(III) oxyhydroxide, about <NUM> to <NUM> wt-% sucrose and about <NUM> to <NUM> wt-% starches based on the total dry weight (i.e. <NUM> wt-%) of phosphate binder particles based on such mixture. A particular preferred mixture of iron(III) oxyhydroxide, sucrose and starches comprises about <NUM> to <NUM> wt-% iron(III) oxyhydroxide, about <NUM> to <NUM> wt-% sucrose and about <NUM> to <NUM> wt-% starches based on the total dry weight (i.e. <NUM> wt-%) of phosphate binder particles based on such mixture, wherein the iron(III) oxyhydroxide preferably comprises β-iron(III) oxyhydroxide.

In the present invention the term "sucroferric oxyhydroxide" covers a mixture of iron(III) oxyhydroxide, sucrose and starches, wherein the mixture comprises one, two or more starches e.g. only native starch (PA21-<NUM>) or only pregelatinized starch or a mixture of native starch and pregelatinized starch (PA21-<NUM>), etc. A preferred "sucroferric oxyhydroxide" contains a mixture of native starch and pregelatinized starch as herein above defined.

As is known to the skilled person in the art "phosphate binders" are compounds or compositions that are capable to act as an adsorbent for phosphate from aqueous medium, for example from aqueous solutions, in particular from physiological aqueous solutions. They are particularly suitable as an adsorbent for inorganic phosphate and phosphate bonded to foodstuffs, especially in a preparation for oral application for the prophylaxis and treatment of hyperphosphataemia conditions, in particular in patients with chronic renal insufficiency, which have a pathologically increased serum phosphate level due to the decrease in the glomular filtration rate. The term "phosphate binders" according to the present invention covers any salt, isomer, enantiomer or crystal form of such active ingredient.

The sucroferric oxyhydroxide, may be combined with one or more pharmaceutically acceptable carriers and, optionally, one or more other conventional pharmaceutical adjuvants.

The sucroferric oxyhydroxide, may be formulated into pharmaceutical compositions containing an amount of the active substance (phosphate binders) that is effective for treating hyperphosphatemia or conditions resulting from unbalanced phosphate levels (e.g. for therapeutic use in the control of serum phosphorous levels in patients with Chronic Kidney Diseases (CKD) who are on dialysis), such compositions comprising a pharmaceutically acceptable carrier, and such compositions being formulated into unit dosage forms or multiple dosage preparations.

In view of their ability to adsorbs the dietary phosphate in the gastrointestinal tract, the phosphate binders, are useful in treating unbalanced phosphate levels and conditions resulting from unbalanced phosphate levels (e.g. for therapeutic use in the control of serum phosphorous levels in patients with CKD who are on dialysis, or treatment of hyperphosphatemia).

The sucroferric oxyhydroxide, useful in this invention should preferably not be mixed with humid/wet excipients, and are not inherently compressible. Consequently, there is a need to provide a free-flowing and cohesive pharmaceutical formulations in the form of a powder or granulate, compressed or directly compressed into tablets, chewable tablets, mini-tablets (micro-tablets) or comparable dosage forms.

Tablets may be defined as solid dosage pharmaceutical forms containing one or more drug substances with or without suitable inert materials known as excipients. They are produced by compression of a pharmaceutical formulation, in the form of a powder or granules or smaller dosing units (e.g. mini-tablets, pellets), containing the phosphate binder and certain excipients. Without excipients most drugs and pharmaceutical ingredients cannot be directly-compressed into tablets. This is primarily due to the poor flow and cohesive properties of most drugs.

There has been widespread use of tablets and the majority of pharmaceutical dosage forms are marketed as tablets. Major reasons for tablet and chewable tablet popularity as a dosage form are simplicity of use, low cost and the speed of production. Other reasons include stability of drug product, convenience in packaging, shipping and dispensing. To the patient or consumer, tablets offer convenience of administration, ease of accurate dosage, compactness, portability, blandness of taste, and ease of administration.

Tablets may be plain, film or sugar coated bisected, embossed, layered or sustained-release. They can be made in a variety of sizes, shapes and colors. Tablets may be swallowed, chewed or dissolved in the buccal cavity or beneath the tongue. They may be dissolved in water for local or topical application.

Other desirable characteristics of excipients and active ingredients include the following:.

There are four commercially important processes for making compressed tablets: wet granulation followed by compression, direct compression, dry granulation (slugging or roller compaction) followed by compression and extrusion (e.g. melt extrusion) followed by compression. The method of preparation and the type of excipients used are tailored to give the tablet formulation the desired physical characteristics that allow for the rapid compression of the tablets. After compression, the tablets must fulfill a number of attributes, such as e.g. appearance, hardness, disintegration time, friability, uniformity of mass, chewability, and dissolution profile. Choice of fillers and other excipients will depend on the chemical and physical properties of the drug, behavior of the mixture during processing and the properties of the final tablets.

The properties of the drug, its dosage forms and the economics of the operation will determine selection of the best process for tableting.

The dry granulation method may be used where one of the constituents, either the drug or an excipient, and/or the mixture thereof has sufficient cohesive properties to be compacted. The method consists of blending, slugging the ingredients, compaction, dry screening, lubrication and compression.

The wet granulation method is used to convert a powder mixture into granules having suitable flow and cohesive properties for tableting. The procedure consists of mixing the powders in a high-shear granulator followed by adding the granulating solution under shear to the mixed powders to obtain a granulation or to add the liquid by spraying in a fluid bed dryer to result the granulate. The damp mass may be screened through a suitable screen and dried by tray drying or other suited drying techniques. The overall process may include weighing, dry powder blending, wet granulating, drying, milling, blending lubrication and compression.

Typically drug substance powders do not have sufficient adhesive or cohesive properties to form hard, strong granules. A binder is usually required to form larger particles (granules). Heat and moisture sensitive drugs mostly cannot be manufactured using wet granulation. The drawback of this the wet granulation technology is the number of processing steps and needed processing time materializing in the manufacturing costs.

Direct compression is regarded as preferred process where the solid components are compressed directly without changing the physicochemical properties of the drug. The active ingredient(s), direct compression excipients and other auxiliary substances, such as a glidant and lubricant are blended in a bin blender before being compressed into tablets. The advantages of the direct compression technology include e.g. the uniformity of the blend, few manufacturing steps involved, i.e., the overall process involves weighing of powders, blending and compression, hence limited cost; eradication of heat and moisture, prime particle dissociation and physical stability.

Pharmaceutical manufacturers do prefer to use direct compression techniques over wet or dry granulation methods because of the short processing time and limited process steps resulting in advantageous cost. Direct compression however is usually limited to cases where the active ingredient has acceptable physicochemical characteristics required to form a pharmaceutically acceptable dosage form. Many active ingredients do no exhibit all necessary properties and therefore often must be combined with suited excipients to allow for direct compression. Since each excipient added to the formulation increases the tablet size of the final product, manufacturers are often limited to using the direct-compression method in formulations containing a low dose of the active ingredient per compressed tablet.

A solid dosage form containing a high-dose drug, i.e. the drug itself comprises a substantial portion of the total compressed tablet weight, can only be directly compressed if the drug itself has appropriate physical characteristics, e.g. cohesiveness, to be directly compressed. The claimed compressed tablet for oral administration, comprising sucroferric oxyhydroxide is considered a high-dose drug i.e. high-dose of sucroferric oxyhydroxide per unit dosage form (e.g. per tablet). Unit dosage formulations can include above <NUM>%, <NUM>%, <NUM>%, or <NUM>% and more by weight of the sucroferric oxyhydroxide per unit dosage form (e.g. per tablet). A single oral dosage form of sucroferric oxyhydroxide shall contain preferably more than <NUM>, or more than <NUM> or more than <NUM> or more than <NUM> or more than <NUM> or <NUM> of phosphate binder. This high-dose drug, combined with its rather poor physical characteristics for direct compression, has not permitted the use of the direct compression technology to prepare the final product with acceptable physical characteristics. The phosphate binders are relatively unstable in the presence of free water (or have poor microbiological stability), a factor militating against the use of the wet granulation technology (the large amount of phosphate binder in an adequate single dose formulation would require too much water).

Earlier used tablets comprising sucroferric oxyhydroxide, such as described in the patent <CIT> did only partially meet the expected physical characteristics e.g. still remaining potential cohesiveness issues. Tablets could more easily break, and had still not an acceptable friability or hardness or compressibility or chewability or disintegration time or dissolution profiles.

As patients suffering from unbalanced phosphate levels (e.g. patients with CKD (Chronic Kidney Diseases) who are on dialysis) need to be administered with several oral dosage forms per day, over several months or years, there is a clear need for improvement of the oral dosage forms e.g. improved physical characteristics.

All % weights (w/w) throughout this description are expressed in relation to the total weight of the pharmaceutical composition (dry composition), if not indicated otherwise. Another limitation of direct compression as a method of tablet manufacturing is the potential size of the compressed tablets. The amount of excipients needed in wet granulation is less than that required for direct compression since the process of wet granulation contributes toward the desired physical properties of the tablet.

Therefore, if the amount of active ingredient is high, a pharmaceutical formulator may choose to wet granulate the active ingredient with other excipients to attain an acceptable sized tablet with the desired amount of active ingredient. As herein described, the sucroferric oxyhydroxide is preferably administered to the patients as single dosage form, wherein said dosage form contains a high drug load of phosphate binder. Furthermore, due to the behavior of the claimed phosphate binders in the presence of water, it is desirable to perform direct compression of tablets containing high-dose sucroferric oxyhydroxide. Therefore, there is strong technical hurdles which need to be overcome in order to manufacture compressed (or direct compressed) big sized tablets which exhibit acceptable friability, hardness, chewability, cohesiveness, disintegration time and dissolution profiles. Depending on the intended use of the tablet, i.e. whether it is for intact swallowing or rapid disintegration (in the oral cavity or in a small amount of liquid prior to ingestion) or to be chewed, such as e.g. a chewable tablet, usually excipients, such as disintegrants, superdisintegrants, glidants, lubricants, binder compression aids and the like may be added if desired. The tablet may be coated or not, as pharmaceutically necessary or desired. Thus, the invention includes preferably direct compressed tablets, either in a form for intact swallowing (e.g. also film-coated) or in a form capable of rapid disintegration (either in the oral cavity after ingestion or in a small amount of liquid prior to ingestion), including chewable forms, mini tablets or sachets containing these mini-tablets (micro-tablets),. The form for intact swallowing may be film-coated, if desired. The pharmaceutical composition of the invention includes also powders or granules which can be compressed or compacted into tablets.

Dosage forms include tablets, either in a form for intact swallowing (e.g. film-coated) or in a chewable form. In the case of orally administrated dosage forms, if desired film-coated, these are swallowed intact and disintegration takes place in the stomach or/and other parts of the intestine, whereupon the active agent is released for adsorption of phosphate to reduce its systemic uptake.

With the herein claimed tablets, the administration can be at as minimal as <NUM> to <NUM> unit dosage forms per day.

As herein described, the sucroferric oxyhydroxide is preferably administered to the patients in the form of a single dosage form per administration, wherein said dosage form contains a high load of phosphate binder i.e. more than <NUM> or more than <NUM> or more than <NUM> or more than <NUM> or more than <NUM> of phosphate binders, preferably between <NUM> to <NUM> or between <NUM> to <NUM> of phosphate binders. Dependent on the API load, the choice of appropriate solid dosage form is limited. Chewable tablets offer the advantage of more flexibility in not requiring access to water and in the fact that the medication can be more discretely taken, i.e. at work, while travelling or at social occasions. In addition, avoiding additional water intake is of advantage for the patient group with CKD (Chronic Kidney diseases). Also, surveys indicate that patients prefer to take a single dose e.g. a tablet per administration instead of multiple dose like it would be required with swallowable tablets or tablet with smaller size for high dosed medications. The mechanical strength of chewable tablets can however be of concern with regard to damage to teeth or mandibular joints from chewing tablets with unsuitable mechanical properties. As CKD patients have to chew several tablets per day for several months or years, the chewability of the tablets is critical. Several testing procedures and additional methods with the objective of obtaining a meaningful evaluation of the chewability of tablets and confirming the appropriateness of the phosphate binder selected formulations/tablets from the chewability perspective were applied.

In the present invention the term "compressed" covers any physical compaction process resulting in solid dosage units.

It is an object of the invention to provide a compressed (or directly compressed) phosphate binder tablet in unit dosage form having an acceptable dissolution profile, as well as acceptable degrees of hardness and resistance to chipping, as well as acceptable friability and chewability profiles, as well as a fast disintegration time.

It is a further object of the invention to provide a compressed (or preferably direct compressed) phosphate binder tablet which is a rapid disintegration tablet (in the oral cavity or in a small amount of liquid prior to ingestion), like e.g. a chewable tablet or mini tablets.

It is a further object of the invention to provide a process for preparing a compressed phosphate binder tablet by direct compression in a unit dosage forms.

The present invention uses a tableting, free-flowing particulate phosphate binder composition in the form of a tableting powder (comprising preferably at least one additional pharmaceutically acceptable excipient as herein after described), capable of being compressed, or directly compressed into a tablet having adequate hardness, friability, chewability, rapid disintegration time and an acceptable dissolution pattern.

In the development of the herein described pharmaceutical compositions the applicant has discovered that it is particularly advantageous to use a compressed tablet, comprising a phosphate binder, said phosphate binder comprises particles having a particle size distribution, wherein at least <NUM> % by volume of the particles have a particle size within the range of <NUM> to <NUM> as defined in claim <NUM>.

In particular, the present invention concerns a compressed pharmaceutical tablet preferably a direct compressed tablet, comprising sucroferric oxyhydroxide. Said sucroferric oxyhydroxide, has unfavorable physical properties to be converted into an acceptable compressed preferably direct compressed pharmaceutical tablet. These unfavorable physical properties can be e.g. bulkiness, sticking, fluffiness and the like. During development of the herein described pharmaceutical compositions and tablets, the applicant has discovered that the processing properties or physical properties of the pharmaceutical formulation, such as hygroscopicity, flowability, bulkiness, fluffiness is unexpectedly improved if the particles comprising the sucroferric oxyhydroxide have a particle size distribution wherein at least <NUM>%, or at least <NUM>%, or at least <NUM>%, or at least <NUM>% by volume is in the range of <NUM> to <NUM> (preferably in the range of <NUM> to <NUM>) and a d50 (related to the volume of the particles) in the particle size distribution in the range of <NUM> to <NUM>, or preferably of <NUM> to <NUM> (preferably in the range of <NUM> to <NUM>). The applicant also surprisingly discovered that the tablets show improved physical characteristics such as solubility, friability, hygroscopicity, hardness, compressibility, chewability, or disintegration.

An additional unexpected advantage of the selected particle size distribution, is the possibility to increase the compression force during the tableting process, without any alterations (except hardness) of the tablet physical properties but with the possibility to increase the tablet hardness to the targeted hardness range.

The present invention concerns compressed tablets preferably direct compressed pharmaceutical tablets, wherein the powder to be compressed contains particles comprising sucroferric oxyhydroxide, and at least one further pharmaceutically acceptable excipient, and wherein at least <NUM>%, preferably <NUM>%, most preferably <NUM>% even more preferably <NUM>% (by volume) of the particles of the phosphate binder particle size distribution in the tablet are between <NUM> to <NUM> or between <NUM> to <NUM> or between <NUM> to <NUM>, and wherein the phosphate binder particles have a d50 (by volume) in the particle size distribution in the range of <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM> or preferably in the range of <NUM> to <NUM>.

In a preferred embodiment (c) the present invention concerns compressed tablets preferably direct compressed pharmaceutical tablets, wherein the dispersion contains particles comprising sucroferric oxyhydroxide and at least one further pharmaceutically acceptable excipient, and wherein:.

The term "wherein at least <NUM>%, preferably at least <NUM>%, or at least <NUM>%, or at least <NUM>%" means that at least <NUM>%, preferably at least <NUM>%, or at least <NUM>%, or at least <NUM>% of the particles (phosphate binder particles) are of the said size i.e. belong to the said size range. The percentages are volume-%.

The term "d50 particle size distribution" means that <NUM>% (per volume) of the particles have a particle size above or below the defined d50 value expressed in µm.

The term "d10 particle size distribution" means that <NUM>% (per volume) of the particles have a particle size lower than the d10 value expressed in µm.

The term "d90 particle size distribution" means that <NUM>% (per volume) of the particles have a particle size lower than the d90 value expressed in µm.

These d-values relate in particular to the cumulative particle volume in the particle distribution curve.

The above embodiment (c) parameters provide compressed tablets preferably direct compressed tablets with particularly improved physical characteristics as herein above defined.

Thus this invention concerns compressed tablets (e.g. a chewable tablet), preferably direct compressed tablets, which contains particles comprising sucroferric oxyhydroxide and at least one further pharmaceutically acceptable excipient as defined in claim <NUM> and wherein one or more of the following features i) to vi) is met:.

In a further embodiment, this invention concerns compressed tablets, wherein the hardness of the tablets is between <NUM> to <NUM> N or between <NUM> and <NUM> N or <NUM> to <NUM> N, or between <NUM> to <NUM> N or between <NUM> to <NUM> N or between <NUM> N to <NUM> N.

In a preferred embodiment, this invention concerns any of the herein described compressed tablets preferably direct compressed pharmaceutical tablets, preferably chewable tablets.

In a preferred embodiment, this invention concerns a chewable tablet as hereinabove described, wherein; i) the phosphate binder is sucroferric oxyhydroxide, and ii) the tablet contains between <NUM> to <NUM> or between <NUM> to <NUM> of sucroferric oxyhydroxide.

Preferably the sucroferric oxyhydroxide phosphate binder particles as herein described, represent more than <NUM>% of the total tablet mass (total tablet weight), preferably more than <NUM>% or more than <NUM>% or even more than <NUM>% of the total mass of the tablets (by weight on a dry weight basis).

As described above the phosphate binder to be used is polynuclear iron(III)-oxyhydroxide stabilized by sucrose, and starches (known as sucroferric oxyhydroxide or PA21) or a polynuclear β-iron(III)-oxyhydroxide stabilized by sucrose, and starches (known as sucroferric oxyhydroxide or PA21). Accordingly the particles of sucroferric oxyhydroxide, i.e. consisting essentially of polynuclear iron(III)-oxyhydroxide, sucrose, and starches have a particle size distribution wherein at least <NUM>%, or at least <NUM>%, or at least <NUM>%, or at least <NUM>% by volume is in the range of <NUM> to <NUM> (preferably in the range of <NUM> to <NUM>) and a d50 (related to the volume of the particles) in the particle size distribution in the range of <NUM> to <NUM> or <NUM> to <NUM> or <NUM> to <NUM> (preferably in the range of <NUM> to <NUM>). A particularly preferred mixture of iron(III) oxyhydroxide, sucrose and starches comprises about <NUM> to <NUM> wt-% iron(III) oxyhydroxide, about <NUM> to <NUM> wt-% sucrose and about <NUM> to <NUM> wt-% starches based on the total dry weight (i.e. <NUM> wt-%) of the phosphate binder particles of such mixture. A particular preferred mixture of iron(III) oxyhydroxide, sucrose and starches comprises about <NUM> to <NUM> wt-% iron(III) oxyhydroxide, about <NUM> to <NUM> wt-% sucrose and about <NUM> to <NUM> wt-% starches based on the total dry weight (i.e. <NUM> wt-%) of phosphate binder particles of such mixture, and the iron(III) oxyhydroxide preferably comprises β-iron(III) oxyhydroxide.

Accordingly the sucroferric oxyhydroxide phosphate binder particles as herein described are the active ingredient particles (i.e. particles of polynuclear iron(III)-oxyhydroxide stabilized by sucrose, and starches), before mixing such particles with other excipients. Preferably the sucroferric oxyhydroxide particles comprise more than <NUM>% or even more than <NUM>% of sucroferric oxyhydroxide, by weight on a dry weight basis of the particles (i.e. of the drug substance particles before mixture with additional excipients). Preferably not more than <NUM>% to <NUM>% of side products or impurities resulting from manufacturing process should be present in the sucroferric oxyhydroxide particles (e.g. sodium chloride etc.). Active ingredient particles can also be named drug substance (DS) particles.

Preferably the sucroferric oxyhydroxide phosphate binder particles as herein described, represent more than <NUM>%, preferably more than <NUM>%, or preferably more than <NUM>% and even more than <NUM>% of the total weight of the tablet (by weight on a dry weight basis). Sucroferric oxyhydroxide particles can be formed by spray drying or an alternative size increasing process well known in the field like e.g. granulation, direct compression etc. microgranulation.

Sucroferric oxyhydroxide particles comprise more than <NUM>% of sucroferric oxyhydroxide, preferably more than <NUM>% or preferably more than <NUM>% or even more than <NUM>% or even more than <NUM>% of sucroferric oxyhydroxide, by weight on a dry weight basis.

In a further embodiment the inventions relates to the herein described, wherein the single oral dosage form of the sucroferric oxyhydroxide shall contain preferably more than <NUM>, or more than <NUM> or more than <NUM> or more than <NUM> or more than <NUM> or more than <NUM> of phosphate binder.

In a further embodiment the inventions relates to the herein described tablets, wherein the single oral dosage form of sucroferric oxyhydroxide, contains between <NUM> to <NUM> of sucroferric oxyhydroxide, or between <NUM> to <NUM> of sucroferric oxyhydroxide, or between <NUM> to <NUM> of sucroferric oxyhydroxide, or between <NUM> to <NUM> of sucroferric oxyhydroxide.

It has been discovered that the selected particle size distribution of the sucroferric oxyhydroxide are particularly important to enable the compaction of the tablets as hereinabove described, among other advantages.

If there are further excipients in addition to the phosphate binder particles the particle size distribution of the selected further excipients comprised in the tablets is similar to the particle size distribution of the sucroferric oxyhydroxide particles. The term "similar" means that the particle size distribution of the excipients in the tablet comprises particles in the range of <NUM> to <NUM>, or between <NUM> to <NUM>, preferably between <NUM> to <NUM>. Preferably at least <NUM>% or at least <NUM>%, at least <NUM>%, or at least <NUM>% (by volume) of the excipient particles are in the range of <NUM> to <NUM>, or between <NUM> to <NUM>, preferably between <NUM> to <NUM>.

The preferred excipients with an adapted particle size distribution can be selected by use of e.g. the "<NPL>".

Particle size of sucroferric oxyhydroxide particles size, can be controlled by crystallization, drying, preferably spray drying, compaction and/or milling/sieving (non limiting examples are described below). Producing the desired particle size distribution is well known and described in the art such as in "<NPL>ON)". According to the present invention the desired particle size distribution for the used sucroferric oxyhydroxide particles is obtained by a spray drying process, which comprises the step of spray-drying an aqueous suspension of the phosphate binder particles (being comprised of a mixture of iron(III) oxyhydroxide, sucrose, starches in case of the preferred sucroferric oxyhydroxide), wherein the aqueous suspension of the phosphate binder particles is subjected to atomization prior to spray-drying. Atomization of the feed might be generally achieved by basic feed devices of the single fluid nozzle or pressure type, of the two-fluid nozzle or pneumatic type, and of the centrifugal (spinning disc) type. In the present invention atomization is preferably done with the centrifugal (spinning disc) type atomizer. Centrifugal atomization achieves dispersion by centrifugal force, with the feed liquor being pumped to a spinning disc. In the present invention in particular spray drying on an Anhydro Spray drying plant type CSD No. <NUM> was found to result in an appropriate drying process. For the atomization of the concentrated aqueous PA21 suspension a centrifugal atomizer CE <NUM> can be used, that atomizes by feeding the liquid feed onto a high-speed wheel. With a rotary atomizer, it is possible to adjust the wheel speed and thereby the particle size better than with a nozzle. Further, rotary atomization is better suited for a shorter spray dryer. The powder received from the spray drying process should have a good flowability and the particle size of the dried product should not be too small. With the rotary atomizer, the particle size can be adjusted in particular by variation of the wheel speed. The wheel speed of the atomizer defines the size of the drops which fall into the drying chamber of the spray dryer. The size of the drops influences the particle size of the dried powder as well as its loss on drying. A higher wheel speed produces smaller drops resulting in a smaller particle size of the dried powder and a lower loss on drying, because a smaller drop contains less water which is faster vaporized during its way through the drying chamber. Since the correlation between the wheel speed and the particle size depends on the chamber geometry, it has to be adapted for each individual plant. For the geometry of the preferred Anhydro Spray drying plant type CSD No. <NUM> used a wheel speed of between <NUM> and <NUM> rpm, was found to be suitable for achieving desired particle size distribution. The inlet temperature of the air defines the drying energy which is brought into the spray dryer. Together with the inlet gas flow it defines the drying capacity. The inlet gas flow was kept constant at about <NUM> x <NUM><NUM> m<NUM>/h. The inlet temperature was found suitable in the range of <NUM> -<NUM> for the Anhydro Spray drying plant type CSD No. <NUM>. The desired particle size distribution in particular for the used sucroferric oxyhydroxide particles can be obtained from any form especially from any physicochemical form of the sucroferric oxyhydroxide (e.g. different secondary structures such as amorphous or crystalline forms).

Multiple particle sizes have been studied and it has been discovered that the herein described specific size range provides unexpected good results for compression, preferably direct compression and especially for chewable tablets.

Particle size distributions might be measured using Sieve analysis, or laser diffraction (international standard ISO <NUM>-<NUM>), or electronic sensing zone, light obstruction, sedimentation or microscopy which are procedures well known by the person skilled in the art. Sieving is one of the oldest methods of classifying powders by particle size distribution. A further method includes the determination of the volume particle size distribution by TEM (see e.g. Clariant Analytical Services TECHNICAL SHEET <NUM> TEM-Partikelgröße). Such methods are well known and described in the art such as in any analytical chemistry text book or by the <NPL>. )) which describes the <NPL> is a good example. It also mentions (page <NUM>) additional methods: Electronic sensing zone, light obstruction, air permeation, sedimentation in gas or liquid. However, the values of the particle size distributions used in the present invention are generally obtained by the Laser diffraction analytical technologies (see for example http://pharmazie-lehrbuch. de/kapitel/<NUM>-<NUM>. More specifically the particle size distributions are obtained according to the invention with a LS <NUM><NUM> Laser Diffraction Particle Size Analyzer of Beckmann Coulter thereby relying in particular on the the corresponding "LS <NUM><NUM> Laser Diffraction Particle Size Analyzer Instructions For Use PN B05577AB (October <NUM>)" using in particular the complete Mie theory. These laser diffraction analytical technologies yield volume weighted distributions. Here the contribution of each particle in the distribution relates to the volume of that particle (equivalent to mass if the density is uniform), i.e. the relative contribution will be proportional to size. More specifically the particle size distribution (PSD) in accordance with the present invention is carried out with a <NUM> sample of the phosphate binder which is analyzed with a laser particle size analyzer Beckman Coulter LS equipped with a dry powder system. A run length of approx <NUM>" and an obscuration of <NUM>% is applied. The PSD is calculated from the cumulative percentage undersize size distribution using a computer program. Further details are shown in example <NUM> below.

Tablet thickness is measurable using a ruler, vernier caliper, a screw gauge or any electronic method to measure dimensions. Such methods are well known and described in the art such as in any analytical chemistry text book or by the United State Pharmacopeia's (USP) publication USP-NF (<NUM>) which describes the US Food and Drug Administration (FDA) enforceable standards.

This invention provides a compressed tablet or direct compressed tablet, especially chewable tablet, which is capable of disintegrating in water within a period of less than <NUM> minutes, or preferably between <NUM> to <NUM> minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of <NUM> in accordance with the herein defined British Pharmacopoeia test for dispersible tablets.

Preferably the disintegrating time of a tablet according to the invention is less than <NUM> minutes, more preferably less than <NUM> minutes and most preferably less than <NUM> minutes, still more preferably <NUM> to <NUM> minutes.

Furthermore the disintegrating times and relatively fine dispersions obtained with tablets according to the invention are also advantageous regarding the phosphate absorption capabilities. Thus tablets according to the invention can be presented for disintegrating in water or in the oral cavity as chewable tablets and also for directly swallowing. Those tablets according to the invention that are intended to be swallowed are preferably film-coated to ease application.

In a preferred embodiment, the used compressed tablet contains a lubricant, which is preferably magnesium stearate.

In addition to the active ingredient (phosphate binder particles), the tableting powders or tableting granules may contain a number of inert materials known as excipients (or pharmaceutically acceptable excipients). They may be classified according to the role they play in the final tablet. Excipients are selected to aid in the processing and to improve the properties of the final product, and may be classified according to the role they play in the final tablet. They may include fillers, binders or diluents, lubricants, disintegrants and glidants. Other excipients which contribute to the physical characteristics of the finished tablet are e.g. coloring agents, and flavors in the case of chewable tablets. Typically, excipients are added to a formulation to impart good flow and compression characteristics to the material being compressed. Such excipients and corresponding ranges are particularly described in the International Patent application <CIT>. Typically not more than <NUM>% (by weight on a dry weight basis) of excipients are added to the total of the pharmaceutical composition.

In a preferred embodiment, this invention concerns any of the herein described compressed tablets preferably direct compressed pharmaceutical tablets, wherein at least one of the pharmaceutically acceptable excipients is used in an amount of for example <NUM>% to <NUM>% or <NUM>% to <NUM>% or <NUM>% to <NUM>% (by weight on a dry weight basis). Using sucroferric oxyhydroxide as the phosphate binder particles (consisting essentially (i.e. except impurities, i.e. generally more than <NUM> or <NUM> wt-%) of iron(III)-oxyhydroxide stabilized by sucrose, and starches) as an additional excipient only those selected from flavor, sweeteners or taste-enhancing agents, glidants or lubricants, the latter being preferably selected from magnesium stearate or collodial silicas like Aerosil®, are used in an amount of at most <NUM> %, preferably at most <NUM> %, more preferably at most <NUM> % (by weight on a dry weight basis).

In a preferred embodiment, this invention concerns compressed tablets preferably direct compressed pharmaceutical tablets, wherein at least one the pharmaceutically acceptable excipient is a lubricant preferably magnesium stearate and a flavor agent.

One, two, three or more diluents or fillers can be selected as further pharmaceutically acceptable excipient. Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, e.g. confectioner's sugar, compressible sugar, dextran, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc. The preferred diluents include e.g. microcrystalline cellulose. Microcrystalline cellulose is available from several suppliers. Suitable microcrystalline cellulose includes Avicel products, manufactured by FMC Corporation. Another diluent is e.g. lactose. The diluent, fillers, e.g., may be present in an amount from about <NUM>% to <NUM>% and about <NUM>%-<NUM>% respectively by weight of the composition.

One, two, three or more disintegrants can be selected. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, e.g. starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone, cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose; soy polysaccharides; and guar gum. The disintegrant, e.g., may be present in an amount from about <NUM>% to about <NUM>% by weight of the composition. A disintegrant is also an optional but useful component of the tablet formulation. Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration. Typical disintegrants include starch derivatives and salts of carboxymethylcellulose. Sodium starch glycolate is the preferred disintegrant for this formulation.

One, two, three or more lubricants can be selected. Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, e.g. colloidal silica, magnesium trisilicate, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, stearic acid, polyethylene glycol and glycerol behenate. The lubricant, e.g., may be present in an amount from about <NUM> to <NUM>% or from <NUM>% to about <NUM>% by weight of the composition; whereas, the glidant, e.g., may be present in an amount from about <NUM> to <NUM>% or about from <NUM>% to about <NUM>% by weight. Lubricants are typically added to prevent the tablet blend from sticking to punches, minimize friction during tablet compression and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually around or less than <NUM>% by weight. The lubricant component may be hydrophobic or hydrophilic. Examples of such lubricants include e.g. stearic acid, talc and magnesium stearate. Magnesium stearate reduces the friction between the die wall and tablet mix during the compression and ejection of the tablets. It helps prevent adhesion of tablets to the punches and dies. Magnesium stearate also aids in the flow of the powder in the hopper and into the die. The preferred lubricant, magnesium stearate is also employed in the formulation. Preferably, the lubricant is present in the tablet formulation in an amount of from about <NUM> to <NUM>% or from about <NUM>% to about <NUM>%; also preferred is a level of about <NUM>% to about <NUM>% by weight; and most preferably from about <NUM>% to about <NUM>% by weight of the composition. Other possible lubricants include talc, polyethylene glycol, silica and hardened vegetable oils. In an optional embodiment of the invention, the lubricant is not present in the formulation, but is sprayed onto the dies or the punches rather than being added directly to the formulation.

In addition, tablets often contain diluents or fillers which are added to increase the bulk weight of the blend resulting in a practical size for compression (often when the dose of the drug is smaller).

Conventional solid fillers or carriers are substances such as, e.g. cornstarch, calcium phosphate, calcium sulfate, calcium stearate, glyceryl mono- and distearate, sorbitol, mannitol, gelatin, natural or synthetic gums, such as carboxymethyl cellulose, methyl cellulose, alginate, dextran, acacia gum, karaya gum, locust bean gum, tragacanth and the like, diluents, binders, disintegrating agent, coloring and flavoring agents could optionally be employed.

Binders are agents, which impart cohesive qualities to the powdered material. Examples of pharmaceutically acceptable binders as excipients include, but are not limited to, starches, sugars; celluloses and derivatives thereof, e.g., microcrystalline cellulose, hydroxypropyl cellulose, hydroxylethyl cellulose and hydroxylpropylmethyl cellulose; sucrose; glucose, dextrose, lactose dextrose; corn syrup; polysaccharides; and gelatin. During the clinical trials, the applicant has furthermore realized that the taste of the phosphate binder was not appreciated by the subjects and did directly affect the compliance with the therapeutic treatment (treatment adherence). For sake of clarity it should be noted that sucrose and starches being part of the active ingredient sucroferric oxyhydroxide or PA21 do not count as excipients, like binders, sweeteners, etc. listed here.

In further embodiment the tablets of the invention comprise one or more flavoring or taste-masking and coloring additives such as e.g., flavours, sweeteners, taste-enhancing agents, colorants, and the like, which are typically used for oral dosage forms.

In preferred embodiment the tablets of the invention comprise a flavouring agent with Woodberry flavour. The Woodberry flavor provides better compliance and acceptance of the claimed phosphate binder tablets.

Taste-masking agents, such as a taste-enhancing agent, flavouring agent, and/or natural or artificial sweetener, including intense sweetener, are incorporated into oral dosage forms, such as chewable dosage forms, to give them a more pleasant taste or to mask an unpleasant one.

Typical sweeteners as excipient include, but are not limited to, sugars like e.g. sucrose, fructose, lactose, confectionery sugar, powdered sugar, or are polyols which is e.g. sorbitol (e.g. Neosorb), xyitol, maltitol, maltose and polydextrose, or a mixture thereof. Typical intense sweeteners may include, but not be limited to, e.g. aspartame, sucralose, acesulfam K, and/or saccharin derivatives, or a mixture thereof. Further suitable sweeteners or taste-enhancing agents include glycosides such as e.g. neohesperidin dihydrochalcone (neohesperidin DC or NHDC), glycyrrhizin, glutamate, and the like. The latter may be used in very small quantities and thus may hereinafter also be called taste-enhancing agents. All the above are suitable to be used alone or as mixtures with other sweeteners and/or flavouring agents. These substances insure great lingering of the sweet taste and cover any undesired aftertaste. Preferred sweeteners and/or taste-enhancing agents include glycosides such as neohesperidin dihydrochalcone.

In one embodiment the sweetener of choice may be present in an amount of <NUM> to <NUM> % (w/w), preferably <NUM> to <NUM> % (w/w), most preferably <NUM> to <NUM> % (w/w), in relation to the total weight of the composition.

The taste-enhancing agent of choice may be present in an amount of <NUM> to <NUM> ppm, preferably <NUM> to <NUM> ppm, most preferably <NUM> to <NUM> ppm, in relation to the total weight of the composition. Typical flavoring agents include any natural and artificial flavoring agent suitable for pharmaceutical applications, such as flavoring agents derived from a spice, fruit or fruit juice, vegetable or vegetable juice, and the like, for example flavors based on cocoa, caramel, vanilla, apple, apricot, berry (e.g. blackberry, red currant, black currant, strawberry, raspberry, Woodberry, etc.), mint, panettone, honey, nut, malt, cola, verveine (verbena) or any combination thereof, such as for example caramel/vanilla, fruit/cream (e.g. strawberry/cream)and the like. In one embodiment the flavoring agent of choice may be present in an amount of <NUM> to <NUM> % (w/w), preferably <NUM> to <NUM> % (w/w), most preferably <NUM> to <NUM>% (w/w), in relation to the total weight of the composition.

Additional examples of useful excipients are described in the<NPL>, or <NPL>.

The above described formulations are particularly adapted for the production of compressed tablets or preferably direct compressed tablets and provide the necessary physical characteristics, regarding e.g. dissolution and drug release profiles as required by state of the art dosage forms in the field.

The above compositions are also particularly useful for the production of tablets especially compressed tablets and very preferably direct compressed tablets e.g. chewable tablets. The tablets obtained with the above described compositions especially when processed in the form of direct compressed tablets or the herein described direct compressed tablets, exhibit preferable friability properties very good breaking strength, improved manufacturing robustness, optimal hygroscopicity, hardness, compressibility, chewability, low residual water content especially for direct compressed tablets, short Disintegration time DT (less than <NUM> minutes) according to the British Pharmacopoeia <NUM>, resulting in a fine dispersion with a preferable particle size distribution after disintegration. The Disintegration time DT values claimed in the present application are obtained according to the European Pharmacopoeia (EP) <NUM>/<NUM>:<NUM> defined methodologies.

Preferably the hereinabove described compressed tablets (e.g. direct compressed tablets), have a disintegration time less than <NUM> minutes, preferably between <NUM> and <NUM> minutes. Preferably for the hereinabove described compressed tablets (including direct compressed tablets) have a tablet hardness of comprised between <NUM> N to <NUM> N or between <NUM> to <NUM> N, preferably between <NUM> N to <NUM> N, and a friability of between <NUM>% to <NUM>% or <NUM> to <NUM>%. The direct compression of sucroferric oxyhydroxide involves blending and compression. The choice of grades of excipients added in particular to the sucroferric oxyhydroxide particles, takes the particle size range of the sucroferric oxyhydroxide particles into consideration to be maintained within a range that allows homogeneity of the powder mix and content uniformity of thesucroferric oxyhydroxide particles in the final dosage form, and as explained before the particle size distribution of the selected further excipients comprised in the pharmaceutical formulation or a pharmaceutical composition or tablets is preferably similar to the particle size distribution of the the sucroferric oxyhydroxide particles. This prevents segregation of the particles in the hopper during direct compression. The advantages of using the claimed pharmaceutical compositions are that they impart compressibility, cohesiveness (reducing it) and flowability (increasing it) of the powder blend. In addition, the use of direct compression provides competitive unit production cost, shelf life, eliminates heat and moisture, allows for prime particle dissociation, physical stability and ensures particle size uniformity.

The described advantages of the pharmaceutical compositions are also very useful for e.g. roller compaction or wet granulation or to fill sachets or capsules.

In a further embodiment, the herein described and claimed tablets (e.g. direct compressed tablets) contain one or more further phosphate binder preferably one or two further phosphate binders.

Preferred further phosphate binders are especially organic polymers such as e.g. sevelamer hydrochloride. Management of the phosphorus level is one of the primary treatments for CKD-MBD using phosphate binders to reduce the serum phosphate concentration. Sevelamer is marketed under the brand name Renagel® (hydrochloric acid) and Renvela® (Carbonate formulation) by Genzyme.

Other Phosphate binders that may be used include in particular calcium, magnesium, aluminum, iron, lanthanum and bismuth salts, whose which are better soluble than the corresponding phosphate salts of these cations. In addition, phosphate-binding organic polymers having an anion exchanger function such as AMG <NUM> (Amgen) and MCI-<NUM> (Colestilan, Mitsubishi) are suitable substances for the invention. Suitable aluminum salts include all the pharmaceutically tolerable salts which fulfill the above requirements, especially oxides, in particular algedrate and/or hydroxides. All the pharmaceutically acceptable salts which fulfill the above requirements, in particular lanthanum carbonate including its hydrates are suitable as the lanthanum salts. All the pharmaceutically acceptable salts which fulfill the above requirements, preferably chlorides, sulfates, hydroxides, oxides, carbonates and in particular heavy magnesium carbonate are suitable as the magnesium salts. Preferred phosphate binders based on metal salts are for example, fermagates and calcium salts, preferably calcium carbonate and/or calcium chloride and especially preferably calcium acetate.

The present invention also covers any of the herein above claimed tablets comprising a second phosphate binder selected from e.g. any of Sevelamer hydrochloric acid formulation (Renagel®), Sevelamer Carbonate formulation (Renvela®), calcium, magnesium, aluminum, iron, lanthanum salts and bismuth salts.

The tablets prepared as herein above described can be tested as follows.

A preliminary compactibility assessment is carried out on a Kilian press using different formulations of sucroferric oxyhydroxide with different excipients e.g. magnesium stearate. Data demonstrate that our claimed pharmaceutical compositions on being compressed with increasing levels of pressure (compression force) show a substantially useful increase in tablet strength. In particular e.g. mixture of sucroferric oxyhydroxide with magnesium stearate show a substantially useful increase in tablet strength if sucroferric oxyhydroxide is within the hereinabove claimed particle size distribution. These results indicated that from compressibility point of view the claimed formulations provide a clear improvement. With increasing pressure (compression force) our claimed formulations show a substantially useful increase in tablet strength.

A compressibility study is carried out on an instrumented Fette 102i press with force and displacement sensors on both upper and lower punches.

A clear indication is afforded from these data that sucroferric oxyhydroxide tablets are very likely to have poor tablet hardness/crushing strength unless proper particle size are selected. Our claimed formulations are particularly adapted to provide the required compactibility.

Evaluation can alternatively be carried out using a Fette <NUM> press at <NUM> different settings: strain rate settings of <NUM>'<NUM> to <NUM>'<NUM> tablet per hour) and main compression force of <NUM>-<NUM> kN. The trials use Flat-faced Beveled-edge (FFBE) tooling of <NUM> diameter for <NUM> tablets (other diameters are used depending on the weight of the tested tablet). The friability data and values claimed in the present application have been measured according to the European Pharmacopeia's <NUM>. <NUM> with a Roche friabilator. Total tablet weights were selected so that both the <NUM> FFBE tablets would have <NUM> of sucroferric oxyhydroxide and identical tablet thickness. Friability, Compression profile, Strain rate profile and Weight variation are the measured outcomes. Study design and the friability results obtained from the study are used to determine the variables (particle size distribution in the formulation, tablet weight, tablet thickness and weight, water content in the tablet etc) impacting the outcome of hardness.

The sucroferric oxyhydroxide particle size distribution having particles in the range of <NUM> to <NUM> or <NUM> to <NUM> or <NUM> to <NUM> or between <NUM> to <NUM>, or with a d50 in the particle size distribution or between <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or preferably of between <NUM> to <NUM> or between <NUM> to <NUM>, and which is particularly adapted to produce the herein described formulations especially the direct compressed tablets, can be produced as described below.

The methods and values describe in the below example <NUM>, are the basis supporting the values included in the present claims.

The applicant has discovered a particle size distribution (e.g. having particles mainly (e.g. more than <NUM> volume-%) between <NUM> to <NUM>) of in particular sucroferric oxyhydroxide (or with a d50 of the particle size distribution of between <NUM> to <NUM> or preferably between <NUM> to <NUM>), which is particularly suitable for direct compression tablets of phosphate binders.

Improved results are obtained with a d50 of the particle size distribution of between <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, or preferably between <NUM> to <NUM> or preferably between <NUM> to <NUM>.

The particle size distribution determined by laser light diffraction method is preferably specified as follows: d10 larger or equal <NUM>, d50 larger or equal <NUM>, preferably between <NUM> to <NUM> or between <NUM> to <NUM> and d90 less or equal <NUM>. Particle size have been measured by laser diffraction.

Average vacuum: <NUM>-<NUM>" H<NUM>O; Obscuration approx. <NUM>-<NUM>%; Run length approx. <NUM> seconds'.

Introduce <NUM> of the sample into the Dry Powder dispersion System.

Measurement: Apply the specified vacuum to transfer the sample and determine the cumulative volume distribution using a laser light diffraction instrument in accordance with the instruction manual. The parameters may be adjusted so that the test dispersion is representative, homogeneous and well dispersed.

Evaluation/assessment: Determine the particle sizes at the undersize values of <NUM>%, <NUM>% and <NUM>% (d10, d50, d90), and additional values in question, from the cumulative volume distribution.

The inventive particle size distribution (in particular the sucroferric oxyhydroxide particle size distribution) can be obtained by the below described process, which is a none-limitative example. Alternative processes can easily be implemented by the person skied in the art.

The sucroferric oxyhydroxide drug substance is basically prepared as described in the European Patent <CIT> or in the patent application <CIT>.

The manufacturing process for the sucroferric oxyhydroxide drug substance (named PA21 in the below <FIG>) yields a stabilized polynuclear β-iron(III)-oxyhydroxide with a particularly high phosphate adsorption capacity that is maintained during long-term storage.

A flow chart of the manufacturing process is provided in below. It comprises the following steps:.

The resulting sucroferric oxyhydroxide drug substance can be obtained with the desired particle size distribution by adapting the spray drying settings as described above in particular using a centrifugal atomization unit. By spray drying, the different settings of the atomizer in the spray dryer are selected to obtain the desired particle size distribution. This technique is known by the person skilled in the art and settings can depend on the used spray dryer equipment and suitably adapted. Optionally, the obtained resulting sucroferric oxyhydroxide drug substance can be further processed to obtain the desired particle size distribution by other well-known techniques such as by mechanical stress.

<FIG> shows the Particle Size Distribution of the obtained PA21 Drug Substance resulting from spray drying process and analyzed using a LS <NUM><NUM> Laser Diffraction Particle Size Analyzer of Beckmann Coulter.

Basically the phosphate absorber particles in the desired particle size range can be also obtained by mechanical stress. This stress can be mediated by impact, shear or compression. In most commercially available grinding equipment a combination of these principles occurs. For the sucroferric oxyhydroxide obtained by the above described manufacturing process preferably a mechanical impact or jet mill might be used apart from the preferred spray drying process. The most preferable mechanical impact mill can be equipped with different kind of beaters, screens, liners or with pin plates. For our process an impact mill with plate beater and a slit screen <NUM>*<NUM> is used. The impact speed should be variable between <NUM> and <NUM>/s (as peripheral speed) to adapt to any batch to batch variation. A peripheral speed of the beater of about <NUM>-<NUM>/s is used.

Good results (particle size distribution) can also be obtained by mechanical stress e.g. roller compaction, milling and/or sieving.

Other techniques as described in the art and commonly used by the person skilled in the art can also be used to obtain targeted particle size range.

In order to evaluate the compressibility of API (Active Pharmaceutical Ingredient: sucroferric oxyhydroxide) batch with different particle size distribution different API batch covering the range from approximately <NUM> to <NUM> were selected.

Characteristics of the selected sucroferric oxyhydroxide API batches:.

All API batch presented similar flowability, density and LOD. The variability of iron content was in the usual range for this kind of product. The major difference was only the particle size distribution.

The different API batches (with the different particle size ranges) were all formulated with the following composition (pharmaceutical formulation) in the form of a powder comprising the sucroferric oxyhydroxide particles:.

Following equipment were used for the preparation of the blend :.

An identical manufacturing process by direct compression was applied to all API batch to compare their processability. The manufacturing process consisted of:.

The tablet weight was adjusted according to the drug substance assay to provide a nominal dosage of <NUM> iron i.e. <NUM> of sucroferric oxyhydroxide.

Tabletting trials were performed in order to optimize the hardness of the tablet. For such a <NUM> tablet a hardness of at least <NUM> N is necessary to able filling of the tablet in standard packaging without break of damage of the tablet.

Tablets E222X381 are reference examples.

Based on the knowledge in the art, for a big tablets like the developed high load direct compressed tablets (i.e. <NUM> of sucroferric oxyhydroxide), the ideal d50 should have been between <NUM> to <NUM>. Nobody would have expected that the claimed small sucroferric oxyhydroxide particle size could have resulted in improved tablet (direct compressed high load tablets) i.e. improved physical properties.

Surprisingly the sucroferric oxyhydroxide particles, with a d50 of <NUM> (batch no. <NUM>-<NUM>) could not yield in tablet with the most favorable targeted hardness while still acceptable. A maximum of <NUM> N was reached on the tablet press at this point the compression force was already maximal and the noisy sound of the machine oblige us to stop the experiment to not damage the press. Although the tablet was compressed at the lowest thickness we obtained the lowest hardness. The tabletting trials E222X383B with a d50 of <NUM> and E222X382B with a d50 of <NUM> allowed surprisingly to increase the compression force resulting into the increase of the hardness, which was not the case with e.g. batches with a d50 of <NUM>. With such batches (d50 of > <NUM>) whatever the used compression force is, it was not possible to obtain tablets with improved hardness. Therefore a d50 of around <NUM> is a upper limit zone of what is still acceptable. So a reasonable upper limit is in the zone of <NUM> or <NUM>. At <NUM>, the hardness shall be around <NUM> N or slightly lower than <NUM> N.

Trials performed with sucroferric oxyhydroxide particles with a d50 in the range of <NUM> to <NUM> revealed a surprisingly good compressibility of the material and allowed to target up to <NUM> N of hardness.

Sucroferric oxyhydroxide particles with a d50 less than around <NUM> were considered as less appropriate for tableting as they would result in too much loss of material in a rotating tableting machine.

Based on the experimental evaluations, the hereinabove claimed improvements are observed with sucroferric oxyhydroxide particles having a d50 between <NUM> and <NUM> or a d50 between <NUM> and <NUM>. The best results are observed with sucroferric oxyhydroxide (API) particles having a d50 between <NUM> to <NUM>, <NUM> and <NUM> or preferably between <NUM> and <NUM>.

<FIG> demonstrates that the sucroferric oxyhydroxide (API) particles with a d50 between <NUM> and <NUM> is particularly preferred to get a minimum of <NUM> N.

The disintegration time obtained with the sucroferric oxyhydroxide particles with a d50 of <NUM> (batch <NUM>-<NUM>) for tablet of <NUM> N was <NUM>% higher (<NUM>'<NUM>") than tablet of similar hardness (88N) obtained with an API with a d50 of <NUM> (<NUM>-<NUM>) that disintegrate in <NUM>'<NUM>". Such difference could impact the dissolution time of the tablet and is less favourable.

To confirm the excellent compressibility of the sucroferric oxyhydroxide particles the compression profile has been investigate on an additional batch with a d50 of <NUM>.

The tablet batch <NUM> has been produced on a rotating tableting machine gave following results:.

As shown in <FIG> the sucroferric oxyhydroxide particles with a d50 of <NUM> showed very good compression properties and show a linear increase of the hardness in function of the force. Tablet up to <NUM> N could be manufactured.

The pharmacopoeia tests of (diametrical or radial) hardness (resistance to crushing Ph. <NUM>), friability (Ph. <NUM>) and disintegration (Ph. <NUM>) are carried out with standard equipment (Erweka TBH <NUM> hardness tester, Erweka TA <NUM> friability tester with standard drum and abrasion drum (or Roche friabilator), and Sotax DT3 disintegration tester). To avoid any confusion, it is emphasized that the friability values claimed in the present application have been measured according to the European Pharmacopeia's <NUM>/<NUM>:<NUM> with a Roche friabilator, that the disintegration values claimed in the present application have been measured according to the European <NUM>/<NUM>:<NUM> are carried out with standard equipment (Sotax DT3 disintegration tester), and the tablet hardness values claimed in the present application have been measured using a Schleuniger crushing strength tester, i.e. conditions as described in example <NUM> according to the European Pharmacopeia's <NUM>/<NUM>:<NUM>.

In addition, axial hardness (ring and tube test), grinding properties (plate test) are also measured using the texture analyzer (TAXt2i® Texture Analyser Stabel Micro Systems Ltd, Godalming, UK), used to measure the texture of a wide variety of materials. In addition, the Kramer shear cell, from Instron High Wycombe, UK (), used in the food industry to provide information on bite characteristics, crispness and firmness, and a Typodont D85SDP-<NUM> Model from Kilgore International Inc. , Coldwater, Michigan, USA () are also used in this study to test the chewability of tablets. The load was applied to the Typodont Model by the texture analyzer, which means that the Typodont model is an accessory to the texture analyzer in the tests carried out here.

The following test is carried out with both dry and artificial saliva wetted tablets.

The artificial saliva was prepared according to the modified recipe of Klimek (<NUM>) (Original: Matzker and Schreiber (<NUM>)):.

The prepared solution (<NUM>) was kept refrigerated (<NUM>-<NUM>° C) because of its limited shelf life.

In this test, the plastic tool simulates teeth being loaded onto a tablet, with the ring simulating the lower mandible. The ring test is close to an actual biting event.

The ring external diameter dα is <NUM>. The inner diameter, and consequently the diameter of the central cavity di is <NUM>, since the metal of the ring has a thickness of <NUM>. The plastic tool with rounded site of contact is a standard component of the texture analyser. The speed of descent of the plastic tool was <NUM>/sec. The distance travelled is set at <NUM> with a load cell of <NUM> and the texture operation mode is "return to start".

In addition, the ring test is essentially an axial breaking strength. The tablet rests on the ring. The force, Fmax, where breakage occurs is noted. The energy exerted (area under the force - displacement curve, is calculated. The test is carried out on dry tablets and wet (wet by immersion by means of a tweezers in artificial saliva for <NUM> seconds).

The plate test measures the depth of penetration by the application of maximum force for repeated loadings, and thus simulates the effect of teeth penetration during repeated chewing actions.

Here, the tablet is placed on the grooved reverse side of the base plate of the texture analyzer and a force is repeatedly exerted on the tablet to simulate repeated chewing actions.

The texture analyzer test settings were "cycle until count mode", with a load intensity chosen which does not cause the tablet to break (<NUM> N for a rate of descent of <NUM>/sec). The approaching rate (pre-test speed) was <NUM>/sec for increased sensitivity. The applied force at which the texture analyser should begin the actual measurement is set at <NUM> N with what is called the trigger. A typical force - displacement curve for <NUM> cycles is shown. The plate test measures the depth of penetration by the application of maximum force for repeated loadings.

Other tests such as the Tube test, Kramer shear cell test or Typodont model test can be performed.

The texture tester in the ring test mode (yielding axial breaking strengths) is considered to best characterize the the chewability features of the sucroferric oxyhydroxide direct compressed tablets of the present invention. The test confirms the chewability quality of the tablets of the invention.

A number of tests are evaluated in order to provide in vitro evidence of the chewability quality of a chewable tablet. The results are compared with those of two commercially available chewable tablets.

Of the tests which more closely mirror actual chewing action, the texture analyzer in the plate test mode was considered to be the most reliable, especially with tablets wetted with artificial salvia proved to be the most discriminatory and useful. Those sucroferric oxyhydroxide tablets produced within the target radial hardness of ca. <NUM> N performed well in this test and even the variant 14I (radial hardness <NUM> N) showed good chewable properties, confirming a shelf life limit of <NUM> N as suitable.

Sucroferric oxyhydroxide tablets within the target radial hardness limit exhibited chewability properties closely approaching those of the best non-phosphate binder product (Tablets A - Calcimagon®) and superior to best phosphate binder competitor (Tablets B - Fosrenol®) in these tests.

Claim 1:
A compressed tablet for oral administration, which contains sucroferric oxyhydroxide as phosphate binder, obtained from phosphate binder particles comprising a mixture of iron(III)-oxyhydroxide, sucrose and one or more starches, and at least one further pharmaceutically acceptable excipient, wherein at least <NUM>% by volume, or at least <NUM>% by volume, or at least <NUM>% by volume, or at least <NUM>% by volume of the phosphate binder particles are between <NUM> to <NUM>, or between <NUM> to <NUM>, or between <NUM> to <NUM>, the d50 by volume of the phosphate binder particles is in the range of between <NUM> to <NUM>, the particle size distribution is measured by laser diffraction as herein defined, and the disintegration time of said tablet, determined according to the European Pharmacopoeia <NUM>/<NUM>:<NUM>, is less than <NUM> minutes.