Pharmaceutical composition comprising phosphate binder particles

Abstract

To provide a pharmaceutical composition comprising certain phosphate binder particles having a certain particle size distribution.SOLUTION: A pharmaceutical composition comprises sucroferric oxyhydroxide particles having a particle size distribution, i) the pharmaceutical composition being selected from tablets, granules, or fine granules, ii) the sucroferric oxyhydroxide particles including more than 90 wt.% of sucroferric oxyhydroxide on a dry weight basis, iii) the particles of the sucroferric oxyhydroxide having a particle size distribution in which at least 80% (by volume) of the particles have a particle size in a range of 4 to 200 μm, iv) sucroferric oxyhydroxide phosphate binder particles accounting for more than 65 wt.% of the total weight of the pharmaceutical composition (dry weight basis), and v) the hardness of the tablet being in a range of 70 to 250 N.SELECTED DRAWING: Figure 1

Description

Contents of the detailed description

[0001] The present invention relates to a pharmaceutical composition comprising a certain phosphate binder, wherein the phosphate binder comprises particles having a certain particle size distribution particularly suitable for the preparation of improved tablets and other pharmaceutical compositions.

[0002] International Publication No. 20101015827 discloses a ferric composition for use in a method of treating hyperphosphatemia, which is a solid ligand-modified polyoxo-hydroxy metal ion material represented by the formula (MxLy(OH)n) (wherein M represents one or more metal ions including Fe3+ ions, L represents one or more ligands including a carboxylic acid ligand or its ionized form, and OH represents an oxy or hydroxy group), and the material has a polymer structure in which the ligand L is substantially randomly replaced by oxy or hydroxy groups, and the solid ligand-modified polyoxo-hydroxy metal ion material has one or more reproducible physicochemical properties. This document mentions a certain particle size of the solid ligand-modified polyoxo-hydroxy metal ion material, but does not disclose any particle size distribution for a specific pharmaceutical composition, and only mentions the particle size distribution of the newly prepared phosphate binder material. Therefore, this document teaches nothing about the relevance of the particle size distribution for use in pharmaceutical compositions. International Publication No. 20101015827 does not include any examples of specific pharmaceutical compositions.

[0003] U.S. Patent No. 5,514,281 relates to a method for selectively reducing the amount of inorganic phosphate in an aqueous liquid supply containing inorganic phosphate and protein without significantly adversely affecting the protein, which comprises contacting the aqueous liquid supply with an adsorbent composition containing at least one polynuclear metal oxyhydroxide covalently bonded to an adsorbent substrate. This document mentions a certain particle size of an adsorbent substrate or a support material (e.g., silicate, silicon dioxide, glyceryl-modified silica gel, glyceryl-modified glass, and polymer), but does not mention phosphate adsorbents and polynuclear metal oxyhydroxides. In the examples, phosphate binders are used for extracorporeal treatment. There is no disclosure of specific administrable pharmaceutical compositions except for known soluble metal oxyhydroxide / polyol complexes.

[0004] The present invention further relates to a novel powder containing a phosphate binder that can be directly compressed into a certain pharmaceutical composition, particularly chewable tablets, tablets, mini tablets (micro tablets) formed with and without prior processing such as wet granulation or dry granulation (e.g., roller compaction), particularly direct compression of a certain phosphate binder compound (hereinafter referred to as a phosphate binder), granules and tablets formed by its preparation method, directly compressed into tablets, and filled into capsules or sachets or other suitable carrier systems (e.g., dispensers for mini tablets). The present invention further relates to a method for preparing a pharmaceutical dosage form, for example, by blending an active ingredient and a specific excipient into a novel formulation and then compressing or directly compressing the formulation into a final form (e.g., a direct compression tablet) or a filling, and to its use, for example, in a dispenser or sachet.

[0005] The phosphate binders according to the present invention include, in particular, "iron oxyhydroxide stabilized by a stabilizer" or "stabilized iron oxyhydroxide phosphate binder" as described in WO 97 / 22266 and WO 2009 / 062993. The terms "iron oxyhydroxide stabilized by a stabilizer" or "stabilized iron oxyhydroxide phosphate binder" preferably include iron oxyhydroxide together with a stabilizer including in particular carbohydrates and humic acids. As described in WO 97 / 22266, such stabilizers are suitably not bound as complex compounds with iron oxyhydroxide (which means that water-soluble stabilizers can be removed, for example, by washing the stabilized iron oxyoxide with water). As further described in EP 0 972 226, the stabilizer appears to stabilize the iron oxyhydroxide structure, prevent the aging of iron oxyhydroxide, and thereby ensure and protect its phosphate adsorption capacity. This means that stabilized iron oxyhydroxide (FeOOH) generally has a higher phosphate adsorption capacity (measured in EP 0 972 226) than non-stabilized iron oxyhydroxide. According to the present invention, the preferred "iron oxyhydroxide stabilized by a stabilizer" includes β-iron oxyhydroxide stabilized as described in WO 97 / 22266 having at least one carbohydrate and / or humic acid. According to the present invention, the iron moiety preferably includes a hydrated polynuclear oxyhydroxide sequence "wrapped" by a carbohydrate that is not covalently bound as a sugar, in particular sucrose. The presence of a carbohydrate as a sugar, in particular sucrose, appears to be essential for maintaining the hydrated structure of the polynuclear oxyhydroxide and thus for the high phosphate binding capacity. Sucrose and starch are the preferred carbohydrates used. Sucrose appears to prevent the dehydration ("aging") of polynuclear iron(III) oxyhydroxide, and starch appears to improve the processability during production. Iron oxyhydroxide (FeOOH) can be in the form of microcrystals, for example, in the form of β-FeOOH. The repeating portion of the iron oxyhydroxide microcrystals can be described by the molecular formula FeOOH.The preferred β-FeOOH structure (goethite) contains anions in which Fe(III) ions are arranged in a body-centered cubic array that occurs at the octahedral sites. This structure consists of double chains of edge-sharing octahedra running parallel to the 4-fold symmetric b-axis.

[0006] Generally, due to its chemical properties, the iron oxyhydroxide used and administered according to the present invention is not substantially absorbed by the human body.

[0007] As used herein, the term "stabilizer" preferably includes at least one carbohydrate and / or humic acid, particularly as described in WO 97 / 22266. In one embodiment, at least one carbohydrate is water-soluble. Carbohydrates include at least one monosaccharide, disaccharide or polysaccharide, such as agarose, dextran, dextrin, dextran derivatives, cellulose and cellulose derivatives, sucrose (sucrose), maltose or lactose, preferably sucrose (sucrose), dextrin or starch.

[0008] As used herein, the term "starch" preferably includes any conventionally used starch product in natural, gelatinized, degraded, modified and derivatized forms suitable for direct compression (such as potato starch, corn starch, rice starch, tapioca starch, etc.) and mixtures thereof. The most preferred products include, for example, mixtures of native starch and gelatinized starch having a ratio (native-gelatinized) in the weight range of 10:1 to 0.5:1, preferably in the range of 3:1 to 0.5:1, more preferably in the range of 2:1 to 1:1.

[0009] Preferably, the phosphate binder is sucroxyhydroxide iron (USAN name), which is a mixture of iron(III) oxyhydroxide, sucrose and starch, or is defined by the WHO under the ATC code as V03AE05 or is also known as PA21.

[0010] Preferred phosphate binders include polynuclear iron(III) oxyhydroxide stabilized by sucrose and starch (known as sucrooxyhydroxide iron or PA21 (PA21-1 or PA21-2)) or polynuclear β-iron(III) oxyhydroxide stabilized by sucrose and starch (known as sucrooxyhydroxide iron or PA21 (PA21-1 or PA21-2)). A particularly preferred mixture of iron(III) oxyhydroxide, sucrose and starch contains, based on the total dry weight of the phosphate binder particles based on said mixture (i.e., 100% by weight), about 25 to 40% by weight of iron(III) oxyhydroxide, about 25 to 40% by weight of sucrose and about 25 to 40% by weight of starch. A particularly preferred mixture of iron(III) oxyhydroxide, sucrose and starch contains, based on the total dry weight of the phosphate binder particles based on said mixture (i.e., 100% by weight), about 30 to 35% by weight of iron(III) oxyhydroxide, about 30 to 35% by weight of sucrose and about 30 to 35% by weight of starch, and the iron(III) oxyhydroxide preferably contains β-iron(III) oxyhydroxide.

[0011] In the present invention, the term "sucrooxyhydroxide iron" encompasses mixtures of iron(III) oxyhydroxide, sucrose and starch, and the mixtures include one, two or more starches, for example, natural starch only (PA21-1) or gelatinized starch only or a mixture of natural starch and gelatinized starch (PA21-2), etc. Preferred "sucrooxyhydroxide iron" includes a mixture of natural starch and gelatinized starch as defined above herein.

[0012] In each case, in particular, in the final products of the claims and examples, the final products, pharmaceutical formulations and the subject matter of the claims are incorporated into this application by reference to the publications or patent applications mentioned herein.

[0013] As is known to those skilled in the art, a "phosphate binder" is a compound or composition that can act as an adsorbent for phosphates from an aqueous medium, such as an aqueous solution, particularly a physiological aqueous solution. These are particularly suitable as adsorbents for inorganic phosphates and phosphates bound in foodstuffs in formulations for oral use, particularly for the prevention and treatment of hyperphosphatemic conditions, in patients with chronic renal insufficiency having pathologically increased serum phosphate levels, particularly due to a decrease in glomerular filtration rate. The term "phosphate binder" according to the present invention encompasses any salt, isomer, enantiomer or crystalline form of the above active ingredient.

[0014] A phosphate binder, such as ferric oxyhydroxide, may be combined with one or more pharmaceutically acceptable carriers and optionally one or more other conventional pharmaceutical adjuvants and administered enterally, for example orally, in the form of tablets, chewable tablets, mini-tablets (microtablets), granules, capsules, caplets, granules, powders, etc. Enteral compositions can be prepared by conventional means or enabling techniques.

[0015] A pharmaceutical composition comprising an effective amount of an active substance (phosphate binder), such as ferric oxyhydroxide, to treat a condition resulting from hyperphosphatemia or an imbalanced phosphate level (for example, therapeutic use for controlling the serum phosphate level in patients with chronic kidney disease (CKD) undergoing dialysis), which composition comprises a pharmaceutically acceptable carrier and is formulated into a unit dosage form or a multiple-dose formulation.

[0016] In view of its ability to adsorb dietary phosphates in the gastrointestinal tract, phosphate binders are useful for treating imbalanced phosphate levels and conditions resulting from imbalanced phosphate levels (for example, therapeutic use for controlling the serum phosphate level in patients with CKD undergoing dialysis, or the treatment of hyperphosphatemia).

[0017] The phosphate binders useful in the present invention, particularly scorodite, should preferably not be mixed with wet / wetting excipients and are not inherently compressible. As a result, free-flowing and cohesive pharmaceutical formulations in the form of powders or granules that are filled into capsules or sachets or dosage units, with or without the use of administration aids, and compressed or directly compressed into tablets, chewable tablets, mini-tablets (microtablets) or equivalent dosage forms when used by themselves are required.

[0018] Tablets can be defined as solid dosage pharmaceutical forms containing one or more active ingredients, with or without appropriate inert materials known as excipients. Tablets are manufactured by compressing pharmaceutical formulations in the form of powders or granules or small dosage devices (e.g., mini-tablets, pellets) containing a phosphate binder and certain excipients. Without the use of excipients, most drugs and pharmaceutical ingredients cannot be directly compressed into tablets. This is mainly because most drugs have poor flow and aggregation properties.

[0019] Tablets are widely used and most pharmaceutical dosage forms are commercially available as tablets. The main reasons for the popularity of tablets and chewable tablets as dosage forms are ease of use, low cost, and manufacturing speed. Other reasons include formulation stability, packaging, transportation, and ease of dispensing. Tablets provide patients or consumers with ease of administration, ease of accurate dosing, small size, portability, tastelessness, and ease of administration.

[0020] Tablets can be plain, film or sugar-coated, embossed, layered or sustained release. They can be manufactured in various sizes, shapes and colors. Tablets may be swallowed, chewed, or dissolved in the buccal cavity or under the tongue. They may be dissolved in water for local or topical use.

[0021] Other desirable properties of excipients and active ingredients include the following: - High compressibility that can result in strong tablets with low compression force; - Narrow particle size distribution; - Excellent flow properties that can improve the flow of other components in the formulation; and - Cohesiveness (to prevent the tablets from disintegrating during processing, transportation, and handling).

[0022] 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 preparation method used and the type of excipients are adapted to give the tablet formulation the desired physical properties that enable rapid compression of the tablets. After compression, the tablets must meet several attributes such as appearance, hardness, disintegration time, abrasion, mass uniformity, chewability, and dissolution profile. The choice of filler and other excipients depends on the chemical and physical properties of the drug, the behavior of the mixture during processing, and the properties of the final tablets.

[0023] The properties of the drug, its dosage form, and the economics of the operation determine the choice of the best tableting method.

[0024] When one of the components, either the drug or an excipient, and / or a mixture thereof has sufficient cohesive properties to compress, the dry granulation method can be used. This method consists of blending of the components, slugging, compaction, dry sieving, lubrication, and compression.

[0025] The wet granulation method is used to convert a powder mixture into granules having flow and cohesive properties suitable for tableting. This procedure consists of mixing the mixture in a high-shear granulator and subsequently adding a granulating solution to the mixed powder under shear to obtain granules or adding a liquid by spraying in a fluidized bed dryer to obtain granules. The moist mass can be screened through a suitable sieve and dried by tray drying or other suitable drying techniques. The entire process can include weighing, dry powder blend, wet granulation, drying, milling, blend lubrication, and compression.

[0026] Typically, the active pharmaceutical ingredient powder does not have sufficient adhesive or agglomeration properties to form hard and strong granules. A binder is usually required to form large particles (granules). Thermosensitive and hygroscopic drugs cannot mostly be manufactured using wet granulation. The drawbacks of this wet granulation technology are the number of processing steps that incur manufacturing costs and the processing time required.

[0027] Direct compression is regarded as a preferred method of directly compressing solid components without changing the physicochemical properties of the drug. The active ingredient(s), direct compression excipients and other auxiliary substances, such as lubricants and glidants, are blended in a V-blender before being compressed into tablets. The advantages of direct compression technology include, for example, blend uniformity, fewer manufacturing steps involved (i.e., the whole process involves weighing, blending and compressing of powders, thus the cost is limited); elimination of heat and moisture, dissociation of primary particles and physical stability.

[0028] Pharmaceutical manufacturers prefer to use direct compression technology rather than wet or dry granulation methods due to the short processing time and limited process steps that result in favorable costs. However, direct compression is usually limited to cases where the active ingredient has acceptable physicochemical properties required to form a pharmaceutically acceptable dosage form. Since many active ingredients do not exhibit all the required properties, they usually have to be combined with excipients suitable for enabling direct compression. Each excipient added to the formulation increases the tablet size of the final product, so manufacturers are often limited to using the direct compression method for formulations containing low doses of active ingredient per compressed tablet.

[0029] Solid dosage forms containing high-dose drugs (i.e., the drug itself constitutes a substantial part of the total compressed tablet weight) can only be directly compressed if the drug itself has suitable physical properties for direct compression, such as cohesiveness.

[0030] The claimed pharmaceutical composition containing a phosphate binder, particularly scorodite, is considered a high-dose drug, i.e., a high dose of scorodite per unit dosage form (e.g., per tablet). The unit dosage formulation can contain more than 60% by weight, more than 70% by weight, more than 80% by weight, or more than 90% by weight and above of the phosphate binder per unit dosage form (e.g., per tablet). A single oral dosage form of the phosphate binder, particularly scorodite, should preferably contain more than 400 mg, or more than 800 mg, or more than 1000 mg, or more than 1500 mg, or more than 2000 mg, or more than 2500 mg of the phosphate binder. This high-dose drug, combined with its rather poor physical properties for direct compression, has not allowed the use of direct compression technology to prepare a final product with acceptable physical properties. The phosphate binder is relatively unstable (or has poor microbiological stability) in the presence of free water, which is a factor affecting the use of wet granulation technology (a large amount of phosphate binder in a sufficient single dosage formulation would require too much water).

[0031] Previously used tablets containing scorodite as described in International Patent Application Publication No. WO 2009 / 062993 only partially met the expected physical properties, e.g., the remaining potential agglomeration issues. The tablets were prone to disintegration and did not yet have an acceptable abrasion, hardness, compressibility, chewability, disintegration time, or dissolution profile.

[0032] Patients suffering from unbalanced phosphate levels (e.g., CKD (chronic kidney disease) patients on dialysis) need to be administered several oral dosage forms per day over months or years, so an improvement in the oral dosage form, e.g., improved physical properties, is clearly needed.

[0033] Throughout this specification, all weight percentages (w / w) are expressed with respect to the total weight of the pharmaceutical composition (dry composition) unless otherwise indicated.

[0034] Another limitation of direct compression as a tablet manufacturing method is the potential size of the compressed tablets. Since the wet granulation method contributes to the desired physical properties of the tablets, the amount of excipients required for wet granulation is less than the amount required for direct compression.

[0035] Therefore, when the amount of the active ingredient is high, the pharmaceutical formulator may choose to wet granulate the active ingredient with other excipients to obtain tablets of an acceptable size containing the desired amount of the active ingredient. As described herein, the phosphate binder, particularly iron oxyhydroxide, is preferably administered to a patient as a single dosage form containing a high drug load phosphate binder. Further, due to the behavior of the claimed phosphate binder in the presence of water, it is desirable to perform direct compression of tablets containing a high dose phosphate binder, particularly iron oxyhydroxide. Therefore, there are strong technical hurdles that need to be overcome to manufacture compressed (or directly compressed) large tablets that exhibit an acceptable degree of abrasion, hardness, chewability, cohesiveness, disintegration time, and dissolution profile.

[0036] Depending on the intended use of the tablet, i.e., whether it is for swallowing as such, for rapid disintegration (in a small amount of liquid in the mouth or before oral ingestion), or for chewing (e.g., chewable tablets), excipients such as disintegrants, super disintegrants, lubricants, glidants, binder compression aids, etc. may usually be added if desired. The tablets may or may not be coated as pharmaceutically necessary or desired.

[0037] Accordingly, the pharmaceutical composition of the present invention includes any dosage form suitable for oral administration, and in particular includes chewable forms, tablets (preferably in a form for swallowing as such (for example, also film-coated) or in a form capable of rapid disintegration (in the mouth after oral ingestion or in a small amount of liquid before oral ingestion), direct compression tablets and pills), mini tablets, dry powders, granules, capsules, or sachets, wafers, lozenges, etc. containing these granules or mini tablets (micro tablets). If desired, the form for swallowing as such may be film-coated. The pharmaceutical composition of the present invention also includes powders or granules that can be compressed or compacted into tablets.

[0038] Preferred dosage forms include tablets and pills in a form for swallowing as such (for example, film-coated) or in a chewable form, granules and capsules, or sachets containing these granules, and lozenges. In the case of oral dosage forms (film-coated if desired), these are swallowed as such, and disintegration occurs in the stomach and / or other parts of the intestine, after which the active agent is immediately released for the adsorption of phosphate to reduce its systemic uptake.

[0039] In the pharmaceutical preparations, compositions and tablets claimed herein, administration can be minimized to 3 to 4 unit dosage forms per day.

[0040] As described herein, a phosphate binder, particularly ferric oxyhydroxide, is preferably administered to a patient in the form of a single dosage form per administration, said dosage form containing a high load of phosphate binder, i.e., more than 400 mg, or more than 800 mg, or more than 1000 mg, or more than 2000 mg, or more than 2500 mg of phosphate binder, preferably between 1500 - 3000 mg, or between 2000 - 3000 mg of phosphate binder. Depending on the API load, the choice of suitable solid dosage forms is restricted. The most common options for providing unit dosage forms with high drug content are powder / granule / minitablet filled sachets, effervescent tablets or chewable tablets. Chewable tablets offer the advantage of being more flexible in that they do not require access to water and the medicine can be taken surreptitiously, i.e., at work, during travel or in social settings. Furthermore, avoiding additional fluid intake is advantageous for the patient population with CKD (chronic kidney disease). Also, studies have shown that patients prefer to take a single dose per administration, e.g., a tablet, instead of multiple doses as required for swallowable tablets or small tablets for high-dose pharmaceuticals. However, the mechanical strength of chewable tablets can be a concern regarding damage to teeth or the jaw joint from chewable tablets with inappropriate mechanical properties. Since CKD patients have to chew several tablets per day for months or years, the chewability of the tablets is important. Several test procedures and additional methods were applied with the aim of obtaining a meaningful assessment of the chewability of the tablets and confirming the validity of the phosphate binder selection formulation / tablets from the perspective of chewability.

[0041] In the present invention, the "pharmaceutical composition" can be in the form of a powder (preferably a dry powder incorporated into a sachet or capsule), a tablet (compressed into a tablet, preferably a single-layer, two-layer or three-layer tablet), a pill, a granule, or a microparticle, a capsule, a pellet, a wafer, a lozenge or a coated tablet, and contains a phosphate binder compound as the active ingredient (preferably one, two or three kinds) and preferably at least one pharmaceutically acceptable excipient.

[0042] In the present invention, the term "granules" encompasses "fine granules". The granules may be used for direct administration, or may be further processed into tablets, mini-tablets, or chewable tablets.

[0043] In the present invention, the term "tablet" encompasses any type of tablet obtained from the compression or consolidation of powders, granules (obtained by wet or dry granulation, tableting, or melt extrusion), mini-tablets, fine granules, or pellets, preferably referring to directly compressed tablets.

[0044] In the present invention, the term "compression" encompasses any physical consolidation process that results in a solid dosage unit.

[0045] In the present invention, the term "pharmaceutical formulation (or formulation)" encompasses a mixture of an active ingredient (preferably one, two, or three) and a pharmaceutically acceptable excipient in a form suitable for the preparation / manufacture of a pharmaceutical product (e.g., a pharmaceutical composition). In the present invention, preferred formulations are powders or granules suitable for consolidation, compression, or direct compression into tablets.

[0046] It is also an object of the present invention to provide a phosphate binder as described below in the form of a pharmaceutical formulation, preferably in the form of a free-flowing cohesive tableting powder (powder formulation) that can be compressed or directly compressed into tablets.

[0047] It is also an object of the present invention to provide a phosphate binder as described below in the form of a tablet granule (obtained by wet or dry granulation or melt extrusion) that can be mixed with further excipients and can be consolidated, compressed, or directly compressed into tablets.

[0048] It is a further object of the present invention to provide a compressed (or directly compressed) phosphate binder tablet in a unit dosage form having an acceptable dissolution profile, as well as an acceptable degree of hardness and chip resistance, and an acceptable abrasion and chewability profile, and a fast disintegration time.

[0049] It is a further object of the present invention to provide a compressed (or preferably, direct compressed) phosphate binder tablet which is a rapidly disintegrating tablet (in the mouth or in a small amount of liquid before oral ingestion), for example, a chewable tablet or a mini tablet.

[0050] It is a further object of the present invention to provide a method for preparing a compressed phosphate binder tablet in a unit dosage form by direct compression.

[0051] The present invention also provides a tableting free-flowing particulate phosphate binder composition in the form of a tablet powder (preferably containing at least one additional pharmaceutically acceptable excipient described below) which can be compressed or directly compressed into a tablet having sufficient hardness, abrasion resistance, chewability, rapid disintegration time and an acceptable dissolution pattern. BRIEF DESCRIPTION OF THE DRAWINGS

[0052]

Figure 1

Figure 2

Figure 3

Figure 4

[0053] In the development of the pharmaceutical compositions described herein, the applicant has found it particularly advantageous to use a pharmaceutical composition in the form of a tablet, preferably a compressed tablet, containing a phosphate binder, wherein the phosphate binder particles have a particle size distribution in which at least 40% of the particles have a particle size in the range of 4 to 200 μm.

[0054] Preferably, i) A phosphate binder, especially particles of scorodite, preferably having a particle size distribution having particles in the range of 4 to 200 μm, with at least 40 (volume)% of the particles having a particle size in the range of 4 to 200 μm, and / or ii) The phosphate binder particles, especially scorodite particles, have a d50 in a particle size distribution in the range of 30 μm to 120 μm, or 35 μm to 110 μm, or 40 μm to 108 μm, or 40 μm to 100 μm, or preferably 40 μm to 80 μm, or 42 μm to 75 μm, and / or iii) The hardness of the tablet is between 70 and 250 N, or 85 and 250 N, or 85 and 200 N, or 70 and 200 N, or 80 and 200 N, and / or iv) The tablet abrasion degree is between 0% and 7%, or between 0.05% and 7%, and / or v) The tablet has a disintegration time of less than 30 minutes, preferably between 5 and 20 minutes, and / or vi) The tablet diameter is between 15 mm and 30 mm, the tablet weight is between 2000 mg and 3000 mg, and the tablet thickness is between 4.5 mm and 7.5 mm.

[0055] In particular, the present invention relates to a pharmaceutical composition or a compressed pharmaceutical tablet containing a phosphate binder, preferably a direct compression tablet. The phosphate binder, especially scorodite, has unfavorable physical properties for conversion into an acceptable compressed, preferably direct compression pharmaceutical tablet. These unfavorable physical properties can be, for example, bulkiness, adhesion, fluffiness, etc. During the development of the pharmaceutical compositions and tablets described herein, the Applicant has found that particles containing a phosphate binder, especially scorodite, have at least 40% by volume, or at least 60% by volume, or at least 80% by volume, or at least 90% by volume in the range of 4 to 200 μm (preferably in the range of 5 to 160 μm), and / or a particle size distribution having a d50 (with respect to the volume of the particles) in the range of 30 μm to 120 μm, or 35 μm to 110 μm, or 40 μm to 108 μm, or 40 μm to 100 μm, or preferably 40 μm to 80 μm (preferably in the range of 42 μm to 75 μm), the processing properties or physical properties of the pharmaceutical formulation, such as hygroscopicity, fluidity, bulkiness, fluffiness, are unexpectedly improved. The Applicant has also surprisingly found that the tablets exhibit improved physical properties, such as solubility, abrasion resistance, hygroscopicity, hardness, compressibility, chewability or disintegration.

[0056] A further unexpected advantage of the selected particle size distribution is that the compression force can be increased during the tableting process without any change in the physical properties of the tablet (except for hardness), but while increasing the tablet hardness to the target hardness range.

[0057] In a preferred first embodiment (a), the present invention relates to a compressed tablet, preferably a direct compression pharmaceutical tablet, wherein the powder for compression contains particles comprising a phosphate binder (phosphate binder particles), especially scorodite, and at least one further pharmaceutically acceptable excipient, and at least 40% by volume, preferably 60% by volume, most preferably 80% by volume, even more preferably 90% by volume of the particles of the phosphate binder particle size distribution of the tablet is between 4 and 200 μm, or between 5 and 160 μm, or between 21 and 160 μm.

[0058] In a preferred second embodiment (b), the present invention relates to a compressed tablet, preferably a directly compressible pharmaceutical tablet, comprising particles in which the powder for compression comprises a phosphate binder (phosphate binder particles), in particular scorodite hydroxide, and at least one further pharmaceutically acceptable excipient, the phosphate binder particles having a d50 (by volume) in a particle size distribution in the range of 30 μm to 120 μm, or 35 μm to 110 μm, or 40 μm to 108 μm, or 40 μm to 100 μm, or preferably 40 μm to 80 μm, or preferably 42 μm to 75 μm.

[0059] In a preferred third embodiment (c), the present invention relates to a compressed tablet, preferably a directly compressible pharmaceutical tablet, comprising particles in which the dispersant comprises a phosphate binder (phosphate binder particles), in particular scorodite hydroxide, and at least one further pharmaceutically acceptable excipient, i) at least 40% by volume, preferably 60% by volume, most preferably 80% by volume, even more preferably 90% by volume of the particles in the phosphate binder particle size distribution being between 4 and 200 μm, or between 5 and 160 μm, or between 21 and 160 μm, and ii) the phosphate binder particles having a (by volume) d50 in a particle size distribution between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 108 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, or preferably between 42 μm and 75 μm, and / or iii) the hardness of the tablet being between 70 and 250 N, and / or iv) the tablet abrasion being between 0% and 7% or between 0.05% and 7%, and / or v) the tablet having a disintegration time of less than 30 minutes, preferably between 5 and 20 minutes, and / or vi) the tablet having a diameter between 16 mm and 30 mm, a tablet weight between 1500 mg and 3000 mg (preferably between 2000 and 3000 mg), and a tablet thickness between 4.5 mm and 7.5 mm, and / or vii) the tablet containing between 1500 mg and 3000 mg of a phosphate binder, in particular scorodite hydroxide. The present invention relates to a compressed tablet, preferably a directly compressible pharmaceutical tablet.

[0060] In a preferred fourth embodiment (d), the present invention comprises particles comprising a phosphate binder, particularly scorodite, and at least one additional pharmaceutically acceptable excipient, wherein the phosphate binder particles have a d50 in a particle size distribution between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 108 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, or between 42 μm and 75 μm, and the d50 relates to a pharmaceutical composition with respect to the volume of the particles.

[0061] In a preferred fifth embodiment (e), the present invention comprises particles comprising a phosphate binder, particularly scorodite, and at least one additional pharmaceutically acceptable excipient, and relates to a pharmaceutical composition in which at least 40% by volume, preferably at least 60% by volume, more preferably at least 80% by volume, or at least 90% by volume of the particle size distribution of the formulation or composition is between 4 μm and 200 μm, or between 5 μm and 160 μm, or between 21 μm and 160 μm.

[0062] The terms "at least 40%, preferably at least 60%, or at least 80%, or at least 90%" mean that at least 40%, preferably at least 60%, or at least 80%, or at least 90% of the particles (phosphate binder particles) are of the said size, i.e., belong to the said size range. The percentage is by volume.

[0063] The term "d50 particle size distribution" means that 50% (by volume) of the particles have a particle size above or below the d50 value (expressed in μm) that is defined.

[0064] The term "d10 particle size distribution" means that 10% (by volume) of the particles have a particle size lower than the d10 value (expressed in μm).

[0065] The term "d90 particle size distribution" means that 90% (by volume) of the particles have a particle size lower than the d90 value (expressed in μm).

[0066] These d-values are particularly related to the cumulative particle volume in the particle size distribution curve.

[0067] The combination of parameters of the above-described third embodiment (c) provides compressed tablets, preferably direct compression tablets, having particularly improved physical properties as defined above herein.

[0068] Accordingly, the present invention also includes particles comprising a phosphate binder (phosphate binder particles), particularly scorodite, and at least one further pharmaceutically acceptable excipient, and satisfying one or more of the following characteristics i) to vii): i) at least 40% by volume, preferably at least 60% by volume, or preferably at least 80% by volume, or at least 90% by volume of the particles of the phosphate binder particle size distribution of the tablet is between 4 and 200 μm, or between 5 and 160 μm, or between 21 and 160 μm, ii) the phosphate binder particles have a d50 (particularly by volume) in the particle size distribution between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, or between 42 μm and 75 μm, iii) the hardness of the tablet is between 70 and 250 N, iv) the tablet abrasion degree is between 0% and 7% or between 0.05% and 7%, v) the tablet has a disintegration time of less than 30 minutes, preferably between 5 and 20 minutes, vi) the tablet diameter is between 16 mm and 30 mm, the tablet weight is between 2000 mg and 3000 mg, and the tablet thickness is between 4.5 mm and 7.5 mm, vii) the tablet contains between 1500 mg and 3000 mg of a phosphate binder, particularly scorodite, Relates to compressed tablets (e.g., chewable tablets), preferably direct compression tablets.

[0069] In a further embodiment, the present invention relates to any of the compressed tablets described herein, wherein the hardness of the tablets is between 85 and 250 N, or between 70 and 200 N or between 85 and 200 N, or between 85 and 200 N, or between 80 and 200 N, or between 100 N and 230 N.

[0070] In a preferred embodiment, the present invention relates to any of the compressed tablets described herein, preferably direct compression pharmaceutical tablets, preferably chewable tablets.

[0071] In a preferred embodiment, the present invention relates to the above chewable tablets, wherein i) the phosphate binder is scorosic iron hydroxide and ii) the tablets contain between 1500 mg and 3500 mg, or between 2000 and 3000 mg of scorosic iron hydroxide.

[0072] Preferably, the phosphate binder particles in the formulation or tablets, in particular the scorosic iron hydroxide phosphate binder particles described herein, are more than 65% of the total tablet mass (total tablet weight), preferably more than 80% by weight, or more than 90% by weight, or more than 95% by weight of the tablet (dry weight basis) or the total mass of the formulation.

[0073] As described above, preferred phosphate binders for use in the pharmaceutical compositions according to the invention include polynuclear iron(III) oxyhydroxide stabilized by sucrose and starch (known as sucrooxyhydroxide iron or PA21) or polynuclear β-iron(III) oxyhydroxide stabilized by sucrose and starch (known as sucrooxyhydroxide iron or PA21). Thus, that is, particles of sucrooxyhydroxide iron consisting essentially of polynuclear iron(III) oxyhydroxide, sucrose and starch have a particle size distribution in which at least 40% by volume, or at least 60% by volume, or at least 80% by volume, or at least 90% by volume is in the range of 4 to 200 μm (preferably in the range of 5 to 160 μm), and / or a d50 (with respect to the volume of the particles) in a particle size distribution in the range of 30 μm to 120 μm, or 35 μm to 110 μm, or 40 μm to 108 μm, or 40 μm to 100 μm, or preferably 40 μm to 80 μm (preferably in the range of 42 μm to 75 μm). A particularly preferred mixture of iron(III) oxyhydroxide, sucrose and starch contains about 25 to 40% by weight of iron(III) oxyhydroxide, about 25 to 40% by weight of sucrose and about 25 to 40% by weight of starch, based on the total dry weight (i.e., 100% by weight) of the phosphate binder particles of the mixture. A particularly preferred mixture of iron(III) oxyhydroxide, sucrose and starch contains about 30 to 35% by weight of iron(III) oxyhydroxide, about 30 to 35% by weight of sucrose and about 30 to 35% by weight of starch, based on the total dry weight (i.e., 100% by weight) of the phosphate binder particles of the mixture, and the iron(III) oxyhydroxide preferably contains β-iron(III) oxyhydroxide.

[0074] Therefore, the scorloxy iron phosphate binder particles described in this specification are preferably active ingredient particles (i.e., particles of polynuclear β-iron(III) oxyhydroxide stabilized by sucrose and starch) before mixing the particles with other excipients. Preferably, the scorloxy iron particles contain more than 95% by weight, or more than 98% by weight of scorloxy iron based on the dry weight of the particles (i.e., the drug substance particles before mixing with additional excipients). Preferably, 2% to 5% or less of by-products or impurities resulting from the manufacturing process should be present in the scorloxy iron particles (e.g., sodium chloride, etc.). The active ingredient particles can also be referred to as drug substance (DS) particles.

[0075] Preferably, the phosphate binder particles in the tablets or pharmaceutical compositions, particularly the scorloxy iron phosphate binder particles described in this specification, are more than 65% by weight, preferably more than 80% by weight, or preferably more than 90% by weight, and further more than 95% by weight of the total weight (dry weight basis) of the tablets or pharmaceutical compositions.

[0076] The phosphate binder particles, particularly the scorloxy iron particles, can be formed by spray drying or alternative size-increasing methods well-known in the art, such as granulation, direct compression, etc., microgranulation.

[0077] Preferably, the scorloxy iron particles contain 65% by weight of scorloxy iron, preferably more than 80% by weight, or preferably more than 90% by weight, or even more than 95% by weight, or even more than 98% by weight of scorloxy iron based on the dry weight.

[0078] In a further embodiment, the present invention relates to tablets or pharmaceutical compositions described herein, wherein a single oral dosage form of a phosphate binder, particularly scorloxy iron, preferably contains more than 400 mg, or more than 800 mg, or more than 1000 mg, or more than 1500 mg, or more than 2000 mg, or more than 3000 mg of the phosphate binder.

[0079] In a further embodiment, the present invention relates to a pharmaceutical composition in the form of a single oral dosage form of a phosphate binder, particularly ferric oxyhydroxide, comprising ferric oxyhydroxide between 800 mg and 3500 mg, or ferric oxyhydroxide between 1500 mg and 3500 mg, or ferric oxyhydroxide between 1500 mg and 3000 mg, or ferric oxyhydroxide between 2000 mg and 3000 mg, in the form of tablets as described herein.

[0080] The present invention also relates to tablets or pharmaceutical compositions as described herein, wherein the phosphate binder particles have a d50 in a particle size distribution between 40 μm and 80 μm, and at least 60% by volume, most preferably at least 80% by volume, of the particles of the tablet's phosphate binder particle size distribution are between 4 and 200 μm, or between 5 and 160 μm, or between 21 and 160 μm.

[0081] It has been discovered that the selected particle size distribution of the phosphate binder, particularly ferric oxyhydroxide, is particularly important for enabling compaction of the above tablets, among other advantages.

[0082] In a preferred embodiment, the phosphate binder according to the present invention is a sucrose-based phosphate binder stabilized multinuclear iron(III) oxyhydroxide containing sucrose and one or more starches, such as potato starch, corn starch, etc., and modified starches, such as pregelatinized starch.

[0083] In a further embodiment, the present invention is a pharmaceutical composition comprising ferric oxyhydroxide particles and optionally at least one further pharmaceutically acceptable excipient, i) at least 40% by volume, or at least 60% by volume, at least 80% by volume, or at least 90% by volume of the ferric oxyhydroxide particles in the particle size distribution are between 4 and 200 μm, or between 5 and 160 μm, or between 21 and 160 μm, ii) The (volume-based) d50 in the particle size distribution of the scorodite hydroxide particles is between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm. iii) The scorodite hydroxide defined above is more than 80% by weight, or more than 90% by weight, or more than 95% by weight, or more than 97% by weight of the scorodite hydroxide particles on a dry weight basis. Relates to a pharmaceutical composition.

[0084] When there are additional excipients in addition to the phosphate binder particles, the particle size distribution of the selected additional excipients included in the pharmaceutical formulation or pharmaceutical composition or tablet is similar to that of the phosphate binder particles, preferably the scorodite hydroxide particles. The term "similar" means that the particle size distribution of the excipients in the tablet contains particles in the range of 5 to 400 μm, or between 5 and 300 μm, preferably between 1 and 200 μm. Preferably, at least 40% by volume, or at least 60% by volume, at least 80% by volume, or at least 90% by volume of the excipient particles are in the range of 5 to 400 μm, or between 5 and 300 μm, preferably between 1 and 200 μm.

[0085] Preferred excipients having a suitable particle size distribution can be selected, for example, by the use of "Handbook of Pharmaceutical Excipients (6th Edition), Editor Raymond C Rowe - Publisher: Science and Practice".

[0086] The particle size of the phosphate binder, for example, the schwertmannite particle size, can be controlled by crystallization, drying, preferably spray drying, compaction and / or milling / sieving (non-limiting examples are given below). The production of the desired particle size distribution is well known and is described in the art, for example, in "Pharmaceutical dosage forms: Volume 2, 2nd Edition, Editors: H.A. Lieberman, L. Lachman, J.B. Schwartz (Chapter 3: SIZE REDUCTION)". According to the present invention, the desired particle size distribution for the particularly preferably used schwertmannite particles is obtained by the spray drying method, which comprises spray drying an aqueous suspension of phosphate binder particles (in the case of the preferred schwertmannite, composed of a mixture of iron(III) oxyhydroxide, sucrose, and starch), and subjecting the aqueous suspension of the phosphate binder particles to micronization before spray drying. The micronization of the feed can generally be achieved by basic feed devices such as a single-fluid nozzle or pressure type, two-fluid nozzle or pneumatic type, and centrifugal (rotating disk) type. In the present invention, the micronization is preferably carried out by a centrifugal (rotating disk) atomizer. Centrifugal atomization pumps the feed liquid onto a rotating disk to obtain dispersion by centrifugal force. In the present invention, in particular, it has been found that spray drying in an Anhydro Spray drying plant type CSD73 provides a suitable drying process. To micronize the concentrated aqueous PA21 suspension, a centrifugal atomizer CE250 can be used, which micronizes by supplying the liquid feed to a high-speed wheel. In a rotary atomizer, the wheel speed and thus the particle size can be better adjusted than with a nozzle. Furthermore, rotary micronization is well suited for shorter spray dryers. The powder received from the spray drying process should have excellent fluidity, and the particle size of the dried product should not be too small. In a rotary atomizer, the particle size can be adjusted particularly by changing the wheel speed. The wheel speed of the atomizer defines the size of the droplets falling into the drying chamber of the spray dryer. The droplet size affects the particle size of the dried powder as well as its loss during drying. Smaller droplets contain less water, and this water evaporates faster as it passes through the drying chamber. So, the higher the wheel speed, the smaller the droplets generated, the smaller the particle size of the dried powder, and the less the loss during drying.Since the correlation between wheel speed and particle size depends on the chamber geometry, it has to be adapted to each individual plant. For the geometry of the preferred Anhydro Spray Dryer plant type CSD73 used, it was found that wheel speeds between 12,000 and 20,000 rpm are suitable to achieve the desired particle size distribution. The inlet temperature of the air defines the drying energy imparted to the spray dryer. Together with the inlet gas flow, this defines the drying efficiency. The inlet gas flow was kept constant at about 1.9x10. 4 m 3 / hour. It was found that an inlet temperature range of 130 - 180 °C is suitable for the Anhydro Spray Dryer plant type CSD73.

[0087] The desired particle size distribution for particularly preferably used schloopoxy iron hydroxide particles can be obtained from any form of phosphate binder, particularly from any physicochemical form of schloopoxy iron hydroxide (e.g., different secondary structures such as amorphous or crystalline forms).

[0088] Multiple particle sizes were tested and it was found that the specific size ranges described herein result in unexpectedly excellent results for compression, preferably direct compression and particularly for chewable tablets.

[0089] The particle size distribution can be measured by sieve analysis, which is a procedure well known to those skilled in the art, or by laser diffraction (International Standard ISO 13320-1), or by electrical sensing zone, light obscuration, sedimentation or microscopy. Sieving is one of the oldest methods of classifying powders according to particle size distribution. Further methods include measurement of the volume particle size distribution by TEM (see, for example, Clariant Analytical Services TECHNICAL SHEET 106 TEM-Particle Size). Such methods are well known and are described in the art, for example, in any analytical chemistry textbook or in the United States Pharmacopeial Convention, Inc., Rockville, Md., United States Pharmacopeial Convention (USP) publication USP-NF (2004 - Chapter 786) which describes standards with the force of law of the United States Food and Drug Administration (FDA). The techniques used are described, for example, in Pharmaceutical dosage forms: Volume 2, 2nd Edition, Editors: H.A. Lieberman, L. Lachman, J.B. Schwartz, which is a good example. This document also mentions additional methods: electrical sensing zone, light obscuration, air permeability, sedimentation in gases or liquids (page 187). However, the values of the particle size distribution used in the present invention are generally obtained by laser diffraction analysis techniques (see, for example, http: / / pharmazie-lehrbuch.de / kapitel / 3-1.pdf). More specifically, the particle size distribution is determined, in particular using the complete Mie theory, in particular according to the corresponding "LS 13 320 Laser Diffraction Particle Size Analyzer Instructions For Use PN B05577AB (October 2011)" for the LS 13 Obtained by the present invention with a Beckmann Coulter 320 Laser Diffraction Particle Size Analyzer. These laser diffraction analysis techniques result in a volume-weighted distribution. Here, the contribution of each particle in the distribution is related to the volume of that particle (the same as the mass if the density is uniform), i.e., the relative contribution is proportional to the size. More specifically, the particle size distribution (PSD) according to the present invention is carried out with a 20 g sample of a phosphate binder analyzed with a Beckman Coulter LS laser particle size analyzer equipped with a dry powder system. Apply a run length of about 13’’ and an obscuration of 4%. Use a computer program to calculate the PSD from the cumulative percentage undersize particle size distribution. Further details are shown in Example 4 below.

[0090] Tablet thickness can be measured using a ruler, calipers, screw gauge or any electronic method for measuring dimensions. Such methods are well known and are described in the art, for example, in any analytical chemistry textbook or in the United States Pharmacopeia (USP) publication USP-NF (2004) which describes the standards with the force of the United States Food and Drug Administration (FDA).

[0091] The present invention particularly provides a compressed tablet or a direct compression tablet, especially a chewable tablet, which can disintegrate in water within a period of less than 30 minutes, or preferably between 5 and 25 minutes, according to the British Pharmacopoeia test defined herein for dispersible tablets, resulting in a dispersion that can pass through a sieve screen having a mesh aperture of 710 μm.

[0092] Preferably, the disintegration time of the tablets according to the present invention is less than 20 minutes, more preferably less than 18 minutes and most preferably less than 20 minutes, even more preferably between 12 and 20 minutes.

[0093] Furthermore, the disintegration time and relatively fine dispersion obtained with the tablets according to the invention are also advantageous with respect to phosphate absorption capacity. Thus, the tablets according to the invention can be provided to disintegrate in water or in the oral cavity as chewable tablets, and also to be swallowed directly. The tablets according to the invention intended to be swallowed are preferably film-coated to facilitate application.

[0094] The invention also relates to the use of particles, in particular particles comprising scorodite, as a phosphate binder for preparing pharmaceutical compositions, in particular compressed or direct compression tablets, wherein at least 40% by volume, preferably 60% by volume, most preferably 80% by volume, even more preferably 90% by volume of the particles in the particle size distribution, in particular scorodite particles, are between 4 and 200 μm, preferably between 5 and 160 μm, or in the range of 21 to 160 μm.

[0095] The invention also relates to the use of a phosphate binder, in particular particles comprising scorodite, for preparing compressed or direct compression tablets, wherein the phosphate binder has a d50 in the particle size distribution between 40 μm and 80 μm, or between 42 μm and 75 μm.

[0096] The invention also relates to the use of a phosphate binder, in particular particles comprising scorodite, for preparing pharmaceutical compositions or compressed or direct compression tablets, i) the phosphate binder has a d50 in the particle size distribution between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 108 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, or between 42 μm and 75 μm, and / or ii) at least 40% by volume, preferably 60% by volume, most preferably 80% by volume, even more preferably 90% by volume of the scorodite particles have particles in the particle size distribution between 4 and 200 μm, or preferably between 5 and 160 μm, or between 21 and 160 μm.

[0097] In a more preferred embodiment, the pharmaceutical composition can be further mixed with at least one pharmaceutically acceptable excipient and is in the form of a powder or granules, most preferably in the form of a powder when directly compressing the pharmaceutical formulation into tablets or using it for granules.

[0098] In a preferred embodiment, the pharmaceutical formulation preferably used contains a lubricant, preferably magnesium stearate.

[0099] In addition to the active ingredient (phosphate binder particles), the pharmaceutical composition (e.g., tableting powder or tableting granules) may contain several inert materials known as excipients (or pharmaceutically acceptable excipients). These can be classified according to the role they play in the final tablet. Excipients are selected to assist in processing and improve the properties of the final product and can be classified according to the role they play in the final tablet. These can include fillers, binders or diluents, lubricants, disintegrants and glidants. Other excipients that contribute to the physical properties of the finished tablet include, for example, colorants and, in the case of chewable tablets, flavoring agents. Typically, excipients are added to the formulation to impart excellent flow and compression properties to the material being compressed. Such excipients and corresponding ranges are described in particular in International Patent Application Publication No. WO 2009 / 06993. Typically, excipients are added to the entire pharmaceutical composition at 35% by weight or less (on a dry weight basis).

[0100] In a preferred embodiment, the present invention relates to a pharmaceutical composition or a compressed tablet as described herein, preferably a direct compression pharmaceutical tablet, in which at least one pharmaceutically acceptable excipient is used in an amount of, for example, 0.01 wt% to 10 wt%, or 0.01 wt% to 6 wt%, or 0.1 wt% to 6 wt% (on a dry weight basis). In a most preferred embodiment using scorosic iron oxyhydroxide (essentially consisting of iron(III) oxyhydroxide stabilized by sucrose and starch, i.e., excluding impurities, i.e., generally more than 95 or 98 wt%) as the phosphate binder particles, as additional excipients, only those selected from flavoring agents, sweetening agents or taste enhancers, lubricants or lubricating agents (the latter are preferably selected from magnesium stearate or colloidal silica, e.g., Aerosil®) are used in an amount of up to 10 wt%, preferably up to 6 wt%, more preferably up to 3 wt% (on a dry weight basis).

[0101] In a preferred embodiment, the present invention relates to a pharmaceutical composition or a compressed tablet as described herein, preferably a direct compression pharmaceutical tablet, in which at least one pharmaceutically acceptable excipient is a lubricant, preferably magnesium stearate and a flavoring agent.

[0102] One, two, three or more diluents or fillers can be selected as further pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, for example, powdered sugar, compressed sugar, dextran, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, scroll and talc. Preferred diluents include, for example, microcrystalline cellulose. Microcrystalline cellulose is available from several suppliers. Suitable microcrystalline cellulose includes Avicel products manufactured by FMC Corporation. Another diluent is, for example, lactose. The diluent and filler can be present, for example, in amounts of about 0.1 wt% to 20 wt% and about 0.5 wt% to 40 wt% of the composition, respectively.

[0103] One, two, three, or more disintegrants can be selected. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, for example, starch; clay; cellulose; alginates; gums; cross-linked polymers such as cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose calcium, and cross-linked carboxymethylcellulose sodium; soy polysaccharide; and guar gum. The disintegrant can be present, for example, in an amount of about 0.01% to about 10% by weight of the composition. The disintegrant is also an optional but useful component of the tablet formulation. Ensure that the tablet has an acceptable disintegration rate, including the disintegrant. Typical disintegrants include starch derivatives and salts of carboxymethylcellulose. Sodium starch glycolate is a preferred disintegrant for this formulation.

[0104] One, two, three or more lubricants can be selected. Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, talc, tricalcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, stearic acid, polyethylene glycol, and glyceryl behenate. The lubricant can be present, for example, in an amount of about 0.01 to 10% by weight, or 0.1% to about 6% by weight of the composition, while the glidant can be present, for example, in an amount of about 0.01 to 10% by weight, or about 0.1% to about 10% by weight. Typically, a lubricant is added to prevent the tablet blend from sticking to the punches, minimize friction during tablet compression, and enable removal of the compressed tablets from the die. Such lubricants are generally included in the final tablet mixture in an amount of usually about 2% by weight or less. The lubricant component can be hydrophobic or hydrophilic. Examples of such lubricants include, for example, stearic acid, talc, and magnesium stearate. Magnesium stearate reduces the friction between the die wall and the tablet mixture during tablet compression and removal. This helps prevent the tablet from sticking to the punches and die. Magnesium stearate also aids in the flow of the powder into the hopper and die. The preferred lubricant magnesium stearate is also used in the formulation. Preferably, the lubricant is present in the tablet formulation in an amount of about 0.01 to 10% by weight, or about 0.1% to about 6% by weight of the composition; more preferably about 0.1% to about 4% by weight; most preferably at a level of about 0.1% to about 2% by weight. Other possible lubricants include talc, polyethylene glycol, silica, and hydrogenated vegetable oil. In any embodiment of the present invention, the lubricant is not present in the formulation, but instead of adding it directly to the formulation, it is sprayed onto the die or punches.

[0105] Furthermore, tablets usually contain a diluent or filler added to increase the bulk weight of the blend that provides the particle size for compression (usually when the drug dose is low).

[0106] Conventional solid fillers or carriers are substances such as, for example, corn starch, calcium phosphate, calcium sulfate, calcium stearate, glyceryl mono- and distearate, sorbitol, mannitol, gelatin, natural or synthetic gums (such as carboxymethyl cellulose, methyl cellulose, alginates, dextran, acacia gum, karaya gum, locust bean gum, tragacanth, etc.), and diluents, binders, disintegrants, coloring and flavoring agents may optionally be used.

[0107] A binder is an agent that imparts agglomeration properties to a powdery material. Examples of pharmaceutically acceptable binders as excipients include, but are not limited to, starch, sugars; cellulose and its derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methyl cellulose; sucrose; glucose; dextrose, lactose dextrose; corn syrup; polysaccharides; and gelatin. During clinical trials, the Applicant further understood that the taste of phosphate binders was not acceptable to the subjects and directly affected the compliance (treatment adherence) of the treatment. For clarity, it should be noted that sucrose and starch, which are part of the active ingredient sucroxy iron hydroxide or PA21, are not counted as excipients such as the binders, sweeteners, etc. listed herein.

[0108] In a further embodiment, the formulations, compositions and tablets of the present invention comprise one or more flavor or taste-masking and coloring additives typically used in oral dosage forms, such as flavoring agents, sweeteners, taste enhancers, coloring agents, etc.

[0109] In a preferred embodiment, the formulations, compositions and tablets of the present invention comprise a flavoring agent having the flavor of woodberry. The woodberry flavor provides excellent compliance and acceptability of the claimed phosphate binder tablets.

[0110] Flavoring agents, such as taste enhancers, flavoring agents and / or natural or artificial sweeteners (including high-intensity sweeteners), are incorporated into oral dosage forms such as chewable dosage forms to impart a pleasant taste or mask unpleasant tastes thereby.

[0111] Typical sweeteners as excipients include, but are not limited to, sugars such as sucrose, fructose, lactose, caster sugar, icing sugar, or polyols such as sorbitol (e.g., Neosorb), xylitol, mannitol, maltose and polydextrose or mixtures thereof. Typical high-intensity sweeteners include, but are not limited to, for example, aspartame, sucralose, acesulfame K and / or saccharin derivatives, or mixtures thereof. Further suitable sweeteners or taste enhancers include, for example, glycosides such as neohesperidin dihydrochalcone (neohesperidin DC or NHDC), glycyrrhizin, glutamate, etc. The latter can be used in extremely small amounts and can thus also be referred to as taste enhancers hereinafter. All of the above are suitable for use alone or as mixtures with other sweeteners and / or flavoring agents. These substances ensure that the sweetness lasts a long time and hide any unwanted aftertaste. Preferred sweeteners and / or taste enhancers include glycosides such as neohesperidin dihydrochalcone.

[0112] In one embodiment, the selected sweetener may be present in an amount of 0.00001 to 2% (w / w), preferably 0.00001 to 0.1% (w / w), most preferably 0.00001 to 0.001% (w / w) with respect to the total weight of the composition.

[0113] The selected taste enhancer may be present in an amount of 0.1 to 50 ppm, preferably 1 to 10 ppm, and most preferably 1 to 5 ppm, based on the total weight of the composition. Typical flavoring agents include any natural and artificial flavoring agents suitable for pharmaceutical use, such as flavoring agents derived from spices, fruits or fruit juices, vegetables or vegetable juices, for example, cocoa, caramel, vanilla, apple, apricot, berries (e.g., blackberry, red currant, black currant, strawberry, raspberry, woodberry, etc.), mint, panettone, honey, nuts, malt, cola, verbena or any combination thereof, for example, flavoring agents based on caramel / vanilla, fruit / cream (e.g., strawberry / cream), etc. In one embodiment, the selected flavoring agent may be present in an amount of 0.01 to 12% (w / w), preferably 0.1 to 6% (w / w), and most preferably 0.1 to 4% (w / w), based on the total weight of the composition.

[0114] Further examples of useful excipients are described in Handbook of pharmaceutical excipients, 3rd edition, edited by A.H. Kibbe, published by American Pharmaceutical Association, Washington D.C., ISBN: 0-917330-96-X or Handbook of Pharmaceutical Excipients (4th edition), edited by Raymond C Rowe - Publisher: Science and Practice, which are incorporated herein by reference.

[0115] The above formulations are particularly suitable for the manufacture of pharmaceutical compositions, such as tablets, compressed tablets or preferably direct compression tablets, caplets or capsules, and provide the necessary physical properties, such as dissolution and drug release profiles, required by prior art dosage forms in the art. Thus, in a further embodiment, the present invention relates to the use of any of the above pharmaceutical compositions, tablets, chewable tablets, granules, caplets or capsules, particularly for granulation, direct compression and dry granulation (slugging or roller compaction).

[0116] The above composition is also particularly useful for the manufacture of tablets, especially compressed tablets, and very preferably direct compression tablets, such as chewable tablets.

[0117] Particularly when processed into the form of direct compression tablets or the direct compression tablets described herein, the tablets obtained with the above composition have favorable abrasion degree characteristics, extremely excellent breaking strength, improved manufacturing robustness, optimal hygroscopicity, hardness, compressibility, chewability, especially a low residual water content for direct compression tablets, and a short disintegration time DT (less than 30 minutes) according to the British Pharmacopoeia 1988, which results in a fine dispersion with a favorable particle size distribution after disintegration. However, the disintegration time DT value claimed in this application was obtained by the European Pharmacopoeia (EP) 04 / 2011:20901 prescribed methodology.

[0118] Preferably, the above compressed tablets (such as direct compression tablets) have a disintegration time of less than 30 minutes, preferably between 5 and 20 minutes.

[0119] Preferably, the above compressed tablets (including direct compression tablets) have a tablet hardness including between 70 N and 250 N, or between 80 and 200 N, preferably between 100 N and 230 N, and an abrasion degree between 0% and 7% or between 0.5% and 7%.

[0120] The direct compression of the phosphate binders of the present invention, particularly scorodite, involves blending and compression. In particular, the selection of the grade of excipient added to the claimed scorodite particles is maintained within a range that enables the homogeneity of the powder mixture and the content uniformity of the phosphate binder particles, particularly scorodite particles, in the final dosage form. Taking into account the particle size range of the scorodite particles, as previously explained, the particle size distribution of the selected additional excipients included in the pharmaceutical formulation or composition or tablet is preferably similar to that of the phosphate binder particles, preferably scorodite particles. This prevents the separation of particles in the hopper during direct compression. The advantages of using the claimed pharmaceutical composition are that the composition imparts compressibility, cohesiveness (which is reduced), and flowability (which is increased) to the powder blend. Furthermore, the use of direct compression provides competitive unit production costs, shelf life, removes heat and moisture, enables dissociation of the main particles, physical stability, and guarantees particle size uniformity.

[0121] The described advantages of the claimed pharmaceutical composition are also extremely useful, for example, for roller compaction or wet granulation, or for filling sachets or capsules.

[0122] In a further embodiment, the pharmaceutical compositions and tablets (e.g., direct compression tablets) described and claimed herein include one or more additional phosphate binders, preferably one or two additional phosphate binders.

[0123] Preferred additional phosphate binders are, in particular, organic polymers such as sevelamer hydrochloride. Management of phosphate levels is one of the primary treatments for CKD-MBD to reduce serum phosphate concentration using phosphate binders. Sevelamer is marketed by Genzyme under the trade names Renagel® (hydrochloride) and Renvela® (carbonate formulation).

[0124] Other phosphate binders that can be used include, in particular, calcium, magnesium, aluminum, iron, lanthanum and bismuth salts which are more soluble than the corresponding phosphates of these cations. Further, phosphate-binding organic polymers having an anion-exchange function such as AMG 223 (Amgen) and MCI-196 (Colestilan, Mitsubishi) are substances suitable for the present invention. Suitable aluminum salts include all pharmaceutically acceptable salts that meet the above requirements, in particular oxides, in particular algeldrate and / or hydroxides. Lanthanum carbonate, including all pharmaceutically acceptable salts that meet the above requirements, in particular its hydrates, is suitable as a lanthanum salt. All pharmaceutically acceptable salts that meet the above requirements, preferably chlorides, sulfates, hydroxides, oxides, carbonates and in particular heavy magnesium carbonate are suitable as magnesium salts. Preferred phosphate binders based on metal salts are, for example, Fermagate and calcium salts, preferably calcium carbonate and / or calcium chloride, and particularly preferably calcium acetate.

[0125] The present invention also encompasses any of the pharmaceutical compositions or tablets claimed herein above that comprise a second phosphate binder selected from, for example, sevelamer hydrochloride formulations (Renagel®), sevelamer carbonate formulations (Renvela®), calcium, magnesium, aluminum, iron, lanthanum salts and bismuth salts.

Examples

[0126] Example 1: The tablets prepared as described above herein can be tested as follows. Tablet evaluation method 1. Average tablet weight Weigh 20 tablets on an analytical balance and calculate the average tablet weight. 2. Tablet breaking strength N Test 5 tablets individually using a Schleuniger crushing strength tester and calculate the average breaking strength. 3. Abrasion degree (loss %) Ten tablets accurately weighed are subjected to an abrasion degree test for 10 minutes using a Roche Friabilator (described and measured under the conditions of Example 4 (C)). The tablets are dusted off, reweighed, and the weight loss due to abrasion degree is calculated as a percentage of the initial weight. The abrasion degree data and values claimed in this application are measured using a Roche abrasion meter in accordance with the European Pharmacopoeia 01 / 2010:20907. 4. Disintegration time DT (as defined in the European Pharmacopoeia 04 / 2011:20901) Six tablets are tested by the EP test defined above. 5. Dispersion quality For dispersible tablets, in accordance with the BP uniformity of the dispersion test (BP 1988 Volume 2, page 895), two tablets are placed in 100 ml of water at 19 - 21 °C and dispersed.

[0127] Granule evaluation method 1. Loss on drying (LOD) The residual moisture content (LOD) of the granules can be measured on a 3 - 4 g sample using a Mettler moisture meter set at 105 °C for 10 minutes, operated in accordance with the manufacturer's procedure. 2. Particle size distribution (PSD) A 20 g sample of iron oxyhydroxide as a phosphate binder is analyzed using a Beckman Coulter LS 13 320 laser particle size analyzer equipped with a dry powder system, particularly using the complete Mie theory and in accordance with the corresponding "LS 13 320 Laser Diffraction Particle Size Analyzer Instructions For Use PN B05577AB (October 2011)". These laser diffraction analysis techniques result in a volume - weighted distribution (see, for example, Figure 2). Apply a run length of approximately 13'' and an obscuration of 4%. Use a computer program to calculate the PSD from the cumulative volume percentage undersize particle distribution.

[0128] Example 2: Improved manufacturing robustness Using different formulations of iron oxyhydroxide containing different excipients, such as magnesium stearate, perform a preliminary formability determination using a Kilian press. The data demonstrate that the pharmaceutical compositions claimed by the present applicants exhibit a substantially useful increase in tablet strength when compressed at increasing levels of pressure (compressive force). In particular, for example, a mixture of scorloxy iron hydroxide and magnesium stearate exhibits a substantially useful increase in tablet strength when the scorloxy iron hydroxide is within the claimed particle size distribution. These results indicate that the claimed formulations provide a clear improvement from a compressibility perspective. Increasing the pressure (compressive force), the formulations claimed by the present applicants exhibit a substantially useful increase in tablet strength. A compressibility test is performed on a Fette 102i press equipped with force and displacement sensors for both the upper and lower punches. From these data, it is evident that scorloxy iron hydroxide tablets will likely have poor hardness / crush strength unless appropriate particle sizes are selected. The formulations claimed by the present applicant are particularly suitable for providing the required formability.

[0129] Example 3: Abrasion Degree Alternatively, the evaluation can be performed using a Fette 2200 press at six different settings: strain rate settings of 30,000 - 70,000 tablets / hour and a main compressive force of 35 - 55 kN. The test uses a flat face bevel edge (FFBE) tool with a diameter of 20 mm for tablets weighing 2577.5 mg (other diameters can be used depending on the weight of the tablets to be tested). The abrasion degree data and values claimed in the present application were measured using a Roche abrasion meter in accordance with the European Pharmacopoeia 2.9.7. The total tablet weight was selected such that both 20 mm FFBE tablets had 2500 mg of scorloxy iron hydroxide and the same tablet thickness. The results of the measured abrasion degree, compression profile, strain rate profile, and weight variation are presented. Using the test design and the abrasion degree results obtained from the test, variables (particle size distribution of the formulation, tablet weight, tablet thickness and weight, water content in the tablet, etc.) that affect the hardness results are determined.

[0130] Example 4: Particle Size Distribution Measured by Laser Diffraction Particles in the range of 1 to 200 μm, or 4 to 200 μm, or 5 to 160 μm, or 21 to 160 μm, or the d50 in the particle size distribution is between 30 μm and 120 μm, 35 μm and 110 μm, or 40 μm and 100 μm, or preferably between 40 μm and 80 μm, or between 42 μm and 75 μm, and a schrooxihydroxy iron particle size distribution particularly suitable for manufacturing the formulations described herein, especially direct compression tablets, can be produced as follows.

[0131] The methods and values described in Example 4 below form the basis for supporting the values included in this claim. 1. Preparation of particle size distribution via schrooxihydroxy iron applied to direct compression tablets The applicant has discovered a particle size distribution that is particularly suitable for direct compression tablets of phosphate binders, especially a particle size distribution of schrooxihydroxy iron (e.g., having (more than 50% by volume) particles mainly between 10 and 152 μm) (or having a d50 of a particle size distribution between 40 μm and 80 μm, or preferably between 42 μm and 75 μm). Improved results are obtained with a d50 of a particle size distribution between 30 μm and 120 μm, or 35 μm and 110 μm, or 40 μm and 108 μm, or 40 μm and 100 μm, or preferably between 40 μm and 80 μm, or preferably between 42 μm and 75 μm. The particle size distribution measured by the laser diffraction method is preferably specified as follows: d10 is 5 μm or more, d50 is 35 μm or more, preferably between 40 μm and 80 μm, or between 42 μm and 75 μm, and d90 is 380 μm or less. The particle size was measured by laser diffraction.

[0132] Equipment: Measuring device: For example, LS 13 320 Laser Diffraction Particle Size Analyzer of Beckmann Coulter, Beckman Coulter International S.A. Switzerland Sample Module: Vacuum Pressure Dispersion System, e.g., Dry Powder System (Tornado), Beckman Coulter International S.A. Switzerland

[0133] Conditions: Average vacuum: 25 - 30’’H2O; Observation about 48 - 10%; Run length about 25 seconds.

[0134] Procedure: Introduce 20 g of the sample into the Dry Powder dispersion system. Measurement: Apply the specified vacuum to move the sample and determine the cumulative volume distribution using a laser light diffraction instrument according to the instruction manual. The parameters may be adjusted so that the test dispersion is representative, homogeneous, and well-dispersed. Evaluation / Judgment: Determine the particle sizes at cumulative volume fractions of 10%, 50%, and 90% (d10, d50, d90), as well as other additional values, from the cumulative volume distribution.

[0135] The particle size distribution of the present invention (particularly, the schwertmannite particle size distribution) can be obtained by the following process, which is a non-limiting example. Alternative processes can be readily implemented by those skilled in the art. A. Manufacturing Process Prepare the schwertmannite raw drug basically as described in European Patent International Publication No. 9722266 or International Patent Application Publication No. 2008 / 062993. Through the manufacturing process of the schwertmannite raw drug (referred to as PA21 in Figure 1 below), a stabilized polynuclear β - iron(III) oxyhydroxide with particularly high phosphate adsorption capacity that is maintained during long-term storage is obtained. The flowchart of the manufacturing process is provided below. This process includes the following steps: · Synthesis of iron(III) oxyhydroxide by precipitation of an iron salt (e.g., iron(III) chloride) with a base (sodium carbonate, which was found to be the best choice). This process was optimized by continuously adding iron(III) chloride and adjusting the stirring speed. ·Desalination: The formed excess sodium chloride is removed by a washing step with water. ·Under constant stirring, preferably at a relative mass ratio of starch:sucrose:iron of 1.5:1.5:1, starch and sucrose are added to the iron(III) oxyhydroxide suspension. This step is carried out to stabilize the iron(III) oxyhydroxide and enable further processing. ·Perform spray drying under the above controlled conditions.

[0136] The resulting iron(III) oxyhydroxide crude drug can be obtained with a desired particle size distribution, particularly by adapting the above spray drying settings using a centrifugal atomization device. By spray drying, different settings of the atomizer of the spray dryer are selected to obtain the desired particle size distribution. This technique is known to those skilled in the art, and the settings depend on the spray dryer equipment used and can be appropriately adapted. Optionally, the resulting iron(III) oxyhydroxide crude drug can be further processed by other well-known techniques such as mechanical stress to obtain the desired particle size distribution.

[0137] Figure 2 shows the particle size distribution of the obtained PA21 crude drug obtained from the spray drying process and analyzed using the LS 13 320 Laser Diffraction Particle Size Analyzer of Beckmann Coulter.

[0138] B. Mechanical stress Basically, phosphate absorbent particles in a desired particle size range can also be obtained by mechanical stress. This stress can be mediated by impact, shear or compression. In the most commercially available grinding devices, a combination of these principles occurs. For the iron(III) oxyhydroxide obtained by the above manufacturing process, preferably separately from the preferred spray drying process, a mechanical impact or jet mill may be used. The most preferred mechanical impact mill can be equipped with different types of beaters, screens, liners or pin plates. For the process of the present inventors, plate beaters and slit screens 5 *Use an impact mill equipped with 2.5 cm. The impact speed should be variable between 20 - 100 m / s (as peripheral speed) to accommodate any batch - to - batch variation. Use a beater peripheral speed of about 40 - 50 m / s. Excellent results (particle size distribution) can also be obtained by mechanical stress, for example, by roller compaction, milling and / or sieving. Other techniques described in the art and commonly used by those skilled in the art can also be used to obtain the targeted particle size range. To evaluate the compressibility of API (Active Pharmaceutical Ingredient: scorloxy iron hydroxide) batches with different particle size distributions, different API batches covering the range of about 40 μm - 110 μm were selected.

[0139] Properties of the selected scorloxy iron hydroxide API batches:

Table 1

[0140] C. Tablet Compression Equipment: Tableting process: Rotary Killian E 150 equipped with 20 mm flat - face punches Tablet hardness: Five tablets are individually tested using a Schleuniger crushing strength tester, and the average breaking strength is calculated. Tablet hardness is measured according to European Pharmacopoeia 01 / 2008:20908. Tablet thickness: Five tablets are individually measured using calipers, and the average thickness is calculated. Tablet friability: Friability is measured using a Roche friabilator according to European Pharmacopoeia 01 / 2010:20907. Average mass: Ten tablets are weighed, and the average mass is calculated. Six tablets are subjected to disintegration (as defined in European Pharmacopoeia 04 / 2011:20901) using standard equipment (Sotax DT3 disintegration tester).

[0141] 1. Preparation of Pharmaceutical Powder All different API batches (with different particle size ranges) were formulated into powders containing goethite particles in the following composition (pharmaceutical formulation):

Table 2

[0142] 2. Preparation of Compressed Tablets The following equipment was used for the preparation of the blend: Tumbling blender (Roehnrad Engelsmann), Quadro comill 193 Magnesium stearate, silica and neohesperidin DHC of PhEur quality were purchased. The selected flavoring agents are standard flavoring agents used in food and pharmaceutical products. The same manufacturing process by direct compression was applied to all API batches to compare their processability. The manufacturing process consisted of: · Sieving and blending of all components · Lubrication by addition of magnesium stearate · Tableting on a rotary tableting machine into two-plane tablets with a diameter of 20 mm The tablet weight was adjusted according to the drug substance assay to obtain a nominal dose of 500 mg of iron, i.e., 2500 mg of goethite. In order to optimize the hardness of the tablets, tableting tests were carried out. For the 20 mm tablets, a hardness of at least 100 N is required in order to be able to fill the tablets into standard packaging without damage or breakage of the tablets.

[0143] The following tableting tests were carried out:

Table 3

[0144] Based on the knowledge in the art, for large tablets such as the developed high-load direct compression tablets (i.e., 2500 mg of sucroxy iron hydroxide), the ideal d50 should be between 200 and 350 μm. No one would have expected that the claimed small particle size of sucroxy iron hydroxide could result in improved tablets (direct compression high-load tablets), i.e., could bring about improved physical properties. Surprisingly, sucroxy iron hydroxide particles with a d50 of 109 μm (batch number 030609-02) were still acceptable but could not result in tablets with the most preferred target hardness. The compression force reached up to 83 N on the tableting machine, and at this point, the compression force was already at its maximum, and the noise of the machine forced the inventors to stop the experiment so as not to damage the tableting machine. The tablets were compressed to the minimum thickness, but the inventors obtained the minimum hardness. Surprisingly, with E222X383B with a d50 of 43 μm and E222X382B with a d50 of 75 μm in the tableting test, an increase in compression force and an increase in hardness were obtained (which was not the case for the batch with a d50 of 109 μm). For such batches (d50 above 109 μm), it was impossible to obtain tablets with improved hardness using any compression force. Therefore, a d50 of about 109 μm is still the upper limit within the acceptable range. Therefore, a reasonable upper limit is in the range of 110 or 120 μm. At 120 μm, the hardness should be about 80 N or slightly lower than 80 N.

[0145] Tests conducted on sucroxy iron hydroxide particles with a d50 in the range of 42 - 75 μm revealed surprisingly excellent compressibility of the material, enabling targeting a maximum hardness of 140 N. Sucroxy iron hydroxide particles with a d50 of less than about 42 μm were considered not very suitable for tableting because they caused too much loss of the material in the rotary tableting machine. Based on the experimental evaluation, the improvements claimed above are observed with schwertmannite particles having a d50 between 30 μm and 120 μm, or between 35 μm and 110 μm. The best results are observed with schwertmannite (API) particles having a d50 between 40 μm and 108 μm, between 40 μm and 100 μm, or preferably between 40 μm and 80 μm. Figure 3 demonstrates that schwertmannite (API) particles having a d50 between 40 and 80 μm are particularly preferred to obtain at least 100 N. The disintegration time obtained with schwertmannite particles having a d50 of 109 μm (batch 030609-02) for 83 N tablets was 300% higher (19'51'') than that obtained with an API having a d50 of 42 μm (110709-01) and a similar hardness (88 N) that disintegrated in 6'28''. Such a difference can affect the dissolution time of the tablets and is thus less preferred. To confirm the excellent compressibility of the schwertmannite particles, the compression profile was investigated in an additional batch having a d50 of 50.3 μm.

[0146] Tablet batch 1260111 manufactured with a rotary tableting machine gave the following results:

Table 4

[0147] Example 5: Alternative test for testing the chewability of the compressed chewable tablets of the present invention (Diameter or radius) Pharmacopoeial tests for hardness (crushing resistance Ph.Eur. 2.9.8), abrasion (Ph.Eur. 2.9.7) and disintegration (Ph.Eur. 2.9.1) are carried out using standard equipment (Erweka TBH 220 hardness tester, Erweka TA120 abrasion tester with standard drum and wear drum (or Roche abrasion meter), and Sotax DT3 disintegration tester). To avoid any confusion, the abrasion values claimed in this application are measured using a Roche abrasion meter in accordance with Ph.Eur. 01 / 2010:20907, the disintegration values claimed in this application are measured in accordance with Ph.Eur. 04 / 2011:20901 using standard equipment (Sotax DT3 disintegration tester), and it is emphasized that the tablet hardness values claimed in this application are measured using a Schleuniger crushing strength tester, i.e., under the conditions described in Example 4 in accordance with Ph.Eur. 01 / 2008:20908).

[0148] Furthermore, axial hardness (ring and tube tests), and crushing characteristics (flat plate tests) are also measured using a texture analyzer (TAXt2i® Texture Analyser Stabel Micro Systems Ltd, Godalming, UK) which is used to measure the texture of a wide variety of materials. In addition, a Kramer shear cell manufactured by Instron High Wycombe, UK ( ) and a Typodont D85SDP - 200 Model manufactured by Kilgore International Inc, Coldwater, Michigan, USA ( ) which are used in the food industry to provide information about chewiness, crispness and hardness are also used in this test to test the chewability of tablets. The load is applied to the Typodont Model by the texture analyzer (this means that the Typodont model is attached to the texture analyzer for the tests carried out here).

[0149] The following tests are carried out on both dry tablets and tablets moistened with artificial saliva. Artificial saliva is prepared according to Klimek (1982) (Original: Matzker and It was prepared according to the modified prescription of Schreiber (1972). Ascorbic acid 0.002 g / l Glucose 0.030 g / l NaCl 0.580 g / l CaCl2 0.170 g / l NH4Cl 0.160 g / l KCl 1.270 g / l NaSCN 0.160 g / l KH2PO4 0.330 g / l Urea 0.200 g / l Na2HPO4 0.340 g / l Mucin 2.700 g / l The prepared solution (500 ml) was refrigerated (4 - 6 °C) due to its limited shelf life.

[0150] Ring test In this test, a plastic tool simulates a tooth on which a tablet is loaded, and a ring simulates the lower jaw. The ring test is close to an actual biting event. Ring outer diameter d a is 20 mm. Since the metal of the ring is 3 mm thick, the inner diameter, and as a result the diameter d of the central cavity i is 14 mm. The plastic tool with a rounded contact part is a standard component of the texture analyzer. The descending speed of the plastic tool was 2 mm / second. Using a load cell of 50 KG, the moving distance was set to 5 mm, and the texture operation mode was set to "return to start". Furthermore, the ring test is essentially the axial fracture strength. The tablet is placed on the ring. The force F max at which fracture occurs is recorded. The energy exerted (the area under the force - displacement curve) is calculated. The test is performed on dry tablets and wet tablets (moistened by immersing in artificial saliva for 10 seconds with tweezers).

[0151] Flat plate test The flat plate test measures the penetration depth by applying the maximum force for repeated loading, thus simulating the effect of tooth penetration during repeated chewing movements. Here, the tablet is placed on the grooved back surface of the substrate of the texture analyzer, and force is repeatedly applied to the tablet to simulate the repeated chewing movement. The texture analyzer test setting was the "cycle mode up to count" with a load intensity (35 N for a descent rate of 0.2 mm / sec) selected that does not break the tablet. The approach speed (preliminary test speed) was set to 0.5 mm / sec for increased sensitivity. The applied force at which the texture analyzer starts the actual measurement was set to 0.0493 N, which is called the trigger. A typical force-displacement curve for 10 cycles is shown. The flat plate test measures the penetration depth by applying the maximum force for repeated loading. Other tests such as the tube test, Kramer shear cell test, or Typodont model test can be performed.

[0152] Conclusion: The texture tester in the ring test mode (resulting in axial fracture strength) is considered to best characterize the chewability characteristics of the scorloxy iron hydroxide direct compression tablets of the present invention. The chew quality of the tablets of the present invention is confirmed by the test. To provide in vitro evidence of the chew quality of chewable tablets, several tests are evaluated. The results are compared with the results of two commercially available chewable tablets. Among the tests that more closely mimic the actual chewing movement, the texture analyzer in the flat plate test mode is considered the most reliable, and it was found that tablets moistened with artificial saliva in particular are the most discriminatory and useful. The scorloxy iron hydroxide tablets manufactured within a target radius hardness of about 130 N worked well in this test, showing excellent chewing characteristics even at a deformation of 14I (radius hardness 231.2 N), and a suitable storage life of 230 N was confirmed.

[0153] The scorloxy iron hydroxide tablets within the target radius hardness limit are close to the best non-phosphate binder product (tablet A - Calcimagon (registered trademark)) and showed better chewability than the best phosphate binder competitor (tablet B - Fosrenol (registered trademark)) in these tests. For patient compliance, it is advantageous that the chewable tablets disintegrate even if chewing is incomplete for some reason, and the robustness of the tablets is sufficient to allow for proper handling and transportation. The scorloxy iron hydroxide tablet deformation meets this requirement.

[0154] Preferred embodiments of the present invention The following summarizes particularly preferred embodiments of the present invention. 1. Embodiment: A compressed tablet containing a phosphate binder, wherein the phosphate binder comprises particles having a particle size distribution with particles in the range of 4 to 200 μm. Preferably, the phosphate binder consists of said particles.

[0155] 2. Embodiment: A compressed tablet according to Embodiment 1 containing a phosphate binder, wherein the phosphate binder comprises particles having a particle size distribution with at least 40% of the particles having a particle size in the range of 4 to 200 μm.

[0156] 3. Embodiment: A compressed tablet containing a phosphate binder, wherein the phosphate binder comprises particles having a particle size distribution with a d50 in the range of 40 μm to 80 μm.

[0157] 4. Embodiment: A compressed tablet according to any of the above embodiments, wherein the phosphate binder contains iron(III) oxyhydroxide.

[0158] 5. Embodiment: A compressed tablet according to any of the above embodiments, wherein the phosphate binder contains iron(III) oxyhydroxide and at least one carbohydrate.

[0159] 6. Embodiment: A compressed tablet according to any of the preceding embodiments, wherein the phosphate binder comprises iron(III) oxyhydroxide and sucrose.

[0160] 7. Embodiment: A compressed tablet according to any of the preceding embodiments, wherein the phosphate binder comprises iron(III) oxyhydroxide, sucrose and at least one starch.

[0161] 8. Embodiment: A compressed tablet according to any of the preceding embodiments, comprising in particular phosphate binder particles of iron(III) oxyhydroxide and at least one further pharmaceutically acceptable excipient, wherein at least 40%, or at least 60%, or at least 80%, or at least 90% of the particles in the phosphate binder particle size distribution of the tablet are between 4 and 200 μm, or between 5 and 160 μm, or between 21 and 160 μm.

[0162] 9. Embodiment: A compressed tablet comprising in particular phosphate binder particles of iron(III) oxyhydroxide and at least one further pharmaceutically acceptable excipient, wherein the phosphate binder particles have a particle size distribution with a d50 between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, or between 42 μm and 75 μm.

[0163] 10. Embodiment: A compressed tablet according to any of the preceding embodiments, wherein the phosphate binder particles have a particle size distribution with a d50 between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, or between 42 μm and 75 μm.

[0164] 11. Embodiment: The compressed tablets according to any of the preceding embodiments, wherein the phosphate binder particles have a particle size distribution having a d50 between 40 μm and 80 μm, and at least 60%, or at least 80% of the particles of the phosphate binder particle size distribution of the tablets are between 4 and 200 μm, or between 5 and 160 μm, or are intermediate between 21 and 160 μm.

[0165] 12. Embodiment: i) The phosphate binder particles have a particle size distribution having a d50 between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, or between 42 μm and 75 μm, and / or ii) The hardness of the tablets is between 70 and 250 N, and / or iii) The tablet abrasion degree is between 0% and 7%, or between 0.05% and 7%, and / or iv) The tablets have a disintegration time of less than 30 minutes, or between 5 and 20 minutes, and / or v) The tablet diameter is between 16 mm and 30 mm, the tablet weight is between 1500 mg and 3000 mg (preferably between 2000 and 3000 mg), and the tablet thickness is between 4.5 mm and 7.5 mm. The compressed tablets according to any of the preceding embodiments.

[0166] 13. Embodiment: i) At least 40%, or at least 60%, or at least 80%, or at least 90% of the particles in the phosphate binder particle size distribution of the tablets are between 4 and 200 μm, or between 5 and 160 μm, or between 21 and 160 μm, and ii) The phosphate binder particles have a d50 in a particle size distribution between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, or between 42 μm and 75 μm, and iii) The hardness of the tablets is between 70 and 250 N, and iv) The tablet abrasion degree is between 0% and 7%, or between 0.05% and 7%, and v) the tablet has a disintegration time of less than 30 minutes, or between 5 and 20 minutes, and vi) the tablet diameter is between 16 mm and 30 mm, the tablet weight is between 1500 mg and 3000 mg, and the tablet thickness is between 4.5 mm and 7.5 mm, The compressed tablet according to any of the above embodiments.

[0167] 14. Embodiment: i) at least 60%, or at least 80%, or at least 90% of the particles in the phosphate binder particle size distribution of the tablet are between 5 and 160 μm, and ii) the phosphate binder particles have a d50 in a particle size distribution between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, and / or iii) the hardness of the tablet is between 70 and 250 N, and / or iv) the tablet abrasion degree is between 0% and 7%, or between 0.05% and 7%, and / or v) the tablet has a disintegration time of less than 30 minutes, or between 5 and 20 minutes, and / or vi) the tablet diameter is between 16 mm and 30 mm, the tablet weight is between 1500 mg and 3000 mg (preferably between 2000 and 3000 mg), and the tablet thickness is between 4.5 mm and 7.5 mm, and / or vii) the tablet contains 800 mg to 3000 mg of sucroseoxy ferric hydroxide, The compressed tablet according to any of the above embodiments.

[0168] 15. Embodiment: i) at least 80%, or at least 90% of the particles in the sucroseoxy ferric hydroxide particle size distribution are between 4 and 200 μm, or in the middle of 5 and 160 μm, and ii) the sucroseoxy ferric hydroxide particles have a d50 in a particle size distribution between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, and iii) The hardness of the tablets is between 70 and 250 N, and iv) The tablet abrasion is between 0% and 7%, or between 0.05% and 7%, and v) The tablets have a disintegration time of less than 30 minutes, or between 5 and 20 minutes, and vi) The tablet diameter is between 16 mm and 30 mm, the tablet weight is between 1500 mg and 3000 mg or intermediate between 2000 and 3000 mg, and the tablet thickness is between 4.5 mm and 7.5 mm, and vii) The tablets contain 1500 mg to 3000 mg of sclerooxy ferric hydroxide, The compressed tablets according to any of the preceding embodiments.

[0169] 16. Embodiment: The compressed tablets according to any of the preceding embodiments, which are direct compression pharmaceutical tablets.

[0170] 17. Embodiment: A pharmaceutical formulation or composition comprising phosphate binder particles, particularly those containing sclerooxy ferric hydroxide, and at least one further pharmaceutically acceptable excipient, wherein the phosphate binder particles have a d50 in the particle size distribution between 40 μm and 105 μm, between 40 and 100 μm, between 40 μm and 80 μm, or intermediate between 42 μm and 75 μm.

[0171] 18. Embodiment: A pharmaceutical formulation or composition comprising phosphate binder particles, particularly those containing sclerooxy ferric hydroxide, and at least one further pharmaceutically acceptable excipient, wherein at least 40%, or at least 60%, or at least 80%, or at least 90% of the phosphate binder particles in the particle size distribution are between 4 and 200 μm, or between 5 and 160 μm, or between 21 and 160 μm.

[0172] 19. Embodiment: The pharmaceutical preparation or pharmaceutical composition according to embodiment 17 or 18, wherein at least 40%, or at least 60%, or at least 80%, or at least 90% of the phosphate binder particles in the particle size distribution are between 4 and 200 μm, or between 5 and 160 μm, or between 21 and 160 μm.

[0173] 20. Embodiment: The tablet or pharmaceutical composition according to any of the above embodiments, wherein the phosphate binder particles, particularly the schrock oxyhydroxide iron phosphate binder particles, are more than 65% by weight, or more than 80% by weight, or more than 90% by weight, or more than 95% by weight of the total weight (dry weight basis) of the tablet or pharmaceutical composition.

[0174] 21. Embodiment: The tablet, pharmaceutical preparation or pharmaceutical composition according to any of the above embodiments, containing more than 65% by weight, or more than 80% by weight, or more than 90% by weight, or more than 95% by weight, or more than 98% by weight of schrock oxyhydroxide iron particles on a dry weight basis.

[0175] 22. Embodiment: i) The phosphate binder is schrock oxyhydroxide iron, ii) At least 80%, or at least 90% of the schrock oxyhydroxide iron particles in the schrock oxyhydroxide iron particle size distribution are between 4 and 200 μm, or between 5 and 160 μm, iii) The schrock oxyhydroxide iron particles have a d50 in the schrock oxyhydroxide iron particle size distribution between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, iv) The tablet contains between 800 mg and 3500 mg, or between 1500 and 3500 mg of schrock oxyhydroxide iron, v) The schrock oxyhydroxide iron phosphate binder particles are more than 80% by weight, or more than 90% by weight of the total weight (dry weight basis) of the tablet. The compressed tablet according to any of the above embodiments.

[0176] 23. Embodiment: The compressed tablets according to any one of the embodiments, which are chewable tablets.

[0177] 24. Embodiment: The compressed tablets according to any one of the embodiments, wherein the hardness of the tablets is between 70 and 250, or between 85 and 250 N, or between 70 and 200 N, or between 85 and 200 N.

[0178] 25. Embodiment: The tablets or pharmaceutical compositions according to any one of the embodiments, wherein the single oral dosage form contains ferric oxyhydroxide between 800 mg and 3500 mg, or between 1500 mg and 3500 mg, or between 1500 mg and 3000 mg.

[0179] 26. Embodiment: The tablets or pharmaceutical compositions according to any one of the embodiments, wherein the single oral dosage form contains ferric oxyhydroxide between 800 mg and 3500 mg, or between 1500 mg and 3500 mg, or between 1500 mg and 3000 mg, and at least 60%, or at least 80%, or at least 90% of the particles in the phosphate binder particle size distribution of the tablets are between 5 and 160 μm, and the d50 of the phosphate binder particle size distribution is between 40 μm and 80 μm.

[0180] 27. Embodiment: Use of particles containing ferric oxyhydroxide for preparing compressed or direct compression tablets, i) at least 40%, or at least 60%, or at least 80%, or at least 90% of the ferric oxyhydroxide particles in the particle size distribution are between 4 and 200 μm, preferably between 5 and 160 μm, or between 21 and 160 μm, and / or ii) the ferric oxyhydroxide particles have a d50 in the particle size distribution between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, or between 42 μm and 75 μm. Use.

[0181] 28. Embodiment: Use of ferric oxyhydroxide particles for preparing a pharmaceutical composition or a compressed or direct compression tablet, i) the ferric oxyhydroxide particles having a d50 in a particle size distribution between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, or intermediate between 42 μm and 75 μm, and / or ii) at least 40%, or at least 60%, or at least 80%, or at least 90% of the ferric oxyhydroxide particles in the particle size distribution being between 4 μm and 200 μm, or preferably between 5 μm and 160 μm, or between 21 μm and 160 μm, Use.

[0182] 29. Embodiment: Use of the ferric oxyhydroxide particles according to embodiment 27 or 28, wherein the ferric oxyhydroxide is more than 80% by weight, or more than 90% by weight, or more than 95% by weight of the ferric oxyhydroxide particles based on the dry weight of the pharmaceutical composition or the compressed tablet.

[0183] 30. Embodiment: The pharmaceutical preparation according to any one of the preceding embodiments, in the form of a powder or granules which can be further mixed with at least one pharmaceutically acceptable excipient.

[0184] 31. Embodiment: The pharmaceutical preparation according to embodiment 30, in the form of a powder for direct compression into tablets or for use in granules.

[0185] 32. Embodiment: The pharmaceutical preparation, pharmaceutical composition or compressed tablet according to any one of the preceding embodiments, comprising at least one further pharmaceutically acceptable excipient selected from lubricants, preferably magnesium stearate.

[0186] 33. Embodiment: i) At least 40%, or at least 60%, or at least 80%, or at least 90% of the schwertmannite particles in the particle size distribution are between 4 and 200 μm, between 5 and 160 μm, or between 21 and 160 μm, ii) The schwertmannite particles have a d50 in a particle size distribution between 30 μm and 120 μm, between 35 μm and 110 μm, between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, Schwertmannite particles comprising schwertmannite and optionally at least one further pharmaceutically acceptable excipient.

[0187] 34. Embodiment: The tablet, pharmaceutical preparation, pharmaceutical composition or use according to any of the preceding embodiments, wherein the schwertmannite is more than 80% by weight, or more than 90% by weight, or more than 95% by weight of the schwertmannite particles, based on the dry weight of the particles.

[0188] 35. Embodiment: Use of the pharmaceutical composition according to any of the preceding embodiments, still in the form of a powder, for the manufacture of compressed tablets.

[0189] 36. Embodiment: The tablet, pharmaceutical composition or use according to any of the preceding embodiments, wherein at least 50%, or at least 60% of the schwertmannite particles in the particle size distribution have a particle size in the range from 30 to 200 μm, or preferably between 40 and 200 μm.

[0190] 37. Embodiment: The tablet, pharmaceutical composition or use according to any of the preceding embodiments, wherein the embodiment refers to the dry form of the tablet or pharmaceutical composition.

[0191] 38. Embodiment: The tablet or pharmaceutical composition according to any of the preceding embodiments, wherein the schwertmannite particles have a particle size distribution curve as shown in Figure 2.

[0192] 39. Embodiment The tablet or pharmaceutical composition according to any one of the above embodiments, wherein the scorodite hydroxide iron particles have a particle size distribution curve with a peak of the curve between 50 μm and 90 μm.

Claims

1. A pharmaceutical composition comprising a phosphate binder, wherein at least 40% of the particles of the phosphate binder have a particle size in the range of 4 to 200 μm and have a particle size distribution with a d50 in the range between 30 μm and 120 μm, and the phosphate binder particles comprise a mixture of iron(III) oxyhydroxide, sucrose, and one or more starches, said pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, comprising a mixture of starches.

3. The pharmaceutical composition according to claim 1 or 2, which is a compressed tablet.

4. Comprising iron(III) oxyhydroxide as a phosphate binder particle and at least one further pharmaceutically acceptable excipient, wherein at least 40%, or at least 60%, or at least 80%, or at least 90% of the particles in the phosphate binder particle size distribution in the tablet are between 4 and 200 μm, or between 5 and 160 μm, or between 21 and 160 μm, the compressed tablet according to claim 3.

5. Comprising iron(III) oxyhydroxide as a phosphate binder particle and at least one further pharmaceutically acceptable excipient, wherein the phosphate binder particles have a particle size distribution with a d50 between 30 μm and 120 μm, or between 35 μm and 110 μm, or between 40 μm and 100 μm, or preferably between 40 μm and 80 μm, or between 42 μm and 75 μm, the compressed tablet according to claim 3.

6. The phosphate binder particles have a particle size distribution with a d50 between 40 μm and 80 μm, and at least 60%, or at least 80% of the particles in the phosphate binder particle size distribution in the tablet are between 4 and 200 μm, or between 5 and 160 μm, or intermediate between 21 and 160 μm, the compressed tablet according to any one of claims 3 to 5.

7. Satisfying one or more or all of the following characteristics: i) The phosphate binder particles have a particle size distribution with a d50 between 40 μm and 120 μm; ii) The hardness of the tablet is between 70 and 250 N; iii) The tablet abrasion degree is between 0% and 7%, or between 0.05% and 7%; iv) The tablet has a disintegration time of less than 30 minutes, or between 5 and 20 minutes. v) the tablet diameter is between 16 mm and 30 mm, the tablet weight is between 1500 mg and 3000 mg (preferably between 2000 and 3000 mg), and the tablet thickness is between 4.5 mm and 7.5 mm; The pharmaceutical composition according to claim 3.

8. The phosphate binder particles contain scorodite hydroxide and satisfy one or more or all of the following characteristics: i) at least 80% of the particles in the particle size distribution of the phosphate binder are between 4 and 200 μm; ii) the phosphate binder particles have a d50 in a particle size distribution between 40 μm and 120 μm; iii) the hardness of the tablet is between 70 and 250 N; iv) the tablet abrasion degree is between 0% and 7%; v) the tablet has a disintegration time of less than 30 minutes; vi) the tablet diameter is between 16 mm and 30 mm, the tablet weight is between 1500 mg and 3000 mg, and the tablet thickness is between 4.5 mm and 7.5 mm, and vii) the tablet contains scorodite hydroxide between 1500 mg and 3000 mg; The pharmaceutical composition according to claim 3 or 7.

9. The pharmaceutical composition according to any one of claims 3, 7, and 8, which is a direct compression pharmaceutical tablet.

10. The pharmaceutical composition according to any one of claims 3, 7, 8, and 9, wherein the phosphate binder particles exceed 65% by weight of the total weight (dry weight basis) of the tablet.

11. The pharmaceutical composition according to any one of claims 1 to 10, which contains more than 80% by weight of scorodite hydroxide based on the total weight (dry weight basis) of the pharmaceutical composition.

12. The pharmaceutical composition according to any one of claims 1 to 11, which is a chewable tablet.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the single oral dosage form contains scorodite hydroxide between 800 mg and 3500 mg.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the single oral dosage form contains scorodite hydroxide between 1500 mg and 3500 mg.

15. The phosphate binder is scorodite hydroxide, at least 80% of the scorodite hydroxide particles in the particle size distribution are between 4 and 200 μm, and the scorodite hydroxide particles have a d50 in the particle size distribution between 30 μm and 120 μm, The pharmaceutical composition according to claim 3.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the phosphate binder is iron oxyhydroxide, and the iron oxyhydroxide particles have a d50 in the particle size distribution between 35 μm and 110 μm.

17. The pharmaceutical composition according to claim 16, wherein the iron oxyhydroxide particles have a d50 in the particle size distribution between 40 μm and 100 μm.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the phosphate binder has a particle size distribution in which at least 80% by volume, or at least 90% by volume, is in the range of 4 to 200 μm.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the phosphate binder is iron oxyhydroxide, and the iron oxyhydroxide particles contain more than 95% by weight, or further more than 98% by weight, of iron oxyhydroxide based on the dry weight of the particles.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the phosphate binder in the pharmaceutical composition exceeds 65% by weight, or exceeds 80% by weight, of the total weight (dry weight basis) of the pharmaceutical composition.

21. The pharmaceutical composition according to any one of claims 1 to 20, comprising at least one additional pharmaceutically acceptable excipient.

22. The pharmaceutical preparation according to claim 1, 2, or 16 to 21, which is in the form of a powder for manufacturing compressed tablets.

23. The pharmaceutical composition according to any one of claims 1 to 22, for use in the prevention and treatment of hyperphosphatemia, particularly in patients with chronic renal insufficiency.

24. A method for manufacturing the pharmaceutical composition according to any one of claims 1 to 23, comprising the step of spray-drying an aqueous suspension of the phosphate binder particles, and subjecting the aqueous suspension of the phosphate binder particles to micronization before spray-drying.

25. Use of particles containing iron oxyhydroxide for manufacturing a pharmaceutical composition, i) at least 40% of the particles in the particle size distribution are between 4 and 200 μm, and / or ii) the particles have a d50 in the particle size distribution between 35 μm and 110 μm, said use.

26. Use of the preparation according to any one of claims 16 to 22, which is in the form of a powder or granule for compression into tablets.

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