A mixture of iron(III)-oxyhydroxide, sucrose and one or more starches, preferably particles of sucroferric oxyhydroxide.

Abstract

The present invention relates to particles of a mixture of iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide, having a specific particle size distribution, a method for their preparation, and pharmaceutical compositions comprising same in specific compressed tablets.

Description

[Background technology]

[0001] Sucroferric oxyhydroxide is a phosphate binder currently marketed as a chewable tablet under the trade name Velphoro®. WO2009 / 062993(A1) describes a pharmaceutical composition comprising a high loading of ferric oxyhydroxide in a form suitable for oral administration. WO2015 / 078900 describes a pharmaceutical composition comprising a phosphate binder, in particular sucroferric oxyhydroxide, in which the phosphate binder particles have a certain particle size distribution at d50 in the range of 30-120 μm. The sucroferric oxyhydroxide described therein is obtained by a spray drying process, then the powder is blended with further excipients and pressed to obtain a chewable tablet containing 2500 mg of sucroferric oxyhydroxide, corresponding to about 500 mg of iron. For certain applications, especially pediatric applications or in the case of patients with swallowing disorders, a chewable tablet of this size is undesirable. Therefore, the inventors have investigated a different dosage form. In attempting to form smaller tablets, such as microtablets, generally having a diameter of 1-4 mm, the inventors faced an unexpected problem. Apparently due to higher release forces in the microtabletting tooling, the use of known sucroferric oxyhydroxide compositions was found to result in dark brown spots on the edges of the microtablets. The inventors therefore sought a way to solve this problem. Surprisingly, they found that when known sucroferric oxyhydroxide particles obtained by spray drying undergo agglomeration leading to a decrease in smaller particles and an increase in larger particles, the use of such agglomerated sucroferric oxyhydroxide particles in tabletting also allows the production of suitable smaller tablets, in particular microtablets or minitablets. Summary of the Invention

[0002] Thus, the present invention provides particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably particles of sucroferric oxyhydroxide, in which the fraction of particles having a particle size of more than 90 μm is 25% by weight or more, preferably 35% by weight or more, more preferably 40% by weight or more, even more preferably 45% by weight or more, most preferably 50% by weight or more, and preferably the fraction of particles having a particle size of more than 125 μm is 25% by weight or more, preferably 30% by weight or more, more preferably 35% by weight or more, based on the total weight of the particles, each determined by sieve analysis. The sieve analysis is carried out in particular based on the particle size distribution estimation of the European Pharmacopoeia 2.9.38 by analytical sieving, preferably by the following determination method: - Sieving method = mechanical vibration (vibrating sieve shaker, e.g. Retsch AS200) - Sample size = 100g - Sieve rows = 0 (bottom plate), 90, 125, 180, 250, 355, 500 and 710 microns - Amplitude level=1.5 - Duration = 10 minutes

[0003] Preferably, the fraction of particles having a particle size in the range of 90 μm to 125 μm is, based on the total weight of the particles as determined by sieve analysis, 3% by weight or more, More preferably, 4% by weight or more. Even more preferably, it is 5% by weight or more.

[0004] Preferably, the fraction of particles having a particle size in the range of 90 μm to 125 μm is, based on the total weight of the particles as determined by sieve analysis, 20% by weight or less, More preferably, 15% by weight or less. Even more preferably, it is 10% by weight or less.

[0005] Preferably, the fraction of particles having a particle size in the range of 90 μm to 125 μm is, based on the total weight of the particles as determined by sieve analysis, in the range of 3% to 20% by weight, More preferably, the range is 4% by weight to 15% by weight. Even more preferably, it is in the range of 5% to 10% by weight.

[0006] Preferably, the fraction of particles having a particle size in the range of 125 μm to 180 μm is, based on the total weight of the particles as determined by sieve analysis, 3% by weight or more, Preferably, 4% by weight or more. More preferably, it is 5% by weight or more.

[0007] Preferably, the fraction of particles having a particle size in the range of 125 μm to 180 μm is 20% by weight or less, More preferably, 15% by weight or less. Even more preferably 12% by weight or less It is.

[0008] Preferably, the fraction of particles having a particle size in the range of 125 μm to 180 μm is, based on the total weight of the particles as determined by sieve analysis, in the range of 3% to 20% by weight, More preferably, the range is 4% by weight to 15% by weight. Even more preferably, it is in the range of 5% to 12% by weight.

[0009] Preferably, the fraction of particles having a particle size in the range of 180 μm to 250 μm is, based on the total weight of the particles as determined by sieve analysis, 3% by weight or more, Preferably, 4% by weight or more. More preferably, 5% by weight or more It is.

[0010] Preferably, the fraction of particles having a particle size in the range of 180 μm to 250 μm is, based on the total weight of the particles as determined by sieve analysis, 20% by weight or less, More preferably, 15% by weight or less. Even more preferably 10% by weight or less It is.

[0011] Preferably, the fraction of particles having a particle size in the range of 180 μm to 250 μm is, based on the total weight of the particles as determined by sieve analysis, in the range of 3% to 20% by weight, More preferably, the range is 4% by weight to 15% by weight. Even more preferably, it is in the range of 5% to 10% by weight. Preferably, the fraction of particles having a particle size in the range of 250 μm to 355 μm is, based on the total weight of the particles as determined by sieve analysis, 3% by weight or more, Preferably, 4% by weight or more. More preferably, 5% by weight or more It is.

[0012] Preferably, the fraction of particles having a particle size in the range of 250 μm to 355 μm is, based on the total weight of the particles as determined by sieve analysis, 20% by weight or less, More preferably, 16% by weight or less. Even more preferably 13% by weight or less It is.

[0013] Preferably, the fraction of particles having a particle size in the range of 250 μm to 355 μm is based on the total weight of the particles as determined by sieve analysis: in the range of 3% to 20% by weight, More preferably, the range is 4% by weight to 16% by weight. Even more preferably, it is in the range of 5% by weight to 13% by weight.

[0014] Preferably, the fraction of particles having a particle size in the range of 355 μm to 500 μm is, based on the total weight of the particles as determined by sieve analysis, 3% by weight or more, Preferably 5% by weight or more, More preferably, 8% by weight or more. It is.

[0015] Preferably, the fraction of particles having a particle size in the range of 355 μm to 500 μm is, based on the total weight of the particles as determined by sieve analysis, 20% by weight or less, More preferably, 18% by weight or less. Even more preferably, 16% by weight or less It is.

[0016] Preferably, the fraction of particles having a particle size in the range of 355 μm to 500 μm is, based on the total weight of the particles as determined by sieve analysis, in the range of 3% by weight to 20% by weight, More preferably, the range is 5% by weight to 18% by weight. More preferably, the range is 8% by weight to 16% by weight. is located.

[0017] Preferably, the fraction of particles having a particle size in the range of 500 μm to 710 μm is, based on the total weight of the particles as determined by sieve analysis, 3% by weight or more, Preferably, 4% by weight or more. More preferably, 5% by weight or more It is.

[0018] Preferably, the fraction of particles having a particle size in the range of 500 μm to 710 μm is, based on the total weight of the particles as determined by sieve analysis, 20% by weight or less, More preferably, 16% by weight or less. Even more preferably 13% by weight or less It is.

[0019] Preferably, the fraction of particles having a particle size in the range of 500 μm to 710 μm is, based on the total weight of the particles as determined by sieve analysis, in the range of 3% by weight to 20% by weight, More preferably, the range is 4% by weight to 16% by weight. Even more preferably, the range is 5% to 13% by weight. is located.

[0020] Preferably, the fraction of particles having a particle size in the range of 90 to 710 μm is, based on the total weight of the particles as determined by sieve analysis, 30% by weight or more, Preferably 35% by weight or more, More preferably, 40% by weight or more. It is.

[0021] Preferably, the fraction of particles having a particle size in the range of 90 to 710 μm is, based on the total weight of the particles as determined by sieve analysis, 70% by weight or less, More preferably, 60% by weight or less. Even more preferably, 55% by weight or less It is.

[0022] Preferably, the fraction of particles having a particle size in the range of 90 μm to 710 μm is, based on the total weight of the particles as determined by sieve analysis, In the range of 30% by weight to 70% by weight, More preferably, the range is 35% by weight to 60% by weight. Even more preferably, the range is 40% to 55% by weight. is located.

[0023] Preferably, each Based on the total weight of the particles as determined by sieve analysis, The fraction of particles having a particle size in the range of 125 μm to 180 μm is 3% by weight or more, preferably 4% by weight or more, more preferably 5% by weight or more, The fraction of particles having a particle size in the range of 180 μm to 250 μm is 3% by weight or more, preferably 4% by weight or more, more preferably 5% by weight or more, The fraction of particles having a particle size in the range of 250 μm to 355 μm is 3% by weight or more, preferably 4% by weight or more, more preferably 5% by weight or more, The fraction of particles having a particle size in the range of 355 μm to 500 μm is 3% by weight or more, preferably 5% by weight or more, more preferably 8% by weight or more, The fraction of particles having a particle size in the range of 500 μm to 710 μm is It is 3% by weight or more, preferably 4% by weight or more, and more preferably 5% by weight or more.

[0024] Preferably, each based on the total weight of the particles as determined by sieve analysis: The fraction of particles having a particle size in the range of 125 μm to 180 μm is 20% by weight or less, more preferably 15% by weight or less, even more preferably 12% by weight or less; The fraction of particles having a particle size in the range of 180 μm to 250 μm is 20% by weight or less, more preferably 15% by weight or less, and even more preferably 10% by weight or less; The fraction of particles having a particle size in the range of 250 μm to 355 μm is 20% by weight or less, more preferably 16% by weight or less, even more preferably 13% by weight or less; The fraction of particles having a particle size in the range of 355 μm to 500 μm is 20% by weight or less, more preferably 18% by weight or less, even more preferably 16% by weight or less; The fraction of particles having a particle size in the range of 500 μm to 710 μm is It is 20% by weight or less, more preferably 16% by weight or less, and even more preferably 13% by weight or less.

[0025] Preferably, each based on the total weight of the particles as determined by sieve analysis: the fraction of particles having a particle size in the range of 125 μm to 180 μm is in the range of 3% to 20% by weight, more preferably in the range of 4% to 15% by weight, even more preferably in the range of 5% to 12% by weight, the fraction of particles having a particle size in the range of 180 μm to 250 μm is in the range of 3% to 20% by weight, more preferably in the range of 4% to 15% by weight, even more preferably in the range of 5% to 10% by weight, the fraction of particles having a particle size in the range of 250 μm to 355 μm is in the range of 3% to 20% by weight, more preferably in the range of 4% to 16% by weight, even more preferably in the range of 5% to 13% by weight, the fraction of particles having a particle size in the range of 355 μm to 500 μm is in the range of 3% to 20% by weight, more preferably in the range of 5% to 18% by weight, even more preferably in the range of 8% to 16% by weight, the fraction of particles having a particle size in the range of 500 μm to 710 μm is in the range of 3% to 20% by weight, more preferably in the range of 4% to 16% by weight, even more preferably in the range of 5% to 13% by weight, Preferably, the fraction of particles having a particle size greater than 710 μm is less than 5% by weight, preferably less than 3% by weight, based on the total weight of the particles as determined by sieve analysis.

[0026] Preferably, the particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches consist of iron(III)-oxyhydroxide, sucrose, one or more starches and optionally residual water. More preferably, the particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches are particles of sucroferric oxyhydroxide. "Sucroferric oxyhydroxide" (the common name adopted by the USAN (United States Adopted Name) Council) is a mixture of iron(III)-oxyhydroxide, sucrose and starch. As described in WO2015 / 078900, sucroferric oxyhydroxide is a stabilized polynuclear iron(III)-oxyhydroxide, and can be obtained in particular by precipitation of polynuclear iron(III)-oxyhydroxide from an iron(III)-chloride solution with sodium carbonate, followed by addition of sucrose and starch and spray drying the suspension. Such a process results in particles of sucroferric oxyhydroxide having generally more than about 80% by weight of particles less than 90 μm, i.e. the fraction of coarse particles greater than 90 μm is generally not more than about 20% by weight, although by applying suitable spray drying conditions it is also possible to obtain the claimed coarse particles directly from the spray drying process. However, according to the present invention, the particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide particles, are preferably agglomerated or granulated by a process which results in a coarser particle size distribution, as described below: The fraction of particles having a particle size of more than 90 μm is 25% by weight or more, preferably 35% by weight or more, more preferably 40% by weight or more, even more preferably 45% by weight or more, most preferably 50% by weight or more, and the fraction of particles having a particle size of more than 125 μm is 25% by weight or more, preferably 30% by weight or more, more preferably 35% by weight or more, based on the total weight of the particles, each determined by the sieve analysis as above. Such particles can be compressed, optionally after mixing with very small amounts of one or more excipients for micro or mini tablets, without forming spots on the edges of the micro or mini tablets, with a loading of especially high amounts of sucroferric oxyhydroxide.

[0027] The term "starch" as used herein includes commonly used starch products in their native, pregelatinized, degraded, modified and derivatized forms, preferably suitable for direct compression (e.g. potato starch, corn starch, rice starch, tapioca starch), and mixtures thereof. Most preferred products include native and pregelatinized starches, such as mixtures, especially in the weight ratio (native:pregelatinized) 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, even more preferably about 2:1. Most preferably, a mixture of potato starch and pregelatinized starch in a weight ratio of about 2:1 is used.

[0028] According to the present invention, the particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, in particular the particles of sucroferric oxyhydroxide, preferably comprise about 20 to about 50% by weight of iron(III)-oxyhydroxide, about 20 to 50% by weight of sucrose, and about 20 to 50% by weight of one or more starches, based on the total weight of the particle. More preferably, the particles comprise about 20 to about 40% by weight of iron(III)-oxyhydroxide, about 20 to 40% by weight of sucrose, and about 20 to 40% by weight of one or more starches, based on the total weight of the particle. Even more preferably, the particles comprise about 28 to about 38% by weight of iron(III)-oxyhydroxide, about 25 to 35% by weight of sucrose, and about 23 to 33% by weight of one or more starches, based on the total weight of the particle. In a further preferred embodiment, the particles according to the present invention comprise a mixture of native starch and pregelatinized starch. Native starches include, for example, potato starch, corn starch, rice starch, and tapioca starch, preferably potato starch. Pregelatinized starch is suitably obtained by starch gelatinization, a process that breaks the intermolecular bonds of starch molecules in the presence of water and heat, and engages hydrogen bonding sites (hydroxy hydrogen and oxygen) with more water. As explained above, mixtures of native and pregelatinized starches are particularly suitable, for example mixtures having a weight ratio (native:pregelatinized) in the range of 10:1 to 0.5:1 by weight, preferably in the range of 3:1 to 0.5:1, more preferably in the range of 2:1 to 1:1, most preferably about 2:1.

[0029] Preferably, the particles according to the present invention have an iron content of from about 15 to about 28% by weight, preferably from about 19 to about 23% by weight, based on the total weight of the particle.

[0030] Particles according to the present invention may contain water in an amount up to about 15% by weight, preferably up to about 10% by weight, based on the total weight of the particle. The particles according to the invention, in particular the particles of sucroferric oxyhydroxide, suitably consist of iron(III)-oxyhydroxide, sucrose, one or more starches and water.

[0031] The present invention further relates to a preferred method for the preparation of particles according to the invention, in which the particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide particles, with less than 25% by weight of particles with a particle size of more than 90 μm, are subjected to an agglomeration or granulation process, such as a dry or wet granulation process, preferably a dry granulation (compaction) process. In a particular preferred embodiment of the preparation method according to the invention, the particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide particles, with less than 25% by weight of particles with a particle size of more than 90 μm, are subjected to compaction by means of a roller compactor. The roller compaction is preferably carried out as follows: the drug substance is subjected to a roller compactor with a defined roller gap and hydraulic pressure to obtain ribbons which are broken by a chopper and then pulverized through a defined final mesh screen size. As mentioned above, alternatively, the particles according to the invention can also be obtained directly by a spray drying process by appropriately adjusting the spray drying conditions.

[0032] Particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide particles, with a fraction of particles with a particle size of more than 90 μm less than 25% by weight, used as starting material for the agglomeration process, are preferably obtained by spray drying an aqueous suspension comprising said iron(III)-oxyhydroxide, sucrose and one or more starches. Preferably, the aqueous suspension comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide, is atomized before spray drying. Atomization of the feed can generally be achieved by basic feed devices of single-fluid nozzle or pressurized, two-fluid nozzle or pneumatic, and centrifugal (rotating disk). In the present invention, atomization is preferably performed in a centrifugal (rotating disk) atomizer. Centrifugal atomization achieves dispersion by centrifugal force, and the feed liquid is pumped to the rotating disk. In the present invention, it was found that spray drying, especially on a spray drying plant of the type CSD No. 73 manufactured by Anhydro, results in a suitable drying process. For the atomization of the concentrated aqueous PA21 suspension, a centrifugal atomizer CE250 can be used. The centrifugal atomizer CE250 performs the atomization by feeding the liquid feed to a high-speed wheel. In a rotary atomizer, the wheel speed can be adjusted, which allows a better adjustment of the particle size than with a nozzle. Furthermore, rotary atomization is more suitable for shorter spray dryers. The powder obtained from the spray drying process must have good flowability and the particle size of the dried product must not be too small. In a rotary atomizer, the particle size can be adjusted especially by the variation of the wheel speed. The wheel speed of the atomizer determines the size of the droplets that enter the drying chamber of the spray dryer. The size of the droplets affects the particle size of the dried powder and the losses of the powder during drying. A faster wheel speed produces smaller droplets, resulting in a smaller particle size dry powder and less losses during drying, since the smaller droplets evaporate faster and contain less water on their way through the drying chamber. The correlation between wheel speed and particle size depends on the geometry of the chamber, which must be adapted to the individual plant.For the geometry of the preferred Anhydro spray drying plant CSD No. 73 type, it has been found that using wheel speeds of 12000-20000 rpm is suitable to obtain the desired particle size distribution. The inlet temperature of the air determines the drying energy brought to the spray dryer. This energy, together with the inlet gas flow, determines the drying capacity. The inlet gas flow is about 1.9 x 10. 4 m 3 The inlet temperature is kept constant at 130° C. / hour. It has been found that an inlet temperature in the range of 130° C. to 180° C. is suitable for an Anhydro spray drying plant CSD No. 73 type.

[0033] The present invention further relates to the use of particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably for the manufacture of a pharmaceutical composition, of sucroferric oxyhydroxide particles, in which the fraction of particles having a particle size of more than 90 μm is 25% by weight or more, preferably 35% by weight or more, more preferably 40% by weight or more, even more preferably 45% by weight or more, most preferably 50% by weight or more and the fraction of particles having a particle size of more than 125 μm is 25% by weight or more, preferably 30% by weight or more, more preferably 35% by weight or more, each based on the total weight of the particles determined by the sieve analysis as described above. and therefore also to a pharmaceutical composition comprising particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably particles of sucroferric oxyhydroxide, in which the fraction of particles having a particle size above 90 μm is 25% by weight or more, preferably 35% by weight or more, more preferably 40% by weight or more, even more preferably 45% by weight or more and most preferably 50% by weight or more and the fraction of particles having a particle size above 125 μm is 25% by weight or more, preferably 30% by weight or more and more preferably 35% by weight or more, each based on the total weight of the particles determined by sieve analysis. A particular preferred embodiment relates to a compressed pharmaceutical composition obtained by compressing a pharmaceutical composition comprising particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably particles of sucroferric oxyhydroxide, in which the fraction of particles having a particle size of more than 90 μm is 25% by weight or more, preferably 35% by weight or more, more preferably 40% by weight or more, even more preferably 45% by weight or more, most preferably 50% by weight or more, and the fraction of particles having a particle size of more than 125 μm is 25% by weight or more, preferably 30% by weight or more, more preferably 35% by weight or more, based on the total weight of the particles, each determined by sieve analysis. The compressed pharmaceutical composition according to the invention is preferably selected from tablets, in particular mini- or micro-tablets, which usually have a diameter of 1 to 4 millimeters. For example, in the case of a cylindrical shape, the diameter is usually the diameter of the base of the cylinder, and in the case of a spherical shape, the diameter is usually the diameter of the sphere.

[0034] In a preferred embodiment of the present invention, the pharmaceutical composition comprises at least about 90% by weight, preferably at least about 95% by weight, and even more preferably at least about 97% by weight of a total of iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide, based on the total weight of the pharmaceutical composition.

[0035] The pharmaceutical composition of the present invention preferably comprises iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide, and one or more excipients, such as fillers, binders, diluents, lubricants, disintegrants, glidants, colourants, flavours, sweeteners, adsorbents, stabilizers, surfactants, coating materials or plasticisers.

[0036] Excipients are typically used in an amount of, for example, 0.01% to 10%, or 0.01% to 6%, or 0.1% to 6% by weight (on a dry weight basis). Preferably, the additional excipient is selected from a flavouring, sweetening or taste enhancer, glidant or lubricant, the latter preferably being selected from magnesium stearate or colloidal silica such as Aerosil®, which are used in an amount of 10% by weight or less, preferably 6% by weight or less, more preferably 3% by weight or less (on a dry weight basis).

[0037] In a preferred embodiment, the pharmaceutical composition according to the present invention comprises at least one lubricant, preferably magnesium stearate, and a flavoring agent. One, two, three or more diluents or fillers can be further selected as pharma- ceutically acceptable excipients. Examples of pharma-ceutically acceptable fillers and pharma-ceutically acceptable diluents include, but are not limited to, for example, powdered sugar, refined sucrose, dextran, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, 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 diluents, fillers may be present, for example, in an amount of about 0.1% to 20% and about 0.5% to 40% by weight of the composition, respectively. One, two, three or more disintegrants can be selected. Examples of pharma- ceutically acceptable disintegrants include, but are not limited to, starch; clay; cellulose; alginates; gums; cross-linked polymers such as cross-linked polyvinylpyrrolidone, cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose; soybean polysaccharides; and guar gum. For example, the disintegrant may be present in an amount of about 0.01% to about 10% by weight of the composition. Disintegrants are also an optional but useful component of tablet formulations. Disintegrants are included to ensure that the tablet has an acceptable disintegration rate. Exemplary disintegrants include starch derivatives and salts of carboxymethylcellulose. Sodium starch glycolate is the preferred disintegrant for this formulation. One, two, three or more lubricants may be selected. Examples of pharma- ceutically acceptable lubricants and pharma-ceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, stearic acid, polyethylene glycol, and glycerol behenate.The lubricant may be present, for example, in an amount of about 0.01-10% or 0.1% to about 6% by weight of the composition, and the glidant may be present, for example, in an amount of about 0.01-10% or about 0.1% to about 10% by weight. Lubricants are typically added to prevent the tablet blend from sticking to the punches, minimize friction during tablet compression, and allow the compressed tablet to be removed from the die. Such lubricants are generally included in the final tablet mix, usually in an amount of about 2% by weight or less. The lubricant component may be hydrophobic or hydrophilic. Examples of such lubricants include, for example, stearic acid, talc, and magnesium stearate. Magnesium stearate reduces friction between the die wall and the tablet mix during tablet compression and ejection. Magnesium stearate 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 into the die. A preferred lubricant, magnesium stearate, is also used in the formulation. Preferably, the lubricant is present in the tablet formulation in an amount of about 0.01-10% by weight or about 0.1% by weight to about 6% by weight, and also preferably in an amount of about 0.1% by weight to about 4% by weight, and most preferably about 0.1% by weight to about 2% by weight of the composition. Other possible lubricants include talc, polyethylene glycol, silica, and hydrogenated vegetable oil. In any embodiment of the invention, the lubricant is not present in the formulation, but is sprayed onto the die or punch rather than added directly to the formulation. Conventional solid fillers or carriers are substances such as, for example, calcium phosphate, calcium sulfate, calcium stearate, glyceryl monostearate and glyceryl distearate, sorbitol, mannitol, gelatin, natural or synthetic gums, for example, carboxymethylcellulose, methylcellulose, alginates, dextran, gum arabic, gum karaya, locust bean gum, gum tragacanth, and the like, and diluents, binders, disintegrants, colorants, and flavoring agents can be optionally used. Binders are agents that impart cohesiveness to powdered materials.Examples of pharma- ceutically acceptable binders as excipients include, but are not limited to, starch, sugar; cellulose and its derivatives, such as microcrystalline cellulose, hydroxypropylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose; sucrose; glucose, dextrose, lactose dextrose; corn syrup; polysaccharides; and gelatin. During clinical trials, the applicant further recognized that the taste of the phosphate binder was not recognized by the subjects and did not directly affect compliance with the therapeutic treatment. For clarity, it is noted that sucrose and starch are part of the active ingredients, including iron(III)-oxyhydroxide, sucrose and one or more starches, and in particular, sucroferric oxyhydroxide is not treated as an excipient, such as binders, sweeteners, etc., listed herein. In a further embodiment, the pharmaceutical composition of the present invention includes one or more flavor or flavor-masking and color additives, such as flavors, sweeteners, taste enhancers, colorants, etc., typically used in oral dosage forms. In a preferred embodiment, the formulations, compositions and tablets of the present invention include a flavoring with woodberry flavor. The woodberry flavor results in better compliance and acceptance of the claimed phosphate binder tablets. Taste masking agents, such as taste enhancers, flavoring agents, and / or natural or artificial sweeteners, including high-intensity sweeteners, can be incorporated into the oral dosage form to provide a more pleasant taste or mask unpleasant tastes. Typical sweeteners as excipients include, but are not limited to, sugars, such as sucrose, fructose, lactose, confectionery sugar, powdered sugar, or polyols, such as sorbitol (e.g., Neosorb), xylitol, maltitol, maltose and polydextrose, or mixtures thereof. Typical high-intensity sweeteners include, but are not limited to, 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, glutamic acid, etc. The latter can be used in very small amounts and therefore may be referred to below as taste enhancers. All of the above are suitable for use alone or in mixtures with other sweeteners and / or flavoring agents. These substances ensure a long-lasting sweet aftertaste and mask unpleasant aftertastes. Preferred sweeteners and / or taste enhancers include glycosides, such as neohesperidin dihydrochalcone. In one embodiment, the generally preferred sweeteners 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), based on the total weight of the composition. The preferred taste enhancers may be present in an amount of 0.1-50 ppm, preferably 1-10 ppm, most preferably 1-5 ppm, based on the total weight of the composition. Typical flavoring agents include any natural and artificial flavoring agent suitable for pharmaceutical use, such as flavoring agents derived from spices, fruits or fruit juices, vegetables or vegetable juices, etc., such as flavoring agents based on 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, such as caramel / vanilla, fruit / cream (e.g., strawberry / cream), etc. In one embodiment, the flavoring agent of choice may be present in an amount of from 0.01 to 12% (w / w), preferably from 0.1 to 6% (w / w), most preferably from 0.1 to 4% (w / w), based on the total weight of the composition.Further examples of useful excipients are described in Handbook of pharmaceutical excipients, 3rd Edition, edited by A. H. Kibbe, American Pharmaceutical Association, Washington DC, ISBN: 0-917330-96-X, or Handbook of Pharmaceutical Excipients, 4th Edition, edited by Raymond C. Rowe, Science and Practice, which are incorporated herein by reference.

[0038] Preferably, the pharmaceutical composition according to the present invention comprises one or more excipients, such as fillers, binders, diluents, lubricants, disintegrants, colorants, flavoring agents, sweeteners, sorbents, stabilizers, surfactants, coating materials or plasticizers, in an amount of about 10% by weight or less, preferably about 5% by weight or less, more preferably about 3% by weight or less, based on the total weight of the pharmaceutical composition. In certain preferred embodiments, the pharmaceutical composition according to the present invention comprises one or more excipients selected from lubricants and glidants. In one embodiment of the present invention, the pharmaceutical composition comprises one or more excipients selected from lubricants and glidants in an amount of about 0.5 to about 5% by weight, based on the total weight of the pharmaceutical composition. In certain preferred embodiments, the pharmaceutical composition of the present invention comprises a) a mixture of iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide as described above; b) magnesium stearate, c) talc, and d) optionally one or more flavoring agents Includes.

[0039] The significantly reduced ejection force in microtabletting tooling makes such pharmaceutical compositions particularly suitable for formation of micro- or mini-tablets.

[0040] Preferably, the pharmaceutical composition comprises at least about 0.5% by weight of magnesium stearate, based on the total weight of the pharmaceutical composition, more preferably about 0.5 to about 1.5% by weight of magnesium stearate, based on the total weight of the pharmaceutical composition. Preferably, the pharmaceutical composition comprises at least about 0.5% by weight of talc, more preferably at least 1.0% by weight of talc, based on the total weight of the pharmaceutical composition.

[0041] In a further preferred embodiment, the pharmaceutical composition comprises about 0.5 to about 1.5 wt% magnesium stearate, based on the total weight of the pharmaceutical composition, and at least about 0.5 wt%, more preferably at least 1.0 wt%, of talc, based on the total weight of the pharmaceutical composition, and preferably about 0.75 to about 1.25 wt% magnesium stearate and about 1.0 to about 3.0 wt%, of talc, each based on the total weight of the pharmaceutical composition.

[0042] In a further preferred embodiment of this pharmaceutical composition according to the invention, the total amount of magnesium stearate and talc does not exceed 3.0% by weight, based on the total weight of the pharmaceutical composition.

[0043] A particularly preferred pharmaceutical composition according to the present invention comprises 96-98% by weight of iron(III)-oxyhydroxide, a mixture of sucrose and one or more starches, preferably sucroferric oxyhydroxide, 0.75-1.25% by weight of magnesium stearate and 1.0-3.0% by weight of talc, each based on the total weight of the pharmaceutical composition, more preferably the pharmaceutical composition according to the present invention consists of 96-98% by weight of iron(III)-oxyhydroxide, a mixture of sucrose and one or more starches, preferably sucroferric oxyhydroxide, 0.75-1.25% by weight of magnesium stearate and 1.0-3.0% by weight of talc, each based on the total weight of the pharmaceutical composition, and optionally a flavouring agent.

[0044] In a preferred embodiment, the pharmaceutical composition according to the present invention does not contain any sweetener. Likewise, in a preferred embodiment, the pharmaceutical composition according to the present invention does not contain any silica. Similarly, in a preferred embodiment, the pharmaceutical composition according to the present invention does not contain any flavoring agent. Similarly, in a preferred embodiment, the pharmaceutical composition according to the present invention does not contain any macrogol. Similarly, in a preferred embodiment, the pharmaceutical composition according to the present invention does not contain any further excipients other than magnesium stearate, talc and flavoring agents.

[0045] The pharmaceutical compositions according to the present invention are particularly useful for use in the prevention and treatment of hyperphosphatemic conditions, especially in patients with chronic renal failure. Thus, the pharmaceutical compositions according to the present invention are effective in treating hyperphosphatemia or conditions resulting from unbalanced phosphate levels (e.g., for therapeutic use in controlling serum phosphorus levels in patients with chronic kidney disease (CKD) who are on dialysis) due to their ability to adsorb dietary phosphate in the gastrointestinal tract.

[0046] The present invention further relates to a method for the preparation of a compressed pharmaceutical composition according to the present invention, comprising a step of compressing a non-compressed pharmaceutical composition as defined above into a tablet. Such a method preferably comprises a step of dry granulation (compacting) a mixture of iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide, prior to compressing the pharmaceutical composition to obtain a compressed tablet. The dry granulation step prior to compression is preferably carried out by roller compaction.

[0047] In a preferred embodiment, the present invention relates to a method for preparing a pharmaceutical composition comprising talc, further comprising the steps of sieving talc, adding the sieved talc to a mixture of iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide, and blending the sieved talc with the mixture of iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide, to obtain a preblend.A particularly preferred such method is a method for preparing a pharmaceutical composition comprising magnesium stearate, further comprising the steps of sieving magnesium stearate, blending the sieved magnesium stearate with a portion of a preblend comprising talc and a mixture of iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide, blending the resulting mixture with the remaining preblend to obtain a final blend, and compressing the final preblend to obtain a compressed pharmaceutical composition.

[0048] Thus, the present invention further relates to compressed tablets obtained by the above-mentioned method, in particular compressed tablets that are mini- or micro-tablets. Usually, such micro- or mini-tablets have a diameter of about 1 to 4 mm. Preferably, the diameter of the mini- or micro-tablet is in the range of about 1 to 4 mm, more preferably in the range of about 1.5 to 3 mm. In a preferred embodiment, the compressed mini- or micro-tablet according to the present invention has a mass of about 9.1 to about 15.9 mg, preferably about 10.2 to about 14.8 mg, more preferably about 11.4 to about 13.6 mg. Preferably, the compressed tablets according to the present invention, in particular the micro- or mini-tablets, are cylindrical, the diameter of the cylinder preferably being in the range of about 1.7 mm to about 2.3 mm, and the height of the cylinder preferably being in the range of about 2.5 to about 3.1 mm. The ratio of the diameter to the height of the cylinder of the compressed tablets according to the present invention, in particular the micro- or mini-tablets, is in the range of about 0.55 to about 0.92, more preferably in the range of about 0.6 to about 0.8, most preferably in the range of about 0.65 to about 0.75.

[0049] Compressed tablets according to the present invention preferably have an average tablet hardness in the range of about 5N to about 25N as determined by a hardness tester according to European Pharmacopoeia monograph 2.9.8.

[0050] Compressed tablets according to the invention preferably have a tablet friability of less than or equal to 2.0, preferably less than 1.0%, determined by a tablet friability test apparatus equipped with an abrasive drum according to European Pharmacopoeia monograph 2.9.7.

[0051] The compressed tablets according to the invention have a tablet disintegration time of 15 minutes or less as determined by Disintegration Test Apparatus A (equipped with discs) according to European Pharmacopoeia monograph 2.9.1.

[0052] A further embodiment of the present invention relates to a sachet or stick pack containing a plurality of the mini- or micro-tablets as described above. Such a sachet or stick pack preferably contains about 100-300, preferably 150-250, more preferably 180-220 mini- or micro-tablets.

[0053] Preferably, the sachet or stick pack according to the invention contains from about 500mg to about 3700mg of a mixture of iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide, more preferably from about 600mg to about 3600mg of a mixture of iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide, even more preferably from about 800mg to about 3500mg of a mixture of iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide, even more preferably from about 1500mg to about 3500mg of a mixture of iron(III)-oxyhydroxide, sucrose and one or more starches. The sachet or stick pack according to the invention is preferably child-resistant, e.g. according to ISO 8317.

[0054] The mini or micro tablets are preferably provided in a micro tablet dispenser, which can range from the most technologically advanced to the simplest, e.g. Sensidose®, sMTS®, IQ dose® or homeopathic tube.

[0055] The following summarizes preferred embodiments of the present invention.

[0056] 1. Particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, each based on the total weight of the particles as determined by sieve analysis, in which the fraction of particles having a particle size greater than 90 μm is 25% by weight or more, preferably 35% by weight or more, more preferably 40% by weight or more, even more preferably 45% by weight or more, most preferably 50% by weight or more, and preferably the fraction of particles having a particle size greater than 125 μm is 25% by weight or more, more preferably 30% by weight or more, even more preferably 35% by weight or more.

[0057] 2. The particles according to embodiment 1, wherein the fraction of particles having a particle size in the range of 90 μm to 125 μm is 3% by weight or more, more preferably 5% by weight or more, based on the total weight of the particles, each determined by sieve analysis.

[0058] 3. Particles according to embodiment 1 or 2, in which the fraction of particles having a particle size in the range of 125 μm to 180 μm is 3% by weight or more, preferably 5% by weight or more, based on the total weight of the particles, each determined by sieve analysis.

[0059] 4. Particles according to any one of embodiments 1 to 3, wherein the fraction of particles having a particle size in the range of 180 μm to 250 μm is 3% by weight or more, preferably 5% by weight or more, based on the total weight of the particles, each determined by sieve analysis.

[0060] 5. Particles according to any one of the preceding embodiments, wherein the fraction of particles having a particle size in the range of 250 μm to 355 μm is 3% by weight or more, preferably 5% by weight or more, based on the total weight of the particles, each determined by sieve analysis.

[0061] 6. Particles according to any one of the preceding embodiments, wherein the fraction of particles having a particle size in the range of 355 μm to 500 μm is 3% by weight or more, preferably 5% by weight or more, based on the total weight of the particles, each determined by sieve analysis.

[0062] 7. Particles according to any one of the preceding embodiments, wherein the fraction of particles having a particle size in the range of 500 μm to 710 μm is 3% by weight or more, preferably 5% by weight or more, based on the total weight of the particles, each determined by sieve analysis.

[0063] 8. Particles according to any one of the preceding embodiments, wherein the fraction of particles having a particle size in the range of 90 μm to 710 μm is 30% by weight or more, preferably 35% by weight or more, based on the total weight of the particles, each determined by sieve analysis.

[0064] 9. The fraction of particles having a particle size in the range of 125 μm to 180 μm is 3% by weight or more, preferably 5% by weight or more, based on the total weight of the particles, each determined by sieve analysis; The particles according to any one of embodiments 1 to 8, wherein the fraction of particles having a particle size in the range of 180 μm to 250 μm is 3% by weight or more, preferably 5% by weight or more, the fraction of particles having a particle size in the range of 250 μm to 355 μm is 3% by weight or more, preferably 5% by weight or more, the fraction of particles having a particle size in the range of 355 μm to 500 μm is 3% by weight or more, preferably 5% by weight or more, and the fraction of particles having a particle size in the range of 500 μm to 710 μm is 3% by weight or more, preferably 5% by weight or more.

[0065] 10. Particles described in any one of embodiments 1 to 9, wherein the fraction of particles having a particle size greater than 710 μm is less than 5% by weight, preferably less than 3% by weight, based on the total weight of the particles as determined by sieve analysis.

[0066] 11. A particle according to any one of the preceding embodiments 1 to 10, consisting of iron(III)-oxyhydroxide, sucrose, one or more starches and optionally water.

[0067] 12. A particle according to any one of the preceding embodiments 1 to 11, formed by sucroferric oxyhydroxide.

[0068] 13. A particle according to any one of the preceding embodiments 1 to 12, comprising about 20 to about 50% by weight of iron(III)-oxyhydroxide, about 20 to 50% by weight of sucrose, and about 20 to 50% by weight of one or more starches, based on the total weight of the particle.

[0069] 14. A particle described in any one of the preceding embodiments 1 to 13, comprising about 20 to about 40% by weight of iron(III)-oxyhydroxide, about 20 to 40% by weight of sucrose, and about 20 to 40% by weight of one or more starches, based on the total weight of the particle.

[0070] 15. A particle described in any one of the preceding embodiments 1 to 14, comprising about 28 to about 38 weight % of iron(III)-oxyhydroxide, about 25 to 35 weight % of sucrose, and about 23 to 33 weight % of one or more starches, based on the total weight of the particle.

[0071] 16. A particle according to any one of the preceding embodiments 1 to 15, comprising a mixture of native starch and pregelatinized starch, preferably a mixture of pregelatinized starch and potato starch, preferably having a weight ratio (native:pregelatinized) in the 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 about 2:1.

[0072] 17. A particle according to any one of the preceding embodiments 1 to 16, having an iron content of about 15 to about 28% by weight, preferably about 19 to about 23% by weight, based on the total weight of the particle.

[0073] 18. A particle according to any one of the preceding embodiments 1 to 17, comprising water in an amount of about 15% by weight or less, preferably about 10% by weight or less, based on the total weight of the particle.

[0074] 19. A particle according to any one of the preceding embodiments 1 to 18, consisting of iron(III)-oxyhydroxide, sucrose, one or more starches and water.

[0075] 20. A particle according to any one of the preceding embodiments 1 to 19, comprising iron(III)-oxyhydroxide, sucrose, a mixture of two or more starches, and water.

[0076] 21. A particle according to any one of the preceding embodiments 1 to 20, comprising iron(III)-oxyhydroxide, sucrose, a mixture of native and pregelatinized starch, and water.

[0077] 22. A method for producing particles according to any one of the preceding embodiments, wherein the particles comprise iron(III)-oxyhydroxide, sucrose and one or more starches, and the fraction of particles having a particle size greater than 90 μm is less than 25% by weight, based on the total weight of the particles as determined by sieve analysis.

[0078] 23. The method of the preceding embodiment 22, wherein the particles are subjected to dry or wet granulation, preferably dry granulation (compression).

[0079] 24. A method for producing particles according to any one of the preceding embodiments 22 or 23, wherein the particles are subjected to compaction by a roller compactor.

[0080] 25. A method for producing particles according to any one of the preceding embodiments 22 to 24, wherein the particles, comprising iron(III)-oxyhydroxide, sucrose and one or more starches, and having a fraction of particles with a particle size greater than 90 μm of less than 25% by weight, are prepared by spray drying an aqueous suspension comprising iron(III)-oxyhydroxide, sucrose and one or more starches.

[0081] 26. Use of particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably particles of sucroferric oxyhydroxide, for the manufacture of a pharmaceutical composition, in which the fraction of particles having a particle size greater than 90 μm is 25% by weight or more, preferably 35% by weight or more, more preferably 40% by weight or more, even more preferably 45% by weight or more, most preferably 50% by weight or more and the fraction of particles having a particle size greater than 125 μm is 25% by weight or more, preferably 30% by weight or more, more preferably 35% by weight or more, each based on the total weight of the particles determined by sieve analysis.

[0082] 27. A pharmaceutical composition comprising particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably particles of sucroferric oxyhydroxide, wherein the fraction of particles having a particle size greater than 90 μm is 25% by weight or more, preferably 35% by weight or more, more preferably 40% by weight or more, even more preferably 45% by weight or more and most preferably 50% by weight or more, and the fraction of particles having a particle size greater than 125 μm is 25% by weight or more, preferably 30% by weight or more, more preferably 35% by weight or more, each based on the total weight of the particles determined by sieve analysis.

[0083] 28. A compressed pharmaceutical composition obtained by compressing a pharmaceutical composition comprising particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably particles of sucroferric oxyhydroxide, in which the fraction of particles having a particle size greater than 90 μm is 25% by weight or more, preferably 35% by weight or more, more preferably 40% by weight or more, even more preferably 45% by weight or more and most preferably 50% by weight or more and the fraction of particles having a particle size greater than 125 μm is 25% by weight or more, preferably 30% by weight or more and more preferably 35% by weight or more, each based on the total weight of the particles determined by sieve analysis.

[0084] 29. The compressed pharmaceutical composition of the preceding embodiment 28, selected from tablets, in particular mini- or micro-tablets.

[0085] 30. A pharmaceutical composition according to any one of the preceding embodiments 27 to 29, comprising a total amount of iron(III)-oxyhydroxide, sucrose and one or more starches of at least about 90% by weight, preferably at least about 95% by weight, and even more preferably at least about 97% by weight, based on the total weight of the pharmaceutical composition.

[0086] 31. A pharmaceutical composition according to any one of the preceding embodiments 27-30, comprising at least about 90% by weight, preferably at least about 95% by weight, and even more preferably at least about 97% by weight, of sucroferric oxyhydroxide, based on the total weight of the pharmaceutical composition.

[0087] 32. The pharmaceutical composition of any one of the preceding embodiments 27 to 31, comprising one or more excipients, such as fillers, binders, diluents, lubricants, disintegrants, glidants, colorants, flavorants, sweeteners, sorbents, stabilizers, surfactants, coating materials or plasticizers.

[0088] 33. The pharmaceutical composition of any one of the preceding embodiments 27 to 32, comprising one or more excipients, such as fillers, binders, diluents, lubricants, disintegrants, glidants, colorants, flavoring agents, sweeteners, sorbents, stabilizers, surfactants, coating materials or plasticizers, in an amount of about 10% by weight or less, preferably about 5% by weight or less, and more preferably about 3% by weight or less, based on the total weight of the pharmaceutical composition.

[0089] 34. The pharmaceutical composition of any one of the preceding embodiments 27-33, comprising one or more excipients selected from a lubricant and a glidant.

[0090] 35. A pharmaceutical composition described in any one of the preceding embodiments 27 to 34, comprising one or more excipients selected from a lubricant and a glidant in an amount of about 0.5 to about 5% by weight, based on the total weight of the pharmaceutical composition.

[0091] 36. a) particles as defined above, b) magnesium stearate, c) talc, and d) optionally one or more flavoring agents 36. The pharmaceutical composition of any one of the preceding embodiments 27-35, comprising:

[0092] 37. A pharmaceutical composition described in any one of the preceding embodiments 27 to 36, comprising at least about 0.5% by weight of magnesium stearate, based on the total weight of the pharmaceutical composition.

[0093] 38. A pharmaceutical composition described in any one of the preceding embodiments 27 to 37, comprising about 0.5 to about 1.5% by weight of magnesium stearate, based on the total weight of the pharmaceutical composition.

[0094] 39. A pharmaceutical composition according to any one of the preceding embodiments 27 to 38, comprising at least about 0.5% by weight of talc, more preferably at least 1.0% by weight of talc, based on the total weight of the pharmaceutical composition.

[0095] 40. A pharmaceutical composition described in any one of the preceding embodiments 27 to 39, comprising about 0.5 to about 1.5% by weight of magnesium stearate, based on the total weight of the pharmaceutical composition, and at least about 0.5% by weight, more preferably at least 1.0% by weight, of talc, based on the total weight of the pharmaceutical composition.

[0096] 41. A pharmaceutical composition according to any one of the preceding embodiments 27 to 40, comprising about 0.75 to about 1.25% by weight of magnesium stearate, and about 1.0 to about 3.0% by weight of talc, each based on the total weight of the pharmaceutical composition.

[0097] 42. The pharmaceutical composition of any one of the preceding embodiments 27-41, wherein the total amount of magnesium stearate and talc does not exceed 3.0% by weight, based on the total weight of the pharmaceutical composition.

[0098] 43. A pharmaceutical composition according to any one of the preceding embodiments 27 to 42, wherein the composition comprises 96 to 98% by weight of particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably particles of sucroferric oxyhydroxide, 0.75 to 1.25% by weight of magnesium stearate, and 1.0 to 3.0% by weight of talc, each based on the total weight of the pharmaceutical composition.

[0099] 44. A pharmaceutical composition according to any one of the preceding embodiments 27 to 43, wherein the composition does not contain any sweetening agents.

[0100] 45. The pharmaceutical composition of any one of the preceding embodiments 27-44, wherein the composition does not contain any silica.

[0101] 46. ​​A pharmaceutical composition of any one of the preceding embodiments 27-45, wherein the composition does not contain any flavoring agents.

[0102] 47. A pharmaceutical composition described in any one of the preceding embodiments 27 to 46, wherein the composition does not contain any macrogols.

[0103] 48. A pharmaceutical composition according to any one of the preceding embodiments 27 to 47, wherein the composition contains no further excipients, except for those excipients set forth above.

[0104] 49. A pharmaceutical composition according to any one of the preceding embodiments 27 to 48, for use in the prevention and treatment of hyperphosphatemic conditions, particularly in patients with chronic renal failure.

[0105] 50. A method for producing a compressed pharmaceutical composition described in any one of the preceding embodiments 28 to 49, comprising compressing a non-compressed pharmaceutical composition described in any one of the preceding embodiments into a tablet.

[0106] 51. A method for preparing a pharmaceutical composition according to embodiment 50, comprising a step of dry granulation (compaction) of particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably particles of sucroferric oxyhydroxide, prior to compressing the pharmaceutical composition to obtain compressed tablets.

[0107] 52. A method for producing a pharmaceutical composition according to embodiment 50, wherein the dry granulation step before compression is carried out by roller compaction.

[0108] 53. A method for preparing a pharmaceutical composition comprising talc according to any one of embodiments 50 to 52, further comprising the steps of sieving talc, adding the sieved talc to particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide particles, and blending the sieved talc with the particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably sucroferric oxyhydroxide particles, to obtain a preblend.

[0109] 54. A method for producing a pharmaceutical composition comprising magnesium stearate as described in embodiment 53, further comprising the steps of sieving magnesium stearate, mixing the sieved magnesium stearate with a portion of the preblend, and mixing it with the remainder of the preblend to obtain a final blend.

[0110] 55. A compressed tablet obtainable by a method according to any one of embodiments 50 to 54.

[0111] 56. The compressed tablet according to embodiment 55, wherein the compressed tablet is a mini- or micro-tablet.

[0112] 57. Compressed mini- or micro-tablets according to embodiment 56, wherein the mass of the tablet is from about 9.1 to about 15.9 mg, preferably from about 10.2 to about 14.8 mg, even more preferably from about 11.4 to about 13.6 mg.

[0113] 58. The compressed tablet of embodiment 56 or 57, wherein the tablet has a cylindrical shape.

[0114] 59. A compressed tablet according to any one of embodiments 56 to 58, wherein the diameter of the mini- or micro-tablets is in the range of about 1 to 4 mm, preferably about 1.5 to 3 mm.

[0115] 60. A compressed tablet according to embodiment 58 or 59, wherein the cylinder diameter is in the range of about 1.7 mm to about 2.3 mm.

[0116] 61. A compressed tablet according to any one of embodiments 58 to 60, wherein the cylinder height is in the range of about 2.5 to about 3.1 mm.

[0117] 62. A compressed tablet according to any one of embodiments 58 to 61, wherein the ratio of the diameter to the height of the cylinder is in the range of about 0.55 to about 0.92, more preferably in the range of about 0.6 to about 0.8, and most preferably in the range of about 0.65 to about 0.75.

[0118] 63. A compressed tablet according to any one of embodiments 55 to 62, wherein the average hardness of the tablet is in the range of about 5 N to about 25 N as determined by a hardness tester according to European Pharmacopoeia monograph 2.9.8.

[0119] 64. A compressed tablet according to any one of embodiments 55 to 63, wherein the friability of the tablet is less than or equal to 2.0, preferably less than or equal to 1.0%, as determined by a tablet fracture test apparatus equipped with an abrasive drum according to European Pharmacopoeia monograph 2.9.7.

[0120] 65. A compressed tablet according to any one of embodiments 55 to 64, wherein the disintegration time of the tablet is 15 minutes or less as determined by Disintegration Test Apparatus A (equipped with discs) according to European Pharmacopoeia monograph 2.9.1.

[0121] 66. A sachet or stick pack comprising a plurality of mini- or micro-tablets according to any one of embodiments 56 to 65.

[0122] 67. A sachet or stick pack according to embodiment 66, comprising about 100 to 300, preferably 150 to 250, more preferably 180 to 220 mini- or micro-tablets.

[0123] 68. A sachet or stick pack according to embodiment 66 or 67, comprising from about 500 mg to about 3700 mg of particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably particles of sucroferric oxyhydroxide.

[0124] 69. A sachet or stick pack according to any one of embodiments 66 to 68, comprising from about 600 mg to about 3600 mg of particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably particles of sucroferric oxyhydroxide.

[0125] 70. A sachet or stick pack according to any one of embodiments 66 to 69, comprising from about 800 mg to about 3500 mg of particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably particles of sucroferric oxyhydroxide.

[0126] 71. A sachet or stick pack according to any one of embodiments 66 to 70, comprising from about 1500 mg to about 3500 mg of particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, preferably particles of sucroferric oxyhydroxide.

[0127] 72. A sachet or stick pack according to any one of embodiments 66 to 71, which is child-resistant.

[0128] The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention. [Brief description of the drawings]

[0129] [Figure 1] FIG. 1 shows the results regarding the generation of ejection forces. [Diagram 2] Figure 2 shows the results for five batches. [Diagram 3] Figure 3 shows the results for the four batches. EXAMPLES

[0130] Comparative Example 1 Sucroferric oxyhydroxide (a mixture of about 33 wt% iron(lll)-oxyhydroxide, about 30 wt% sucrose, about 28 wt% starch, and water) was obtained by spray drying as described in WO2008 / 062993 and WO2015 / 078900. The particle size of the sucroferric oxyhydroxide was such that at least about 82 wt% had a particle size of less than 90 μm as determined by sieve analysis, as shown in Figure 2, which shows the results of five batches. The volume average particle size d50 determined by laser diffraction was about 55-56 μm. Example 1

[0131] The sucroferric oxyhydroxide obtained in Comparative Example 1 was subjected to roller compaction using a roller compactor (model WP120 from Alexanderwerk) with the following process parameters:

[0132] [Table 1]

[0133] During the roller compaction process, the drug substance passes through a roller compactor. The drug substance is compacted into ribbons that are broken in a chopper and then ground through a final mesh screen size of approximately 0.63 mm. This dry compaction step is carried out so that the drug substance particles have a coarser particle size distribution. Thus, the resulting compacted sucroferric oxyhydroxide had about 44% by weight of a particle size less than 90 μm as determined by sieve analysis, as shown in FIG. 3, which shows the results of four batches.

[0134] Tablet example One batch of each of the sucroferric oxyhydroxide particles of Comparative Example 1 and Example 1 was mixed with flavoring agent, sieved talc and sieved magnesium stearate in the amounts (amounts are in parts by weight) shown in the table below.

[0135] [Table 2]

[0136] The mixing process began with a hand blend of sieved talc and flavorings to give pre-preblend 1. This preblend was then mixed with a portion of the sieved drug substance to give pre-blend 2. Sieved magnesium stearate was added to pre-blend 2 to give pre-blend 3, and the pre-blend was mixed for 5 minutes to give the final blend.

[0137] The tablet compositions shown in the table were then tableted using a rotary tablet press equipped with 16 punches and the ejection force (multi-tip punch) was recorded. The key parameters of the tableting process as the final compression force or tableting speed were fixed in order to obtain the granule (microtablet) characteristics in terms of hardness, weight, thickness, friability and disintegration time. Reddish brown cylindrical granules (microtablets) with a diameter of approximately 2 mm and a height (thickness) of approximately 2.8 mm were obtained.

[0138] The results regarding the release force generation are shown in FIG.

[0139] The results show that for the tablet composition according to the invention (compacted sucroferric oxyhydroxide) the ejection force is significantly lower (about 300N lower) than for the comparative tablet composition (non-compacted sucroferric oxyhydroxide). Moreover, for the tablet composition according to the invention the ejection force remains very stable over time, whereas the comparative tablet composition shows a slight increase in the ejection force. The same trend is observed when the tableting speed is increased.

[0140] Corresponding to the higher release force of the comparative tablet composition tablets thus prepared, dark brown spots were observed on the edges of the micro-tablets due to the heating associated with the higher release force, which was not observed with the tablet composition of the present invention.

Claims

1. Particles comprising iron(III)-oxyhydroxide, sucrose and one or more starches, The fraction of particles having a particle size greater than 90 μm is 25% by weight or more, each based on the total weight of the particles as determined by sieve analysis; Particles, wherein the fraction of particles having a particle size greater than 125 μm is 25% by weight or greater.

2. 2. The particles according to claim 1, wherein the fraction of particles having a particle size in the range of 90 μm to 125 μm is equal to or greater than 3% by weight, each based on the total weight of the particles as determined by sieve analysis.

3. 3. Particles according to claim 1 or 2, wherein the fraction of particles having a particle size in the range of 125 μm to 180 μm is equal to or greater than 3% by weight, each based on the total weight of the particles as determined by sieve analysis.

4. 4. The particles according to any one of claims 1 to 3, wherein the fraction of particles having a particle size in the range of 180 μm to 250 μm is equal to or greater than 3% by weight, each based on the total weight of the particles as determined by sieve analysis.

5. 5. The particles according to any one of claims 1 to 4, wherein the fraction of particles having a particle size in the range of 250 μm to 355 μm is equal to or greater than 3% by weight, each based on the total weight of the particles as determined by sieve analysis.

6. 6. Particles according to any one of claims 1 to 5, wherein the fraction of particles having a particle size in the range of 355 μm to 500 μm is equal to or greater than 3% by weight, each based on the total weight of the particles as determined by sieve analysis.

7. 7. The particles according to any one of claims 1 to 6, wherein the fraction of particles having a particle size in the range of 500 μm to 710 μm is equal to or greater than 3% by weight, each based on the total weight of the particles as determined by sieve analysis.

8. 8. Particles according to any one of claims 1 to 7, wherein the fraction of particles having a particle size in the range of 90 to 710 μm is equal to or greater than 30% by weight, each based on the total weight of the particles as determined by sieve analysis.

9. Each based on the total weight of particles determined by sieve analysis the fraction of particles having a particle size in the range of 125 μm to 180 μm is equal to or greater than 3% by weight; the fraction of particles having a particle size in the range of 180 μm to 250 μm is equal to or greater than 3% by weight; the fraction of particles having a particle size in the range of 250 μm to 355 μm is equal to or greater than 3% by weight; the fraction of particles having a particle size in the range of 355 μm to 500 μm is equal to or greater than 3% by weight; The fraction of particles having a particle size in the range of 500 μm to 710 μm is 3% by weight or more; A particle according to any one of claims 1 to 8.

10. Each based on the total weight of particles determined by sieve analysis: the fraction of particles having a particle size in the range of 125 μm to 180 μm is less than or equal to 20% by weight; the fraction of particles having a particle size in the range of 180 μm to 250 μm is less than or equal to 20% by weight; the fraction of particles having a particle size in the range of 250 μm to 355 μm is less than or equal to 20% by weight; the fraction of particles having a particle size in the range of 355 μm to 500 μm is less than or equal to 20% by weight; The fraction of particles having a particle size in the range of 500 μm to 710 μm is less than or equal to 20% by weight; A particle according to any one of claims 1 to 9.

11. Each based on the total weight of particles determined by sieve analysis: the fraction of particles having a particle size in the range of 125 μm to 180 μm is in the range of 3% to 20% by weight; the fraction of particles having a particle size in the range of 180 μm to 250 μm is in the range of 3% to 20% by weight; the fraction of particles having a particle size in the range of 250 μm to 355 μm is in the range of 3% to 20% by weight; the fraction of particles having a particle size in the range of 355 μm to 500 μm is in the range of 3% to 20% by weight; Particles according to any one of claims 1 to 10, wherein the fraction of particles having a size in the range of 500 µm to 710 µm is in the range of 3% to 20% by weight.

12. 12. Particles according to any one of claims 1 to 11, wherein the fraction of particles having a particle size of more than 710 μm is less than 5% by weight, based on the total weight of the particles as determined by sieve analysis.

13. Particles according to any one of claims 1 to 12, consisting of iron(III)-oxyhydroxide, sucrose, one or more starches and water.

14. A method for producing particles according to any one of claims 1 to 13, comprising subjecting particles used as starting material to an aggregation or granulation process to obtain the particle size distribution of the particles according to claim 1, 1. A method for producing said starting particles, comprising: iron(III)-oxyhydroxide; sucrose; and one or more starches, the fraction of particles having a particle size of more than 90 μm being less than 25% by weight, based on the total weight of the particles as determined by sieve analysis.

15. Use of the particles according to any one of claims 1 to 13 for the manufacture of a pharmaceutical composition.

16. A pharmaceutical composition comprising the particles according to any one of claims 1 to 13.

17. A compressed pharmaceutical composition comprising a pharmaceutical composition comprising particles according to any one of claims 1 to 13.

18. 18. The compressed pharmaceutical composition of claim 17 selected from a tablet.

19. 17. The pharmaceutical composition of claim 16, comprising a total amount of iron(III)-oxyhydroxide, sucrose and one or more starches of at least 90% by weight, based on the total weight of the pharmaceutical composition.

20. a) a mixture of iron(III)-oxyhydroxide, sucrose and one or more starches; b) magnesium stearate, c) talc, and d) optionally one or more flavoring agents 19. The compressed pharmaceutical composition of claim 17 or 18, comprising:

21. 21. The compressed pharmaceutical composition of any one of claims 17, 18 and 20, comprising 0.75-1.25% by weight of magnesium stearate and 1.0-3.0% by weight of talc, each based on the total weight of the pharmaceutical composition.

22. 22. The compressed pharmaceutical composition of any one of claims 17, 18, 20 and 21, wherein the composition contains an excipient selected from a filler, a binder, a diluent, a lubricant, a disintegrant, a glidant, a colorant, a flavorant, a sweetener, an adsorbent, a stabilizer, a surfactant, a coating material or a plasticizer.

23. 23. The compressed pharmaceutical composition according to any one of claims 17, 18, 20, 21, 22 for use in the prevention and treatment of hyperphosphatemic conditions, especially in patients with chronic renal failure.

24. 24. A process for producing a compressed pharmaceutical composition according to any one of claims 17, 18, 20, 21, 22 and 23, comprising compressing the pharmaceutical composition according to claim 16 into a tablet.

25. 24. The compressed pharmaceutical composition according to any one of claims 17, 18, 20, 21, 22 and 23, which is a mini-tablet, said mini-tablet having a mass of 9.1 to 15.9 mg.

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