NO20171980A1 - Material - Google Patents

Abstract

There is provided a granular material comprising (i) at least 50% by weight based on the weight of the granular material of a solid water-insoluble mixed metal compound capable of binding phosphate of formula (I): MII1-x MIIIxOH2An-yzH2O, wherein MII is at least one of magnesium, calcium, lanthanum and cerium; MIII is at least iron (III); At least one n-valent anion; x = Σny; O <x <0.67, O <y <1 and O <z <10; (ii) from 3 to 12% by weight based on the weight of the granular material of non-chemically bound water, and (iii) at most 47% by weight excipient, based on the weight of the granular material.

Description

MATERIAL

Area

The present invention relates to granules containing water-insoluble inorganic solids, in particular mixed metal compounds, with pharmaceutical activity, as phosphate binders. It also relates to methods of preparing the granules and their use in unit doses for oral administration.

Background

Various disorders can lead to high phosphate concentrations in the blood in animals, especially in warm-blooded animals such as humans. This can lead to a number of physiological problems such as the deposition of calcium phosphate.

In patients with renal failure treated by regular hemodialysis, phosphate concentrations in the blood plasma can increase dramatically and this condition, known as hyperphosphatemia, can result in calcium phosphate deposition in soft tissues. Plasma phosphate levels can be reduced by oral intake of inorganic and organic phosphate binders.

Classes of inorganic solid phosphate binders discussed in WO 99/15189. These include alkali treated inorganic sulfates such as calcium sulfate and mixed metal compounds which are substantially free of aluminum and which have a high phosphate binding capacity of at least 30% by weight of the total weight of phosphate present, over a pH range of 2-8, as measured by the phosphate binding test as described therein. The inorganic solids are water-insoluble and are primarily intended for oral administration.

Such mixed metal compounds can typically contain iron (III) and at least one of magnesium, calcium, lanthanum and cerium. They also preferably contain at least one of hydroxyl and carbonate anions and optionally in addition at least one sulphate, chloride and oxide.

Mixed metal compounds as described in WO 99/15189 present particular problems in the formulation of the unit dosages containing them. These problems are partly due to the fact that the compounds must be dosed in relatively large amounts. This means that in order for a unit dose to have a size that does not make it too difficult to swallow, which is linked to patient compliance, the inclusion level of the active ingredient must be quite high, which leaves very little room for excipients in the formulation.

There is a need for unit doses containing such inorganic solid phosphate binders which include high levels of the pharmaceutically active ingredient and yet maintain physical integrity and stability upon storage. There is also a need for such unit doses to disintegrate to release the solid inorganic phosphate binder in the stomach and provide rapid phosphate binding, but which does not disintegrate extensively in the mouth or esophagus, resulting in an unpleasant taste and possible lack of patient compliance. There is also a need to investigate routes for forming the solid inorganic phosphate binders into unit doses without problems caused by poor flowability for the material and yet without unreasonably hindering the degree of phosphate binding for the material.

Summary of the invention

A first aspect of the present invention thus provides a granular material comprising (i) at least 50% by weight based on the weight of the granular material of solid water-insoluble mixed metal compound capable of binding phosphate of formula (I):

M<II>1-xM<III>x(OH)2A<n->y.zH2O (I)

wherein M<II>is at least one of magnesium, calcium, lanthanum and cerium; M<III>is at least iron (III); A<n> is at least one nvalent anion; x = Σnew; 0 < x ≤ 0.67, 0 < y ≤ 1 and 0 ≤ z ≤ 10; (ii) from 3 to 12% by weight based on the weight of the granular material of non-chemically bound water, and (iii) not more than 47% by weight of excipient based on the weight of the granular material.

Another aspect of the invention provides a unit dose for oral administration comprising a water-resistant capsule containing granules according to the first aspect of the invention.

A third aspect of the invention provides a unit dose for oral administration comprising a compacted tablet of granules according to the first aspect of the invention. The tablet is preferably coated with a water-resistant coating.

The solid water-insoluble inorganic compound capable of binding phosphate is referred to herein as an "inorganic phosphate binder" or as "binder".

Reference herein to "granules" will likewise be used for the "granular material" according to the invention.

It has surprisingly been found that for such granules for use in unit doses, the water level is critical to maintaining the physical integrity of the granules and of unit doses prepared from the granules during storage. Correct water levels provide good phosphate binding when the granules are ingested, without excessive dissolution of the granules or of the tablets formed from the granules in the mouth. It has also been found that such granules quickly bind phosphate.

It has also been found that by providing the compound of formula I in a granular form rather than in the form of a powder, problems with the flowability of the powders and with the storage stability of powder-based tablets will be overcome, while the rapid disintegration advantage of such systems is maintained . Small particle size that one e.g. fins in the powder results in very poor flowability of the powder which results in poor tablet compression (the tablets are far too soft and not homogeneous), poor storage stability and problems with clogging of equipment. It has surprisingly been found that by first increasing the particle size of the finely divided particulate material by granulating the mixture of the compound of formula I with excipients, drying the granules to a controlled moisture content and reducing the granule size back again to a more finely divided particulate material (such as " small" particle size distribution in Table 7) suitable phosphate binding granules can be obtained without requiring significantly increased levels of excipients while enabling the operation of tablet compression machines typically capable of commercial production rates (eg from 10,000 to 150,000 tablets/hour) and compression into a suitably shaped tablet with a compact size that is not too difficult to swallow. In contrast, typical tablet formulations such as those disclosed in US4415555 or US4629626 Miyata et al of hydrotalcite materials resulted in formulations comprising less than 50% of the active compound and/or which required hydrothermal treatment of the hydrotalcite to increase the storage stability of the tablets.

The water content in the granules according to the invention is expressed as the content of non-chemically bound water in the granules. This non-chemically bound water therefore excludes chemically bound water. Chemically bound water can also be referred to as structural water.

The amount of non-chemically bound water is determined by pulverizing the granules, heating at 105<o>C for 4 hours and immediately measuring the weight loss. The weight equivalent of non-chemically bound water that is driven off can then be calculated as a weight percentage of the granules.

It has been found that if the amount of non-chemically bound water is less than 3% by weight of the granules, tablets formed from the granules become brittle and can be broken into pieces very easily. If the amount of non-chemically bound water is greater than 10% by weight of the granules, the disintegration time of the granules and of tablets prepared from the granules will increase, with an associated decrease in phosphate binding rate and the storage stability of the tablet or granules will become unacceptable, leading to disintegration at storage.

By water-insoluble phosphate binder is meant that the binder has a solubility in distilled water at 25<o>C of 0.5 g/liter or less, preferably 0.1 g/liter or less, more preferably 0.05 g/liter or less .

The water-resistant capsule according to the second aspect of the invention is suitably a hard gelatin capsule. For the water-resistant capsule, water-resistant means that when stored for 4 weeks at 40<o>C and 70% relative humidity, the water absorption for the unit dose (i.e. the capsule containing the granules according to the first aspect of the invention), which is due to changes in moisture content, preferably less than 10% and more preferably less than 5% by weight of the unit dose. Such capsules have the advantage of supporting the stabilization of the moisture content in the granules during storage.

The tablets according to the third aspect of the invention preferably have a water-resistant coating to prevent moisture from penetrating the tablet or to prevent moisture loss from the tablet during storage. However, the water-resistant coating must allow the tablet to break down after a suitable time after ingestion so that the inorganic solid phosphate binder can be effective in the patient's gut. By water resistant is meant that when stored for 4 weeks at 40<o>C and 70% relative humidity, the water absorption in the coated tablet due to changes in moisture content is preferably less than 10%, more preferably less than 5% by weight of the coated tablet. In a preferred aspect, by water resistant is meant that when stored for 12 months at 25<o>C and 60% relative humidity, the water uptake in the coated tablet due to changes in moisture content is preferably less than 10%, more preferably less than 5% by weight of the coated tablet. In a further preferred aspect, by water resistant is meant that when stored for 12 months at 30<o>C and 65% relative humidity, the water absorption in the coated tablet due to changes in moisture content is preferably less than 10%, more preferably less than 5% expressed in weight of the coated tablet. In a preferred aspect, by water resistant is meant that when stored for 6 months at 40<o>C and 75% relative humidity, the water absorption in the coated tablet due to changes in moisture content is preferably less than 10%, more preferably less than 5% expressed in weight of the coated tablet.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

Phosphate binders

By binding phosphate ions, it is meant that the phosphate ions are removed from solution and immobilized in the atomic structure of the water-insoluble inorganic solid phosphate binder.

Suitable water-insoluble inorganic solids for binding phosphate ions from solution (hereinafter also referred to as inorganic phosphate binders or in short as binders) are e.g. disclosed in WO 99/15189 and includes sulphates such as calcium sulphate which have been alkali treated, mixtures of various metal salts and mixed metal compounds as described below. Preferred water-insoluble inorganic solids for use as phosphate binders in the tablets according to the invention are mixed metal compounds.

Due to their water insolubility, it is preferred if the inorganic phosphate binders used in the tablets according to the invention are in a finely divided particle form so that a suitable surface area is provided over which phosphate binding or immobilization can take place. The inorganic phosphate binder particles suitably have a weight median particle diameter (d50) of from 1 to 20 micrometers, preferably from 2 to 11 micrometers. The inorganic phosphate binder particles preferably have a d90 (ie 90% by weight of the particles have a diameter smaller than the d90 value) of 100 micrometers or less.

Mixed metal binders

The present invention provides a granular material comprising (i) at least 50% by weight based on the weight of the granular material of a solid mixed metal compound capable of binding phosphate of formula (I):

M<II>1-xM<III>x(OH)2A<n->y.zH2O (I)

wherein M<II>is at least one of magnesium, calcium, lanthanum and cerium; M<III>is at least iron (III); A<n> is at least one n-valent anion; x = Σnew; 0 < x ≤ 0.67, 0 < y ≤ 1, and 0 ≤ z ≤ 10; (ii) from 3 to 12% by weight based on the weight of the granular material of non-chemically bound water, and (iii) not more than 47% by weight of excipient based on the weight of the granular material. The present invention further provides a unit dose for oral administration comprising a water resistant capsule containing the granular material. The present invention further provides a unit dose for oral administration comprising a compressed tablet of the granular material. The tablet is preferably coated with a water-resistant coating.

A preferred inorganic phosphate binder is a solid water-insoluble mixed compound of formula (I):

M<II>1-xM<III>x(OH)2A<n->y.zH2O (I)

where M<II>is at least one bivalent metal; M<III>is at least one trivalent metal; A<n> is at least one n-valent anion; x = Σny and x, y and z satisfy 0 < x ≤ 0.67, 0 < y ≤ 1.0 ≤ z ≤ 10.

In a preferred aspect, 0.1 < x, such as 0.2 < x, 0.3 < x, 0.4 < x, or 0.5 < x. In another preferred aspect, 0 < x ≤ 0.5. It will be understood that x = [M<III>]/([M<II>] [M<III>]) where [M<II]>is the number of moles of M<II>per mole of compound of formula I and [ M<III>] is the number of moles of M<III>per mole of compound of formula I.

In a preferred aspect, 0 < y ≤ 1. Preferred is 0 < y ≤ 0.8. Preferred is 0 < y ≤ 0.6. Preferred is 0 < y ≤ 0.4. Preferred is 0.05 < y ≤ 0.3. Preferred is 0.05 < y ≤ 0.2. Preferred is 0.1 < y ≤ 0.2. Preferred is 0.15 < y ≤ 0.2.

In a preferred aspect, 0 ≤ z ≤ 10. Preferred is 0 ≤ z ≤ 8. Preferred is 0 ≤ z ≤ 6. Preferred is 0 ≤ z ≤ 4. Preferred is 0 ≤ z ≤ 2. Preferred is 0.1 ≤ z ≤ 2.

Preferred is 0.5 ≤ z ≤ 2. Preferred is 1 ≤ z ≤ 2.

Preferred is 1 ≤ z ≤ 1.5. Preferred is 1 ≤ z ≤ 1.4.

Preferred is 1.2 ≤ z ≤ 1.4. Preferably z is about 1.4.

Preferred are 0 < x ≤ 0.5, 0 < y ≤ 1 and 0 ≤ z ≤ 10.

It will be understood that each of the preferred values for x, y and z can be combined. Thus, any combination of each of the values set forth in the table below is specifically set forth herein and may be provided by the present invention.

In the above formula (I), when A represents more than one anion, the valency (n) of each may vary. "Σny" means the sum of the number of moles of each anion multiplied by its respective valence.

In the formula (I), M<II> is preferably selected from Mg (II), Zn (II), Fe (II), Cu (II), Ca (II), La (II) and Ni(II). Of these, Mg is particularly preferred. M<III> is preferably selected from Mn(III), Fe(III), La(III), Ni(III) and Ce(III). Of these, Fe(III) is particularly preferred. (II) herein means a metal in a divalent state and (III) means a metal in a trivalent state.

A<n> is preferably selected from one or more of carbonate, hydroxycarbonate, oxo anions (e.g. nitrates, sulfate), metal complex anion (e.g. ferrocyanide), polyoxometalates, organic anions, halide, hydroxide and mixtures thereof. Of these, carbonate is particularly preferred.

The compound preferably comprises less than 200 g/kg aluminum, more preferably less than 100 g/kg, even more preferably less than 50 g/kg expressed as weight of aluminum metal per unit weight of the compound.

More preferably, only low levels of aluminum are present such as less than 10 g/kg, preferably less than 5 g/kg.

Even more preferably, the compound is free of aluminum (Al). With the designation "free of aluminum" is meant that the material designated "free of aluminum" comprises less than 1 g/kg, more preferably less than 500 mg/kg, even more preferably less than 200 mg/kg and most preferably less than 120 mg/kg kg, expressed as the weight of elemental aluminum per unit weight of the compound.

The compound contains suitable iron (III) and at least one of magnesium, calcium, lanthanum or cerium, more preferably at least one of magnesium, lanthanum or cerium, and most preferably magnesium.

The compound preferably comprises less than 100 g/kg calcium, more preferably less than 50 g/kg, even more preferably less than 25 g/kg expressed as weight of elemental calcium per unit weight of the compound.

More preferably, only low levels of calcium are present such as less than 10 g/kg, preferably less than 5 g/kg.

Even more preferably, the compound is free of calcium. The term "free of calcium" means that the material designated "free of calcium" comprises less than 1 g/kg, more preferably less than 500 mg/kg, even more preferably less than 200 mg/kg, most preferably less than 120 mg/kg kg expressed as weight of elemental calcium per unit weight of material.

The binder compound is preferably free of calcium and free of aluminium.

The final unit dose comprising granules and any other material that makes up the final unit dose, taken as a whole, is also preferably free of aluminum and/or free of calcium, using the definitions detailed above.

The solid mixed metal compound preferably comprises at least some material which is a "Layered Double Hydroxide" (LDH). More preferably, the mixed metal compound of formula (I) is a "Layered Double Hydroxide". As used herein, the term "Layered Double Hydroxide" is used to denote synthetic or natural lamellar hydroxides with two different types of metal cations in the main layers and the interlayer domains containing anionic types. This extensive family of compounds is sometimes also referred to as anionic clays by comparison with the more common cationic clays whose interlamellar domains contain cationic species. LDHs have also been reported as hydrotalcite-like compounds referring to one of the polytypes of the corresponding [Mg-Al]-based mineral.

A particularly preferred mixed metal compound contains at least one of carbonate ions and hydroxyl ions.

A particularly preferred compound contains magnesium and iron (III) as M<II> and M<III> respectively.

The solid mixed metal compound or compounds may conveniently be prepared by coprecipitation from a solution, e.g. as described in WO 99/15189, followed by centrifugation or filtration, then drying, grinding and sieving. The mixed metal compound is then rewetted as part of the wet granulation process and the resulting granules are dried in a fluidized bed. The degree of drying in the fluidized bed is used to establish the desired water content in the final tablet.

Alternatively, the mixed metal compound can be formed by heating an initial mixture of finely divided single metal salts at a temperature at which solid-solid reaction can occur, leading to the formation of a mixed metal compound.

The solid mixed metal compound of formula (I) can be calcined by heating at temperatures above 200<o>C to decrease the value of z in the formula. In this case, it may be necessary to add water after calcination and before incorporating the solid mixed metal compound into the granules to achieve the desired non-chemically bound water content of the granules.

It will be understood by one skilled in the art that the water provided by zH2O in formula (I) can provide a portion of the 3 to 12%, expressed by weight, of non-chemically bound water (based on the weight of the granular material). One skilled in the art can readily determine the value of z based on standard chemical techniques. When the material according to the invention has been provided, the amount of the non-chemically bound water can then also be easily determined in accordance with the procedure described herein.

By mixed metal compound is meant that the atomic structure of the compound includes the cations of at least two different metals which are evenly distributed throughout the structure thereof.

The term mixed metal compound does not include mixtures of crystals of two salts, where each crystal type includes only one metal cation. Mixed metal compounds are typically the result of coprecipitation from dissolution of different single metal compounds as opposed to a simple solid physical mixture of two different single metal compounds. Mixed metal compounds as used herein include compounds of the same metal type but with the metal in two different valence states, e.g. Fe(II) and Fe(III) as well as compounds containing more than 2 different metal types in one compound.

The mixed metal compound may also comprise amorphous (non-crystalline) material. The term amorphous refers to either crystalline phases that have crystallite sizes below the detection limits of X-ray diffraction techniques, or crystalline phases that have some degree of order but do not exhibit a crystalline diffraction pattern and/or true amorphous materials that exhibit short-range order but not long-range order.

The compound of formula I is preferably formed without aging or hydrothermal treatment to avoid the crystals in the compound growing in size and to maintain a high surface area over which phosphate binding can take place. The non-aging compound of formula I is preferably maintained in a fine particle size form during the post-synthesis route to maintain good phosphate binding.

Phosphate binding

Any reference herein to phosphate binding capacity means phosphate binding capacity as determined by the following method, unless otherwise specifically stated.

40 mmol/litre sodium phosphate solution (pH 4) is prepared and treated with the phosphate binder. The filtered solution of the treated phosphate solution is then diluted and analyzed by ICP-OES for phosphorus content.

Reagents used in this method are:

"Sodium dihydrogen phosphate monohydrate (BDH, AnalaR quality), 1M hydrochloric acid, AnalaR water, standard phosphorus solution (10000 μg/ml, Romil Ltd.), sodium chloride (BDH).

Specific apparatus used are: Rolling hybridization incubator or equivalent (Grant Boekal HIW7), 10 ml blood collection tubes, Nalgene multi-use screw-top tubes (30 ml/50 ml), 10 ml disposable syringes, 0.45 μm disposable syringe filter, ICP-OES (inductively coupled plasma - optical emission spectrometer).

Phosphate solution is prepared by weighing 5.520 g (+/- 0.001 g) of sodium dihydrogen phosphate followed by the addition of some AnalaR water and transfer to a 1 liter volumetric flask.

To the 1 liter volumetric flask, 1 M HCl is then added dropwise to adjust the pH to pH 4 (+/- 0.1) with mixing between additions. The volume is then set exactly up to one liter by using AnalaR water and mixing thoroughly.

NaCl solution is prepared by accurately weighing out 5.85 g (+/- 0.02 g) NaCl and with quantitative transfer thereof to a 1 liter volumetric flask, after which the volume is set with AnalaR water and thoroughly mixed.

Calibration standards are prepared by pipetting the following solutions into 100 ml volumetric flasks:

The solutions were then made up to volume with AnalaR water and mixed thoroughly. These solutions are then used as calibration standards for the ICP-OES apparatus.

The phosphate binder samples are then prepared in accordance with the procedure described below and measured by ICP-OES. The ICP-OES results are initially expressed as ppm but can be converted to mmol by applying the equation: mmol = (ICP-OES reading in ppm/molecular weight of the analyte) x 4 (dilution factor).

Samples of each test sample, with each sample containing 0.5 g of the phosphate binder, are placed in 30 ml Nalgene tubes with screw tops. If the test sample is a unit dose comprising 0.5 g of the phosphate binder, it can be used as such. All samples are produced in duplicate. 12.5 ml samples of the phosphate solution are pipetted into each of the screw top tubes containing the test samples and the screw top is adjusted. The prepared tubes are then placed in the rotary incubator preheated to 37<o>C and rotated at full speed for a set time such as 30 minutes (other times may be used as shown in the examples). The samples are then removed from the rotary incubator, filtered through a 0.45 μm syringe filter and 2.5 ml of filtrate transferred to a blood collection tube.

7.5 ml of AnalaR water is pipetted into each 2.5 ml sample and mixed thoroughly. The solutions are then analyzed on ICP-OES.

The phosphate binding capacity is determined by: phosphate binding (%) = 100 - (T/S x 100)

where

T = Analyte value for phosphate in solution after reaction with phosphate binder.

S = Analyte value for phosphate in solution before reaction with phosphate binder.

The water-insoluble inorganic solid phosphate binders used in the granules according to the invention suitably provide a phosphate binding capacity for the material as measured by the above method which is at least 30% after 30 minutes, preferably at least 30% after 10 minutes, more preferably at least 30% after 5 minutes. The water-insoluble inorganic solid phosphate binders used in the tablets according to the invention preferably have a phosphate binding capacity as measured by the above method of at least 40% after 30 minutes, preferably at least 30% after 10 minutes, more preferably at least 30% after 5 minutes. Even more preferably, the water-insoluble inorganic solid phosphate binders used in the tablets according to the invention have a phosphate binding capacity as measured by the above method which is at least 50% after 30 minutes, preferably at least 30% after 10 minutes, more preferably at least 30% after 5 minutes.

The pH in the phosphate binding measurement can be varied by using the addition of either 1 M HCl or NaOH solution. The measurement can then be used to determine the phosphate binding capacity at varying pH values.

The water-insoluble inorganic solid phosphate binders used in the tablets according to the invention suitably have a phosphate binding capacity at a pH from 3 to 6, preferably at a pH from 3 to 9, more preferably at a pH from 3 to 10, most preferably at a pH from 2 to 10, as measured by the above method, of at least 30% after 30 minutes, preferably at least 30% after 10 minutes, more preferably at least 30% after 5 minutes.

The water-insoluble inorganic solid phosphate binders used in the tablets according to the invention preferably have a phosphate binding capacity at a pH of from 3 to 4, preferably from 3 to 5, more preferably from 3 to 6 as measured by the above method which is at least 40% after 30 minutes, preferably at least 40% after 10 minutes, more preferably at least 40% after 5 minutes.

Even more preferably, the water-insoluble inorganic solid phosphate binders used in the tablets according to the invention have a phosphate binding capacity at a pH of from 3 to 4, preferably from 3 to 5, more preferably from 3 to 6, as measured by the above method, of at least 50 % after 30 minutes, preferably at least 50% after 10 minutes, more preferably at least 50% after 5 minutes. It will be understood that it is desirable to have a high phosphate binding capacity over as large a pH range as possible.

An alternative method of expressing phosphate binding capacity using the method described above is to express the phosphate bound by the binding agent as mmol of phosphate bound per gram of binding agent.

Applying this description for phosphate binding, the water-insoluble inorganic solid phosphate binders used in the tablets according to the invention suitably have a phosphate binding capacity at a pH from 3 to 6, preferably at a pH from 3 to 9, more preferably at a pH from 3 to 10 , most preferably at a pH from 2 to 10 as measured by the above method of at least 0.3 mmol/g after 30 minutes, preferably at least 0.3 mmol/g after 10 minutes, more preferably at least 0.3 mmol/g after 5 minutes. The water-insoluble inorganic solid phosphate binders used in the tablets according to the invention preferably have a phosphate binding capacity at a pH of from 3 to 4, preferably from 3 to 5, more preferably from 3 to 6 as measured by the above method of at least 0.4 mmol/ g after 30 minutes, preferably at least 0.4 mmol/g after 10 minutes, more preferably at least 0.4 mmol/g after 5 minutes. Even more preferably, the water-insoluble inorganic solid phosphate binders used in the table according to the invention have a phosphate binding capacity at a pH of from 3 to 4, preferably from 3 to 5, more preferably from 3 to 6 as measured by the above method of at least 0.5 mmol/g after 30 minutes, preferably at least 0.5 mmol/g after 10 minutes, more preferably at least 0.5 mmol/g after 5 minutes.

Granules

The granules according to the present invention comprise at least 50%, preferably at least 60%, more preferably at least 70%, most preferably at least 75%, expressed by weight, of inorganic phosphate binder.

The granules according to the invention comprise from 3 to 12% by weight of non-chemically bound water, preferably from 5 to 10% by weight.

The rest of the granules comprise a pharmaceutically acceptable carrier for the phosphate binder, mainly an excipient or mixture of excipients, which provides the balance of the granules. Accordingly, the granules may comprise at most 47% by weight of excipient, the granules preferably comprise from 5 to 47% by weight of excipient, more preferably from 10 to 47% by weight of excipient, more preferably from 15 to 47% by weight of excipient.

Granule size

At least 95% by weight of the granules suitably have a diameter of less than 1180 µm as measured by sieving.

At least 50% by weight of the granules preferably have a diameter smaller than 710 μm as measured by sieving.

At least 50% by weight of the granules preferably have a diameter from 106 to 1180 μm, preferably from 106 to 500 μm.

Even more preferably, at least 70% by weight of the granules have a diameter from 106 to 1180 μm, preferably from 106 to 500 μm.

The weight average particle diameter of the granules is preferably from 200 to 400 μm.

Larger granules can lead to unacceptably slow phosphate binding. Too high a proportion of granules smaller than 106 μm in diameter can lead to the problem of poor flowability of the granules. At least 50% by weight of the granules preferably have a diameter greater than 106 μm as measured by sieving, more preferably at least 80% by weight.

Granular components

Suitable excipients which may be included in the granules include conventional solid diluents such as e.g. lactose, starch or talc, as well as materials derived from animal or vegetable proteins, such as gelatins, dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; polypeptide/protein or polysaccharide complexes such as gelatin-acacia complexes; sugars such as mannitol, dextrose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates; and amino acids with from 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.

The term excipient herein also includes auxiliary components such as tablet structuring agents or adhesives, disintegrating agents or bulking agents.

Suitable tablet builders include acacia, alginic acid, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxypropylmethylcellulose, caltodextrin, methylcellulose, polyethylene oxide, povidone, sodium alginate and hydrogenated vegetable oils.

Suitable disintegrants include cross-linked disintegrants. Suitable disintegrants include e.g. cross-linked sodium carboxymethyl cellulose, cross-linked hydroxypropyl cellulose, high molecular weight hydroxypropyl cellulose, carboxymethyl amide, potassium methacrylate divinylbenzene copolymer, polymethyl methacrylate, cross-linked polyvinylpyrrolidone (PVP) and high molecular weight polyvinyl alcohols.

Cross-linked polyvinylpyrrolidone (also known as cross-povidone, e.g. available as Kollidon CL-M ex BASF) is a particularly preferred excipient for use in the tablets according to the invention. The granules in the tablets according to the invention suitably comprise from 1 to 15% by weight of cross-linked polyvinylpyrrolidone, preferably from 1 to 10%, more preferably from 2 to 8%. The cross-linked polyvinylpyrrolidone preferably has a d50 weight-median particle size, before granulation, of less than 50 μm (ie so-called B-type cross-linked PVP). Such a material is also known as micronized cross-povidone. It has been found that the cross-linked polyvinylpyrrolidone at these levels leads to good disintegration of the tablet but with less inhibition of phosphate binding by the inorganic phosphate binder compared to some other excipients. The preferred sizes for the cross-linked polyvinylpyrrolidone provide reduced sandiness and hardness of the formed particles when the tablets disintegrate.

Another preferred excipient for use in the granules in the tablets according to the invention is pregelatinized starch (also known as pre-gelled starch). The granules preferably comprise from 5 to 20% by weight of pre-gelled starch, more preferably from 10 to 20%, even more preferably from 12 to 18% by weight. At these levels, the pregelatinized starch will improve the durability and cohesion of the tablets without preventing the disintegration or phosphate binding of the tablets during use. The pregelatinized starch is suitably fully pregelatinized, with a moisture content of from 1 to 15% by weight and a weight-median particle diameter of from 100 to 250 μm. A suitable material is Lycotab, a fully pregelatinized corn starch available from Roquette.

A combined excipient that includes both pregelatinized starch and cross-povidone is particularly preferred, as this combination of excipients gives the ability to reliably form compacted tablets of different shapes, good granule homogeneity and good disintegration properties from the granules according to the invention.

The granules may also include preservatives, wetting agents, antioxidants, surfactants, effervescent agents, dyes, flavourings, pH modifying agents, sweeteners or taste masking agents. Suitable dyes include red, black and yellow iron oxides and FD & C colors such as FD & C Blue No. 2 and FD & C Red No. 40 available from Ellis & Everard. Suitable flavorings include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavorings and combinations thereof. Suitable pH modifying agents include sodium bicarbonate (ie bicarbonate), citric acid, tartaric acid, hydrochloric acid and malic acid. Suitable sweeteners include aspartane, acesulfame K and thaumatin. Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds and absorbants. Suitable humectants include sodium lauryl sulfate and sodium docusate. A suitable effervescent or gas producing agent is a mixture of sodium bicarbonate and citric acid.

Granulation

Granulation can be carried out by a process comprising the step of:

i) mixing the solid water-insoluble inorganic compound capable of binding phosphate with one or more excipients to form a homogeneous mixture, ii) bringing a suitable liquid into contact with the homogeneous mixture and mixing in a granulator to form wet granules,

iii) optionally passing the wet granules through a sieve to remove granules larger than the sieve size, iv) drying the wet granules to provide dry granules,

v) grinding and/or sieving the dry granules.

The granulation is suitable for wet granulation and included the step of:

i) mixing the inorganic solid phosphate binder with suitable excipients to produce a homogeneous mixture;

ii) adding a suitable liquid to the homogeneous mixture and mixing in a granulator to form granules, iii) optionally passing the wet granules through a sieve to remove granules larger than the sieve size, iv) drying the granules,

v) grinding and screening of the granules.

Suitable liquids for the granulation include water, ethanol and mixtures thereof. Water is a preferred granulating liquid.

The granules are dried to the desired moisture levels as described above prior to their use in tableting or incorporation into a capsule for use as a unit dose.

Lubricant

Prior to tableting the granules into a unit dose composition, it is preferred that the granules are mixed with a lubricant or lubricant so that a lubricant or lubricant is distributed over and between the granules during compaction of the granules to form tablets.

The optimum amount of lubricant required typically depends on the lubricant particle size and the available surface area of the granules. Suitable lubricants include silica, talc, stearic acid, calcium or magnesium stearate, and sodium stearyl fumarate and mixtures thereof. The lubricant is added to the granules in a finely divided form, with no particles typically larger than 40 μm in diameter (which is typically ensured by sieving). The lubricant is suitably added to the granules at a level of from 0.1 to 0.4%, preferably from 0.2 to 0.3%, expressed by weight of the granules. Lower levels can lead to sticking or blocking of the tablet nozzle, while higher levels can reduce the degree of phosphate binding or prevent tablet disintegration. Salts of fatty acids can be used as lubricants, such as calcium and/or magnesium stearate. A suitable lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate and mixtures thereof. It has been found that certain lubricants, such as fatty acids, lead to the formation of holes and loss of integrity in the coating layer of the tablets. It is believed that this may stem from partial melting of the lubricant when the coating layer is dried. It is thus preferred that the lubricant has a melting point in excess of 55<o>C.

Pills

The tablets according to the third aspect of the invention can be prepared by compressing granules, under a high pressure, to form a tablet having the necessary compressive strength for the handling required during packaging and distribution. The use of granules formed from a granulated powder mixture improves the flowability from the storage containers to the tableting press which in turn benefits the efficiency of tablet processing. The inorganic phosphate binders used in the tablets according to the invention typically have poor flow characteristics at their desired particle size as stated in detail above. Because it is desirable that the tablets according to the invention comprise high levels of inorganic phosphate binder, in the order of 50% or more, expressed by weight of the tablet, the inorganic phosphate binder must be formed into granules prior to tablet formation. A fine powder tends to pack or "bridge" in the funnel, "feed shoe" or nozzle, and thus tablets of equal weight or equal compression are difficult to achieve. Even if it were possible to compress fine powders to a satisfactory degree, air can be trapped and compressed leading to splitting of the tablet on ejection. Using granules helps to overcome these problems. Another advantage of granulation is an increase in bulk density of the final tablet when prepared from granules rather than from the fine powder, which reduces the size of the final tablet and improves the likelihood of better patient compliance.

The tablets according to the invention can be circular but have generally preferred a bolus shape or a torpedo shape (also known as a double convex oblong shaped tablet), i.e. having an elongated dimension, to make it easier to swallow larger doses. They can e.g. be in the form of a cylinder with rounded ends or which is elliptical in one dimension and circular in an orthogonal dimension, or which is elliptical in both. Some flattening of one or more parts of the overall shape is also possible.

Where the tablet is in the form of a tablet equipped with a "gastric band", it is preferred that the width of the gastric band is 2 mm or more. It has been found that smaller gastric bands can lead to inadequate coverage or peeling or loss of integrity of the water resistant coating of the tablet.

The tablets in the second aspect of the invention preferably have a hardness of from 5 to 30 kgf as measured using a Holland C50 tablet hardness tester.

Water resistant coating

The tablets according to the second aspect of the invention are, as soon as they are formed from the granules according to the first aspect of the invention, preferably equipped with a water-resistant coating.

The water resistant coating may be applied to the tablet by any commonly used pharmaceutical coating process or equipment. Tablets can e.g. is coated using fluidized bed equipment (e.g., a "Wurster" type fluidized bed dryer, coating pans (rotary, side vented, conventional, etc.), by atomizing nozzles or guns or other atomizing types or by dipping or by newer techniques that include " Supercell tablet coater" from Niro PharmaSystems. Variations in available equipment include size, shape, location of nozzles and air inlets and outlets, air flow pattern, and degree of instrumentation. Heated air may be used to dry the tablets subjected to atomization in a manner that permits continuous atomization while the tablets are simultaneously dried. Discontinuous or intermittent atomization can also be used, but it generally requires longer coating cycles. The number and position of the nozzles can be varied as needed depending on the coating operation and the nozzle(s) preferably aim perpendicularly or almost perpendicularly to the layer, although other aiming directions can be used if wished . A pan can be rotated at a speed selected from several operating speeds. A suitable system capable of applying a coating composition to a tablet can be used. In effect, any tablet is acceptable herein as a tablet to be coated. The term "tablet" may include tablet, pellet or pill. The preferred tablet will typically be in a form that is sufficiently stable, physically and chemically, to be effectively coated in a system that involves some movement of a tablet, such as e.g. a fluidized bed, such as in a fluidized bed dryer or a side-ventilated coating pan, combinations thereof and the like. Tablets can be coated directly, i.e. without a sub-coating to prepare the surface. Sub-coating or top coating can of course be used. If desired, the same or a similar coating system can be used both for a first or second or several coatings. The coating composition is prepared according to the physical properties of its constituents, i.e. soluble materials are dissolved, insoluble materials are dispersed. The type of mixture used is also based on the properties of the ingredients. Liquid mixing at low shear is used for soluble materials and liquid mixing with high shear is used for insoluble materials. Typically, the coating formulation consists of two parts, the colloidal polymer suspension and the pigment suspension or solution (eg red oxide or quinoline yellow dye). These are prepared separately or mixed before use.

A number of coating materials can be used, such as e.g. cellulose derivatives, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, polyethylene glycols, copolymers of styrene and acrylate, copolymers of acrylic acid and methacrylic acid, copolymers of methacrylic acid and ethyl acrylate, copolymers of methyl methacrylate and methacrylate, copolymers of methacrylate and tertiary aminoalkyl methacrylate, copolymers of ethyl acrylate-methyl methacrylate and quaternary aminoalkyl methacrylate and combinations of two or more thereof. Salts of methacrylate copolymers are preferably used, e.g. butylated methacrylate copolymer (commercially available as Eudragit EPO).

The coating is suitably present from 0.05 to 10%, expressed by weight of the coated tablet, preferably from 0.5% to 7%. The coating material is preferably used in combination with red iron oxide pigment (Fe2O3) (1% or more, preferably 2% or more, expressed by weight of the dried coating layer) which is dispersed throughout the coating material and which provides a uniform color of the coating layer on the tablet which gives a pleasant homogeneous appearance.

In addition to protecting the tablet core against loss of moisture or penetration during storage, the water-resistant coating layer will also help prevent the rapid dissolution of the tablet in the mouth, and where this is left until the tablet reaches the stomach. With this purpose in mind, it is preferred if the coating material has low solubility in alkaline solution such as is found in the mouth, but is more soluble in a neutral or acidic solution. Preferred coating polymers are salts of methacrylate copolymers, especially butylated methacrylate copolymer (commercially available as Eudragit EPO). The coating layer preferably comprises at least 30% by weight of a coating polymer, more preferably at least 40% by weight.

The water loss or water uptake in coated tablets is appropriately measured as detailed above for measuring the non-chemically bound water content of granules. From a group of newly manufactured coated tablets, some are measured for non-chemically bound water immediately after manufacture, and others are measured after storage as detailed above.

In another aspect, the invention provides a method for preparing a tablet according to the first aspect of the invention, the method comprising granulating water-insoluble inorganic solid phosphate binder with a pharmaceutically acceptable excipient and optionally, any other ingredients, forming a tablet from the granules by compression and possibly applying a water-resistant coating to the tablet thus formed.

Capsules

Suitable capsules for use in the second aspect of the invention are hard gelatin capsules, although other suitable capsule films may be used.

Application of unit doses

For the treatment and prophylaxis of hyperphosphatemia, amounts from 0.1 to 500, preferably from 1 to 200 mg/kg body weight of inorganic phosphate binder are preferably administered daily to achieve the desired results.

Nevertheless, it may be necessary from time to time to deviate from the amounts mentioned above, depending on the patient's body weight, the animal type of the patient and the patient's individual reaction to the drug or the type of formulation or the time or interval at which the drug is administered. In special cases, it may be sufficient to use less than the minimum amount stated above, while in other cases the maximum dose may have to be exceeded. For a larger dose, it may be advisable to divide the dose into several smaller single doses. Finally, the dose will depend on the judgment of the practitioner. Administration before the meal, e.g. within an hour before a meal is appropriate. Alternatively, the dose can be taken with a meal.

A typical tablet according to the invention for administration to an adult human may comprise from 1 mg to 5 g, preferably from 10 mg to 2 g, more preferably from 100 mg to 1 g, such as from 150 mg to 750 mg, from 200 mg to 750 mg or from 250 mg to 750 mg of water-insoluble inorganic solid phosphate binder.

The unit dose according to the invention preferably comprises at least 200 mg of a water-insoluble solid inorganic phosphate binder. The unit doses according to the invention preferably comprise at least 250 mg of a water-insoluble solid inorganic phosphate binder. The unit dose according to the invention preferably comprises at least 300 mg of a water-insoluble solid inorganic phosphate binder. A more preferred unit dose comprises 500 mg of the phosphate binder. The preferred unit dose weight is less than 750 mg, more preferably less than 700 mg, to support patient compliance for oral dosing. A particularly preferred unit dose contains 200 mg (± 20 mg) of a water-insoluble solid inorganic phosphate binder. A particularly preferred unit dose contains 250 mg (± 20 mg) of a water-insoluble solid inorganic phosphate binder. A particularly preferred unit dose contains 300 mg (± 20 mg) of a water-insoluble solid inorganic phosphate binder. When the unit dose is a tablet, the preferred unit dose weight will include any optional coating.

The tablet forms can be packaged together in a container or presented in foil strips, blister packs or the like, e.g. marked with days or weeks with regard to the respective doses, for patient guidance.

In further aspects of the invention set out in more detail below, granular material refers to the granules according to the first aspect of the invention.

One aspect of the invention is the granular material for use in or as a medicine on humans or animals, particularly as a medicine for binding phosphate, more particularly for the treatment of hyperphosphatemia.

Another aspect is the use of the granular material for the manufacture of a medicament for use in animals or humans in the treatment or therapy of a condition or disease associated with unfavorable phosphate levels, particularly increased plasma phosphate levels, particularly hyperphosphatemia.

Another aspect is a method for the treatment or therapy of a condition or disease associated with unfavorable phosphate levels, particularly increased plasma phosphate levels, particularly hyperphosphatemia by oral administration of the granular material to humans or animals.

Storage

As discussed herein, it has been found that the system according to the invention can provide tablets which are stable over a period of at least 12 months (see table 7 for particle size of small and large granules) as determined at 25<o>C/ 60RH and 30<o> C/65RH. Under more extreme storage conditions (40<o>C/75RH), the storage stability is at least 6 months for both granule types.

Additional aspects

Further aspects of the present invention are described in the following numbered section:

1. Granules comprising at least 50% by weight of a water-insoluble inorganic solid phosphate binder, from 3 to 12% by weight of non-chemically bound water and up to 47% by weight of excipient.

2. Granules according to paragraph 1 wherein the water-insoluble inorganic solid phosphate binder is a mixed metal compound.

3. Granules according to paragraph 2, wherein the mixed metal compound is a compound of formula (I):

M<II>1-xM<III>x(OH)2A<n->y.zH2O (I)

wherein M<II>is at least one bivalent metal; M<III>is at least one trivalent metal; A<n> is at least one n-valent anion; x = Σny and x, y and z satisfy 0 < x ≤ 0.67, 0 < y ≤ 1.0 ≤ z ≤ 10.

4. Granules according to section 3 where x = Σny and x, y and z satisfy 0 < x ≤ 0.5, 0 < y ≤ 1.0 ≤ z ≤ 10.

5. Granules according to one or more of paragraphs 2 to 4 wherein the mixed metal compound is free of aluminum and contains the metals iron (III) and at least one of magnesium, calcium, lanthanum or cerium.

6. Granules as set forth in any of paragraphs 3 to 5 wherein the mixed metal compound of formula (I) is a layered double hydroxide.

7. Granules as set forth in one of several of paragraphs 3 to 6 in which the mixed metal compound contains at least one of hydroxyl and carbonate ions and contains as the metals iron (III) and magnesium.

8. Granules as set forth in any of paragraphs 1 to 7, wherein the granules comprise from 5 to 15% by weight of polyvinylpyrrolidone as an excipient.

9. Granules as set forth in one or more of paragraphs 1 to 8, comprising from 10 to 20% by weight of pregelatinized starch as an excipient.

10. Granules as set forth in any of paragraphs 1 to 9 wherein the granule has a diameter of less than 1000 μm.

11. A unit dose for oral administration comprising a water-resistant capsule containing granules according to any of the above paragraphs.

12. A unit dose for oral administration comprising a compressed tablet of granules according to any one of paragraphs 1 to 10.

13. A unit dose as specified in section 12 which further comprises a lubricant between the granules.

14. A unit dose as indicated in section 13 comprising magnesium stearate as a lubricant between the granules.

15. A unit dose as set forth in any of paragraphs 12 to 14 which is coated with a water resistant coating.

16. A unit dose as set forth in paragraph 15 wherein the water resistant coating comprises at least 30% by weight of a butylated methacrylate copolymer.

17. A unit dose as set forth in one or more of paragraphs 12 to 16 wherein the tablet is provided with a gastric band having a width of 2 mm or more.

18. A unit dose as set forth in one or more of paragraphs 11 to 17 comprising at least 300 mg of a water-insoluble inorganic solid phosphate binder.

1A. A granular material comprising

(i) at least 50% by weight based on the weight of the granular material of a solid water-insoluble inorganic compound capable of binding phosphate,

(ii) from 3 to 12% by weight based on the weight of the granular material of non-chemically bound water, and (iii) at most 47% by weight based on the weight of the granular material of an excipient.

2A. A granular material as set forth in paragraph 1A wherein the water-insoluble inorganic solid phosphate binder is a mixed metal compound.

3A. A granular material as set forth in clause 2A wherein the mixed metal compound is a compound of formula (I): M<II>1-xM<III>x(OH)2A<n->y.zH2O (I)

where M<II>is at least one bivalent metal; M<III>is at least one trivalent metal; A<n> is at least one n-valent anion; x = Σnew; 0 < x ≤ 0.67, 0 < y ≤ 1 and 0 ≤ z ≤ 10.

4A. A granular material as set out in section 3A where x = Σny; 0 < x ≤ 0.5, 0 < y ≤ 1 and 0 ≤ z ≤ 10.

5A. A granular material as set forth in clause 3A or 4A wherein the mixed metal compound of formula (I) is a layered double hydroxide.

6A. A granular material as set forth in one or more of paragraphs 2A to 5A wherein the mixed metal compound contains at least one of hydroxyl and carbonate ions and contains, as the metals, iron (III) and magnesium.

7A. Granular material as set forth in any of paragraphs 1A to 6A wherein the water-insoluble inorganic compound is free of aluminum.

8A. A granular material as set forth in any of paragraphs 1A to 7A wherein the water-insoluble inorganic compound contains iron (III) and at least one of magnesium, calcium, lanthanum or cerium.

9A. A granular material as set forth in any of paragraphs 1A to 8A, wherein the granular material comprises from 5 to 20% by weight of pregelatinized starch as an excipient based on the weight of the granular material.

10A. A granular material as set forth in any of paragraphs 1 to 9A, comprising from 1 to 15% by weight of polyvinylpyrrolidone as an excipient based on the weight of the granular material.

11A. A granular material as set forth in any of paragraphs 1A to 10A wherein at least 95% by weight of the granules of the granular material have a diameter of less than 1180 μm.

12A. A unit dose for oral administration comprising a water-resistant capsule containing a granular material as set forth in any of paragraphs 1A to 11A.

13A. A unit dose for oral administration comprising a compacted tablet of a granular material according to any of paragraphs 1A to 11A.

14A. A unit dose as specified in section 13A which further comprises a lubricant between the granules.

15A. A unit dose as specified in section 14A in which the lubricant is or comprises magnesium stearate.

16A. A unit dose as specified in any of paragraphs 13A to 15A which is coated with a water resistant coating. 17A. A unit dose as set forth in Section 16A wherein the water resistant coating comprises at least 30% by weight of a butylated methacrylate copolymer.

18A. A unit dose as set forth in any of paragraphs 16A to 17A wherein the tablet has a gastric band having a width of 2 mm or more.

19A. A unit dose as set forth in any of paragraphs 12A to 18A wherein the solid water-insoluble inorganic compound capable of binding phosphate is present in an amount of at least 300 mg.

20A. A process for preparing a granular material as defined in any of paragraphs 1A to 11A comprising the step of:

i) mixing the solid water-insoluble inorganic compound capable of binding phosphate with one or more excipients to produce a homogeneous mixture, ii) contacting a suitable liquid with the homogeneous mixture and with the mixture in a granulator to form wet granules,

iii) optionally passing the wet granules through a sieve to remove granules larger than the sieve size, iv) drying the wet granules to provide dry granules,

v) grinding and/or sieving the dry granules.

21A. A process as set forth in section 2A wherein the liquid is selected from water, ethanol and mixtures thereof.

22A. A granular material as set forth in any of paragraphs 1A to 11A for use in medicine.

23A. Use of a granular material as set forth in any of paragraphs 1A to 11A for the manufacture of a phosphate binding medicament.

24A. Use of a granular material as set forth in any of paragraphs 1A to 11A for the manufacture of a medicament for use in the therapy of a condition or disease associated with phosphate levels.

25A. Use of a granular material as set forth in any of paragraphs 1A to 11A for the manufacture of a medicament for use in the therapy of a condition or disease associated with undesirable phosphate levels.

26A. Use of a granular material as set forth in any of paragraphs 1A to 11A for the manufacture of a medicament for use in the therapy of a condition or disease associated with increased plasma phosphate levels.

27A. Use of a granular material as set forth in any of paragraphs 1A to 11A for the manufacture of a medicament for use in the therapy of hyperphosphatemia.

The present invention will now be explained in more detail with reference to the non-limiting examples.

Examples

The phosphate binder used in the following examples was formed by reaction of aqueous solutions of magnesium sulfate and ferric sulfate in the presence of sodium hydroxide and sodium carbonate. The synthesis reaction is described by: 4MgSO4+ Fe2(SO4)3+ 12 NaOH Na2CO3-> Mg4Fe2(OH)12.CO3.nH2O 7Na2SO4. The precipitation was carried out at approximately pH 10.3 at ambient temperature (15-25<o>C). The precipitate obtained was filtered, washed, dried and ground and then sieved so that all material is less than 106 μm. The formula for the phosphate binder was: Mg4Fe2(OH)12.CO3.nH2O and had the following XRF composition: MgO = 29.0%, Fe2O3= 28.7%, Mg:Fe molar ratio = 2:1. The XRF values take into account all water present in the phosphate binder. XRD showed that the phosphate binder was characterized by the presence of the weakly crystalline hydrotalcite-type structure.

Table 1

All values in the table are percentages expressed by weight.

Granules were prepared using the formulations detailed in Table 1. The dry mixtures were formed in 125 ml batches by mixing the components of the Turbula powder mixture for 5 minutes before granulation. Batches of 125 grams of dry powder mixture were granulated by the steady addition of purified water in a planar mixer until small, discrete granules were produced. Each of the powder mixtures required different amounts of water to granulate. Typical values for water used for granulation, as a weight percentage of dry powder weight are: example (1) -106%, example (2) -111%, example (3) -78%, example (4) -83%, example (5 ) -100%, example (6) -70-106%, example (7) -78%. Batches of granules prepared for each of the formulations were then combined and dried in a fluidized bed dryer at an air inlet temperature of 40<o>C to a target moisture content of 4-6% w/w before passing through a sieve of 1.18 mm openings to remove large granules.

The amount of water required for granulating varied depending on the phosphate binder moisture content, particle size distribution, feed rate and degree of dispersion (size of water droplets). If water was used at less than 50%, finer granules were typically obtained, while excess amounts of water (above 110%) resulted in lump formation. The preferred amount of water was between 70 and 100%.

The tablets were produced with hardnesses from 13 to 29 kgf as measured by a Holland C50 tablet hardness tester. Varying compression pressures were used to give tablets of different tablet hardness (as measured in kg force) as detailed in Table 2, from formulations 1 to 4. 0.3% stearic acid was used as a lubricant.

The disintegration time of the tablets was measured using a disintegration bath - Copley DTG 2000 IS.

The phosphate binding capacity in Table 2 was measured as detailed in the phosphate binding test as described above at pH = 4 and at a time = 30 minutes.

Friability was measured by tablet friability tester Erweka TA10.

The results are shown in Table 2 for uncoated tablets prepared from granules of shapes 1, 2, 3 and 4 at three different compressive strengths (tablet hardness) (a, b and c) as indicated in the table.

Table 2

Table 3 shows the effect of adding a water-resistant coating comprising Eudragit EPO to tablets prepared from granules with the formulation as indicated in Example 1.

The coating formulation is:

84.02% purified water, 0.81% sodium dodecyl sulfate, 8.08% butylated methacrylate copolymer (Eudragit EPO), 1.21% stearic acid, 2.09% talc, 2.83% Mg stearate, 0.64% titanium dioxide , 0.32% red iron oxide. The coating was dried after application using hot air at 48<o>C.

The coating level discussed herein is determined from the increase in tablet weight before and after application of the coating formulation and drying in hot air at 48<o>C.

Table 3

Table 3 shows that a coating has the effect of delaying the disintegration of the tablets.

Table 4 shows the effect of different coating types and lubricants on storage performance and tablet properties for tablets formed with a hardness of 10 to 15 kgf from the granules of Examples 1, 5, 6 and 7. Tablets from Examples 1 and 5 included 0.5% by weight of stearic acid which lubricant. Tablets from Examples 6 and 7 included 0.3% by weight of magnesium stearate as a lubricant.

Table 4

The Eudragit coating is as described above.

The Opadry AMB coating has Opaglos 2 sodium carboxymethyl cellulose which replaces Eudragit EPO as coating polymer with other coating ingredients as for the Eudragit coating composition.

It should be noted that the moisture content in Table 4 is for the fully coated tablet and not for the granules.

Storage was carried out with the tablets that were openly exposed at 75<o>C and 40% relative humidity for 4 weeks.

Table 4 shows that the Opadry coating does not prevent pitting when stored with Mg stearate lubricant, while Eudragit does this. Even Eudragit does not prevent pitting with stearic acid. Consequently, the optimal system is Mg stearate lubricant with Eudragit coating.

Table 5 shows the effect of granule size and moisture content on tablet disintegration time for an uncoated tablet in water at pH 7 and in 0.1 Normal HCl, both at 37<o>C. The wording was, for example, 6 (but with varying degrees of humidity). The tablets were compacted to the same approximate hardness of 10-15 kgf.

Table 5

The irregular tablet surface for high moisture granules is due to excess material pushing past the sides of the tablet die during compression.

All the granules were sieved so that less than 25% by weight of the granules had a diameter of less than 106 μm when sieved.

Table 5 shows that increasing the granule size reduces disintegration at granule moisture levels of 1.19 and 7.01%, and that the moisture content has a marked effect on both disintegration time and tablet quality.

A similar effect was found for the effect of granule size on the retardation of phosphate binding. Tablets formed from granules according to Example 6 having a diameter less than 1180 µm were compared for phosphate binding as a function of time against tablets formed from granules having a diameter less than 425 µm. The tablets were both compressed to a strength of 13 kg tablet hardness and were coated with 4.5% dried Eudragit EPO water resistant coating. The tablets prepared from the smaller granules reached 80% of equilibrium phosphate binding after 10 minutes, while the tablets prepared from the larger granules took 30 minutes. The equilibrium phosphate binding is measured after 120 minutes. The phosphate binding results were obtained according to the modified method as described below.

Table 6 shows phosphate binding of coated tablets formed from granules according to Example 6 coated with Eudragit EPO in an amount of 4.5% by weight based on the coated tablet, the granules having a diameter of less than 425 μm.

Tables 6, 7 and 8 show phosphate binding (expressed as mmol of bound phosphate per gram of solid inorganic phosphate binder) at different pH values for the solution in which binding was measured.

The results in Tables 6, 7 and 8 were obtained using the phosphate binding method described above, but with the following modifications: 1 tablet containing 0.5 g of the phosphate binding agent was dispersed in 125 ml of 4 mmol/liter phosphate solution (in contrast to 12, 5 ml of 40 mmol/litre). The samples were then incubated in corked conical polypropylene flasks in a shaking water bath at 37<o>C and 200 rpm for varying lengths of time. The pH of the phosphate solution was varied by using the 1M NaOH or HCl solution. The calibration standards for ICP-OEC were changed accordingly to account for the lower phosphate concentration.

Table 6

Table 7 shows the effect of the particle size distribution for the granules on different parameters. "Transport" refers to the ease of transfer from a hopper to a tablet press in relation to blocking and bridging. The granules were formed according to Example 6. The fine granules (A) were poor.

Phosphate binding was measured using the phosphate binding method previously described in Table 6 at a pH of 4.

The phosphate binding results for A, B, C and D were from tablets (uncoated) while the results for E were from the granules themselves.

Table 7

Examples 1-7 in the form of an uncoated tablet prepared from granules with a diameter less than 1180 μm were also measured using the modified phosphate binding test as shown in Table 8 at pH = 4 and at a time = 30 minutes.

Table 8

From table 8 and from the comparison of example 2 with 3, it can be seen that example 3 has a lower phosphate binding which shows the effect of preventing phosphate binding by the presence of the microcrystalline cellulose and the advantage of using the preferred combination of pre-gelled starch and micronized cross-povidone. This preferred combination of excipients maintained good phosphate binding as well as supported the granulation process and showed good dispersion of the granules and tablets in water.

Material from coated tablets (containing 0.5 g binder) formed from granules according to Example 6 having diameters less than 425 μm was found to have the following Langmuir constants: K1 (1/mmol) = 0.25 and K2 (mmol/g) = 1.88.

Material from coated tablets (containing 0.5 g binder) formed from granules according to Example 6 with diameters less than 1000 μm was found to have the following Langmuir constants: K1 (1/mmol) = 0.19 and K2 (mmol/g) = 1.88.

K1 is the affinity constant and is an indication of the strength of phosphate binder while K2 is the capacity constant and is the maximum amount of phosphate that can be bound per unit weight of binder.

These Langmuir constants were determined by varying the phosphate concentration from 1 to 40 mmol/l and were calculated by performing linear regression on a plot of unbound/bound phosphate versus unbound phosphate measured at equilibrium. The initial pH of the phosphate solutions was pH = 4, temperature = 37<o>C and the chosen equilibrium point was at a time t = 120 minutes.

All publications and patents and patent applications mentioned in the above description are incorporated herein by reference. Various modifications and variations of the present invention will be apparent to the expert in the field without deviating from the scope of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention should not be unduly limited to such specific embodiments. Various modifications of the indicated ways of carrying out the invention and which are obvious to a person skilled in chemistry, biology or related areas must also actually be within the scope of the following claims.

Claims (24)

Patent claims 1. Granular material, characterized in that it comprises (i) at least 50% by weight based on the weight of the granular material of a solid water-insoluble mixed metal compound capable of binding phosphate of formula (I): M<II>1-xM<III>x(OH)2A<n->y.zH2O (I) wherein M is at least one of magnesium, calcium, lanthanum and cerium; M<III>is at least iron (III); A<n> is at least one n-valent anion; x = Σnew; 0 < x ≤ 0.67, 0 < y ≤ 1, and 0 ≤ z ≤ 10; (ii) from 3 to 12% by weight based on the weight of the granular material of non-chemically bound water, and (iii) not more than 47% by weight based on the weight of the granular material of excipient. 2. Granular material as stated in claim 1, wherein x = Σny; 0 < x ≤ 0.5, 0 < y ≤ 1 and 0 ≤ z ≤ 10. 3. Granular material as stated in claim 1 or 2, in which the mixed metal compound of formula (I) comprises a layered double hydroxide. 4. Granular material as stated in one or more of claims 1 to 3, in which the mixed metal compound contains at least one of hydroxyl and carbonate ions and contains, as the metals, iron (III) and magnesium. 5. Granular material as stated in one or more of the preceding claims, wherein the granular material comprises from 5 to 20% by weight pregelatinized starch as excipient based on the weight of the granular material. 6. Granular material as stated in one or more of claims 1 to 5, comprising from 1 to 15% by weight of cross-linked polyvinylpyrrolidone as excipient based on the weight of the granular material. 7. Granular material as stated in one or more of claims 1 to 6, in which the excipient comprises at least pregelatinized starch and cross-povidone. 8. Granular material as stated in one or more of the preceding claims, in which at least 95% by weight of the granules in the granular material have a diameter that is less than 1180 μm. 9. Unit dose for oral administration, characterized in that it comprises a water-resistant capsule containing a granular material as stated in one or more of the preceding claims. 10. Unit dose for oral administration, characterized in that it comprises a compacted tablet of a granular material as stated in one or more of claims 1 to 8. 11. Unit dose as stated in claim 10, which further comprises a lubricant between the granules. 12. Unit dose as stated in claim 11, wherein the lubricant is or comprises magnesium stearate. 13. Unit dose as stated in one or more of claims 10 to 12, which is coated with a water-resistant coating. 14. Unit dose as stated in claim 13, wherein the water-resistant coating comprises at least 30% by weight of a butylated methacrylate copolymer. 15. Unit dose as stated in claim 13 or 14, wherein the tablet has a gastric band with a width of 2 mm or more. 16. Unit dose as set forth in one or more of claims 9 to 15, wherein the solid water-insoluble inorganic compound capable of binding phosphate is present in an amount of at least 200 mg. 17. Method for producing a granular material as specified in one or more of claims 1 to 8, characterized by the fact that it includes the step of: i) mixing the compound of formula (I) with one or more excipients to produce a homogeneous mixture, ii) bringing a suitable liquid into contact with the homogeneous mixture and mixing in a granulator to form wet granules; iii) eventual passage of the wet granules through a sieve to remove granules with a size larger than the sieve size, iv) drying the wet granules to provide dry granules; v) grinding and/or sieving the dry granules. 18. Method as stated in claim 17, in which the liquid is selected from water, ethanol and mixtures thereof. 19. Granular material as specified in one or more of claims 1 to 8 for use in medicine. 20. Use of a granular material as stated in one or more of claims 1 to 8 for the production of a drug for binding phosphate. 21. Use of a granular material as stated in one or more of claims 1 to 8 for the manufacture of a medicament for use in the therapy of a condition or disease associated with phosphate levels. 22. Use of a granular material as set forth in one or more of claims 1 to 8 for the manufacture of a medicament for use in the therapy of a condition or disease associated with unfavorable phosphate levels. 23. Use of a granular material as stated in one or more of claims 1 to 8 for the manufacture of a medicament for use in the therapy of a condition or disease associated with increased plasma phosphate levels. 24. Use of a granular material as stated in one or more of claims 1 to 8 for the production of a drug for use in the therapy of hyperphosphatemia.