Pharmaceutical compositions

Abstract

To provide pharmaceutical compositions for oral administration, as an oral delivery system to be swallowed directly or capable of disintegration in the oral cavity, comprising iron oxy-hydroxide in high loading.SOLUTION: The present invention provides a pharmaceutical composition comprising iron oxyhydroxide in high loading, in a form suitable for oral administration. The invention provides a pharmaceutical composition comprising iron oxyhydroxide in high loading, in a form suitable for oral administration as film-coated dosage forms for intact swallowing or as dosage forms capable of disintegration in the oral cavity. The composition contains at least one carbohydrate and / or humic acid. The carbohydrate is selected from the group consisting of a mono-, di- or poly-saccharide, for example agarose, dextran, dextrin, dextran derivatives, cellulose and cellulose derivatives, saccharose, maltose, and lactose, preferably saccharose, dextrin, and starch. The iron oxyhydroxide is containing beta iron oxyhydroxide.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to pharmaceutical compositions containing high loadings of iron oxyhydroxide in a form suitable for oral administration, particularly as a dosage form for complete swallowing (e.g. film coated) or for administration into an oral delivery system, as a dosage form capable of rapid disintegration, and to methods for their preparation. [Background technology]

[0002] In patients with chronic renal failure, a pathologically elevated serum phosphate level occurs due to a decrease in glomerular filtration rate. The concomitant onset of secondary hyperparathyroidism must be considered as one of the causes of renal osteopathy. Attempts to maintain phosphate balance are commonly made by dialysis, or by administration of oral phosphate binders that inhibit the reabsorption of dietary phosphate in the gastrointestinal tract, or by a combination of the two, but in the current state of the art, none of these are sufficiently efficient, economical, or burdened with side effects.

[0003] Recently, new and effective phosphate adsorbents containing iron oxyhydroxide-based, in particular beta-iron oxyhydroxide stabilized with stabilizing agents such as carbohydrates and / or humic acid, have been described (EP 0 868 125). These adsorbents show excellent phosphate adsorption capacity from aqueous solutions, e.g. for the adsorption of inorganic phosphate and food-bound phosphate (EP 0 868 125), and have been shown to be efficient oral phosphate binders in the treatment of hyperphosphatemia (Neophrol. Dial. Transplant 14, 863, 1999).

[0004] To achieve maximum efficacy while maintaining good patient compliance, it is preferable that the binders be able to be administered in high dosages. However, phosphate binders with high iron loading are not yet available. Factors such as storage and stability issues as well as general ease of administration and unacceptable taste limit the applicability of currently available phosphate binders.

[0005] The applicant's WO2006 / 000547 discloses a method for preparing an iron sulfate-based phosphate adsorbent for use in preventing or treating hyperphosphatemic conditions. An iron oxyhydroxide composition is described, prepared from iron sulfate and / or nitrate containing a stabilizer selected from humic acid and carbohydrates, and having an iron content of at most 20.3-22.3% by weight. The composition is obtained by rotary evaporation. No specific oral dosage form such as a tablet is disclosed. It is stated that the iron composition can be formulated into a tablet or other oral dosage form together with common excipients and adjuvants. This means that the iron content of a tablet obtained from the iron oxyhydroxide composition can be at most 20% (w / w), which corresponds to 32% (w / w) iron oxyhydroxide.

[0006] The applicant's EP 1 757 299 describes iron(III) carbohydrate complexes and their use for the oral or parenteral treatment of iron deficiency in patients with chronic inflammatory bowel disease. In said reference Maltofer® film-coated tablets containing 100 mg iron(III) are described. The iron content of the tablets is 16% by weight, which corresponds to 25.6% w / w iron oxyhydroxide. The formulation is intended for the treatment of iron deficiency, i.e. for the liberation of iron(III), as opposed to phosphate adsorbents as defined within the present invention. A drying process is not described.

[0007] WO92 / 01458 discloses oxy-iron compounds, particularly iron oxide, iron hydroxide, and iron oxyhydroxide, formulated as therapeutic dosage forms for use as phosphate adsorbents. No specific oral dosage forms are disclosed, and no specific iron loadings are mentioned. Furthermore, excipients and manufacturing methods are not specifically disclosed, but "acceptable methods and excipients" are described. It is stated that each oral dose may contain from 50 mg to about 500 mg or more of oxy-iron compound. According to the state of the art, a tablet containing 500 mg of oxy-iron compound, necessary to achieve the desired degree of phosphate adsorption, would be too large for a patient to swallow. The document does not disclose obtaining high iron loadings.

[0008] US 5,514,281 discloses polynuclear iron oxyhydroxide bound to carriers such as saponified divinyl ethylene urea vinyl acetate copolymer, Lewatit®, silica, glass, and organic porous carriers modified with dextran. The maximum iron loading of the carriers carrying iron(III) is reported to be 29.3% by dry weight. The product is molded from the expanded dry carrier, which cannot be subsequently dried, since it cannot function at all unless the phosphate is removed from the dialysate. In all the examples in US 5,514,281, no anhydrous / tablet dosage form for oral administration is described. The examples describing the adsorbent are all for extracorporeal use, and the carriers used in its preparation are not applicable for pharmaceutical use. The preparation of the oral dosage form is simply described as "compressed into powder for...". The above product was developed for iron release.

[0009] For a wide range of drugs, oral dosage forms such as tablets are clearly the preferred mode of administration, not only because of their high level of patient acceptability and compliance (because they provide accurate dosage and are easy to administer), but also because they offer advantageous characteristics during and after manufacture, such as typically exhibiting satisfactory physical and chemical stability, being convenient to package, ship, and administer, and having advantages in manufacturing speed and cost.

[0010] However, oral dosage forms require carefully designed disintegration characteristics to achieve the desired bioavailability for the incorporated drug, i.e., dissolution must precede absorption, while rapid release tablets must disintegrate quickly after ingestion to facilitate drug dissolution. Furthermore, the drug loading of conventional tablet dosage forms is often limited by potential gastrointestinal irritation (due to high local concentrations) and / or patient compliance (restricting size and shape to facilitate easy swallowing).

[0011] These limitations have hindered the development of an effective oral delivery system for high loading iron oxyhydroxide as a phosphate binder.

[0012] The present applicant has discovered that iron oxyhydroxides containing iron oxyhydroxide (hereinafter also referred to as active agent) and beta-iron oxyhydroxide, and in particular iron oxyhydroxides further containing carbohydrates and / or humic acids which can act as stabilizers as described in EP 0 868 125 B1, can be successfully formulated in the form of oral delivery systems (hereinafter also referred to as pharmaceutical compositions or compositions of the invention) at high loadings, preferably as dosage forms for complete swallowing (e.g. film-coated) or dosage forms capable of rapid disintegration (in the oral cavity or in a small amount of liquid before ingestion). Thus, the pharmaceutical compositions of the invention can achieve both high loadings and suitable disintegration characteristics while maintaining a minimal size, thereby overcoming the shortcomings of currently known dosage forms.

[0013] The composition of the present invention has a low iron release rate of less than 2.5% w / w, which is the essential value as a phosphate binder, whereas compositions used to treat iron deficiency have a high iron release rate, which is completely different from the composition of the present invention.

[0014] Furthermore, the pharmaceutical composition of the present invention is preferably obtained through conventional molding and tableting techniques, more preferably through direct tableting techniques, in the presence of one or more excipients, e.g. one or more excipients at once satisfying binders and / or fillers and / or disintegrants.

[0015] It has been discovered that any bad taste associated with an active agent, when administered as an orally disintegrable dosage form, can be eliminated using suitable taste masking agents, sweeteners, and / or taste enhancers.

[0016] It has further been discovered that preferred tablet dosage forms having particularly high iron oxyhydroxide-loadings are obtained when they comprise a substantial amount of a free-flowing powder produced by spray drying an aqueous suspension of the ingredients. [Prior art documents] [Patent documents]

[0017] [Patent Document 1] EP0 868 No. 125 [Patent Document 2] WO2006 / 000547 publication [Patent Document 3] EP1 757 No. 299 Publication [Patent Document 4] WO 92 / 01458 publication [Patent Document 5] Publication US 5,514,281 [Non-patent literature]

[0018] [Non-Patent Document 1] Neophrol. Dial. Transplant 14, 863, 1999 Summary of the Invention [Problem to be solved by the invention]

[0019] It is an object of the present invention to provide pharmaceutical compositions containing iron oxyhydroxide in a form suitable for oral administration, preferably as a dosage form for complete swallowing (e.g. film coated) or capable of rapid disintegration (in the oral cavity or with a small amount of liquid before ingestion), especially in oral delivery systems with high loading.

[0020] In a preferred embodiment, the iron oxyhydroxide-containing pharmaceutical composition contains one or more carbohydrates and / or humic acids, preferably carbohydrates, such as monosaccharides, disaccharides, polysaccharides, preferably sucrose, starch, agarose, dextran, dextrin, cellulose, and their respective derivatives. The carbohydrates and / or humic acids may act as stabilizing agents, as described in EP 0 868 125 B1. Alternatively or additionally, the carbohydrates (etc.) and / or humic acids may act as binders and / or fillers and / or disintegrants.

[0021] In yet other embodiments, the compositions of the present invention contain one or more taste-masking and / or color additives, such as flavoring agents, sweeteners, taste enhancers, colorants, and the like.

[0022] Depending on the intended use of the tablet, i.e., for complete swallowing or for rapid disintegration (in the mouth or with a small amount of liquid before ingestion), e.g., as a chewable tablet, conventional excipients may be added, if desired, such as superdisintegrants, glidants, lubricants, antioxidants, tableting aids, etc. Tablets may be coated, if desired, with conventional film-forming agents.

[0023] In yet other embodiments, the pharmaceutical compositions of the present invention are in any dosage form suitable for oral administration, in particular tablets and pills in a form intended for complete swallowing (e.g. film-coated) or in a form capable of rapid disintegration (in the oral cavity after ingestion or with a small amount of liquid before ingestion), including chewable forms, dry powders, granules, capsules or sachets containing said granules, wafers, films, lozenges, etc.

[0024] It is a further object of the present invention to provide a method for formulating the oral delivery system of the present invention containing high loadings of iron oxyhydroxide by conventional molding or tableting techniques, preferably direct compression, particularly as a dosage form for complete swallowing (e.g. film coated) or as a form capable of rapid disintegration (in the oral cavity or with a small amount of liquid before ingestion). [Means for solving the problem]

[0025] Accordingly, a first aspect of the present invention relates to a pharmaceutical composition in a form suitable for oral administration that contains a high loading of iron oxyhydroxide as an active agent and exhibits desirable disintegration characteristics.

[0026] In particular, the present invention relates to said orally administrable pharmaceutical compositions having a high loading of active agent, either as a dosage form for complete swallowing (e.g. film coated) or as a dosage form capable of rapid disintegration (in the oral cavity or with a small amount of liquid prior to ingestion).

[0027] As mentioned above, the term "activator" as used herein includes iron(III)-oxy-hydroxides. Iron(III)-oxy-hydroxides or iron(III)-oxide-hydroxides are generally referred to as FeO(OH) or Fe2O3×H2O. The iron(III)-oxy-hydroxides used according to the invention are generally formed upon hydrolysis and precipitation in aqueous iron(III) salt solutions (references include, for example, Ro:mpp Lexikon Chemie, 10. Auflage, 1997; U. Schwertmann, RMCornell "Iron Oxides in the Laboratory", VCH Verlagsgesellschaft mbH, 1991, Seiten 95-100). Thus, the term "iron(III)-oxyhydroxide" as used herein includes α, β, γ, and δFeOOH, and mixtures thereof. Preferably, the iron(III)-oxyhydroxide contains βFeOOH, optionally in mixture with other iron(III)-oxyhydroxides (etc.).

[0028] The iron oxyhydroxide used according to the invention is preferably prepared as described in EP 0868125 B1 by adding a base to an aqueous iron(III)-salt solution and subsequent drying.

[0029] Preferably, iron oxyhydroxide stabilized with a stabilizer is used.

[0030] The term "iron oxyhydroxide stabilized with a stabilizing agent" preferably comprises iron oxyhydroxide together with a stabilizing agent, which in particular comprises carbohydrates and humic acid. As described in EP 0868125 B1, the stabilizing agent is generally not bound as a complex to the iron oxyhydroxide, which means that the water-soluble stabilizing agent can be removed, for example by washing the stabilized iron oxyhydroxide with water. Furthermore, as described in EP 0868125 B1, the stabilizing agent is presumed to stabilize the iron oxyhydroxide against ageing, thereby preserving its phosphate adsorption capacity. This means that the stabilized iron oxyhydroxide generally has a higher phosphate adsorption capacity (measured in EP 0868125 B1) compared to non-stabilized iron oxyhydroxide. According to the present invention, a preferred "iron oxyhydroxide stabilized with a stabilizing agent" comprises beta-iron oxyhydroxide stabilized with at least one carbohydrate and / or humic acid, as described in EP 0868125 B1.

[0031] Generally, the iron oxyhydroxides utilized and administered according to the present invention, due to their chemical characteristics, are essentially not absorbed by the human body, i.e., they are essentially non-bioabsorbable.

[0032] Thus, the term "stabilizer" as used herein preferably comprises at least one or more carbohydrates and / or humic acids, in particular as described in EP 0868125 B1. In one embodiment, the at least one or more carbohydrates are soluble and comprise at least one or more monosaccharides, disaccharides or polysaccharides, such as agarose, dextran, dextrin, dextran derivatives, cellulose and cellulose derivatives, sucrose, maltose or lactose, preferably sucrose, dextrin or starch.

[0033] The term "starch" as used herein includes any commonly used starch product in its native, pregelatinized, disintegrated, modified, and derivative form, preferably suitable for direct compression processes (e.g., potato starch, corn starch, rice starch, tapioca starch), and mixtures thereof.

[0034] Preferred products include those which are mixtures of native and pregelatinized starches, for example in ratios (native:pregelatinized) ranging from 10:1 to 0.5:1, preferably from 3:1 to 0.5:1, more preferably from 2:1 to 1:1. The use of a mixture of native and pregelatinized starches is considered to be particularly advantageous for the preparation of tablets with high iron loadings, as this allows for the production of a stabilized premix which can be compressed directly or with very small amounts of additional excipients into suitable tablets.

[0035] In one particular embodiment, the selected stabilizing agent may be present in an amount of 1.0-50% (w / w), preferably 5.0-30% (w / w).

[0036] All percentages by weight (w / w) herein are expressed with respect to the total weight of the pharmaceutical composition, unless otherwise specified.

[0037] The term "high loading" as used herein indicates that the iron oxyhydroxide is present in an amount of 10-80% (w / w), more preferably 30-65% (w / w). The iron oxyhydroxide content is calculated as about 1.6 times the iron content.

[0038] Therefore, the above values ​​correspond to an iron content of 6 to 50% w / w, more preferably 19 to 41% (w / w).

[0039] In a preferred embodiment of the present invention, even higher iron loadings are achieved, i.e., 50-90% (w / w) iron oxyhydroxide, preferably 56-65% (w / w), corresponding to 31-56% (w / w), preferably 35-41% (w / w) iron.

[0040] Additionally, the iron oxyhydroxide is preferably present in an amount greater than 300 mg per dosage form, more preferably from 300 to 2,000 mg per dosage form, it being understood that the amount of active agent will depend on the intended route of administration, i.e., the amount present in a (e.g. film-coated) tablet for intact swallowing is preferably 350 to 850 mg, whereas the amount present in an oral dosage form allowing for rapid disintegration (in the mouth or with a small amount of liquid before ingestion) is preferably 700 to 1,700 mg.

[0041] In addition to the active agent, a typical pharmaceutical composition typically contains a number of additional inactive ingredients known as excipients and / or additives. In particular, when the amount of active agent required to achieve a desired therapeutic, nutritional, or chemical effect is very small, the presence of inert diluents, fillers, binders, excipients, and disintegrants, lubricants, glidants, and sweeteners, taste masking agents, colorants, and the like are generally crucial to ensure the feasibility and convenience of manufacturing an oral dosage form to achieve accurate and effective administration of the active agent.

[0042] In contrast, in the case of orally administered pharmaceutical compositions having high loadings of active agent, as in the present invention, the aforementioned additional non-active ingredients are minimized, since the size of an orally administered pharmaceutical composition is a critical feature for achieving good patient compliance.

[0043] As mentioned above, carbohydrates such as mono-, di- or polysaccharides, preferably sucrose, starch, agarose, dextran, dextrin, cellulose and their respective derivatives, more preferably sucrose, dextrin or starch, act as binders and / or fillers and / or disintegrants in the pharmaceutical compositions of the present invention, regardless of or in addition to their stabilizing effect on the iron oxyhydroxide.

[0044] Accordingly, a preferred composition of the present invention contains the above-mentioned amounts of iron oxyhydroxide, a selected stabilizing agent in an amount of 1.0 to 50% (w / w), preferably 5.0 to 30% (w / w), and a selected excipient different from the stabilizing agent in an amount of 1.0 to 50% (w / w), preferably 5.0 to 30% (w / w), each specified relative to the total weight of the composition.

[0045] In yet another embodiment, the compositions of the present invention contain one or more taste-masking and color additives commonly used in oral dosage forms, such as flavoring agents, sweeteners, taste enhancers, colorants, and the like.

[0046] Taste-masking agents, such as taste enhancers, flavorings, and / or natural or non-natural sweeteners, including high-intensity sweeteners, are incorporated into dosage forms, such as chewable dosage forms, to impart them with a more pleasant taste or to mask unpleasant tastes.

[0047] Typical sweeteners include sugars, such as, but not limited to, dextrose, sucrose, fructose, lactose, tablet sugar, powdered sugar, or polyols, such as, but not limited to, sorbitol (e.g., Neosorb), xylitol, maltitol, maltose and polydextrose, or mixtures thereof. Typical high-intensity sweeteners may include, but are not limited to, aspartame, sucralose, acesulfamine K, and / or saccharin derivatives, or mixtures thereof. Furthermore, suitable sweeteners or taste enhancers include glycosides, such as neohesperidin dihydrochalcone (neohesperidin DC or NHDC), glycyrrhizin, glutamate, etc. The latter are used in very small amounts and therefore may hereafter also be referred to as taste enhancers. All of the above are suitable for use alone or together with other sweeteners and / or flavorings. The substances ensure a considerable duration of the sweet taste and mask any unpleasant aftertaste. Preferred sweeteners and / or taste enhancers include glycosides, such as neohesperidin dihydrochalcone.

[0048] In one embodiment, the selected sweetener may be present in an amount of 0.01 to 2.5% (w / w), preferably 0.1 to 1.5% (w / w), most preferably 0.2 to 1.0% (w / w), relative to the total weight of the composition.

[0049] The selected taste enhancer may be present in an amount of from 0.1 to 50 ppm, preferably from 1 to 10 ppm, most preferably from 1 to 5 ppm, based on the total weight of the composition.

[0050] Exemplary flavorings include any natural or non-natural flavorings suitable for pharmaceutical applications, such as flavorings derived from spices, fruits or fruit juices, vegetables or vegetable juices, etc., such as 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 combinations such as caramel / vanilla, fruit / cream (e.g., strawberry / cream), and the like.

[0051] In one embodiment, the selected flavouring may be present in an amount of 0.01 to 10% (w / w), preferably 0.1 to 5% (w / w), most preferably 0.1 to 1% (w / w), based on the total weight of the composition.

[0052] Thus, other compositions of the invention may contain the above amounts of iron oxyhydroxide, a selected stabilizing agent in an amount of 1.0-50% (w / w), preferably 5.0-30% (w / w), a selected excipient different from the stabilizing agent in an amount of 1.0-50% (w / w), preferably 5.0-30% (w / w), and a selected taste enhancer which may be present in an amount of 0.1-50 ppm, preferably 1-10 ppm, most preferably 1-5 ppm, and / or a selected flavoring agent present in an amount of 0.01-10% (w / w), preferably 0.1-5% (w / w), most preferably 0.1-1% (w / w), each based on the total weight of the composition.

[0053] In yet other embodiments, excipients such as superdisintegrants, glidants, lubricants, antioxidants, etc. may be added to the compositions of the present invention as needed depending on the intended use of the tablet, i.e., whether it is for complete swallowing or for rapid disintegration (in the mouth or with a small amount of liquid before ingestion).

[0054] Thus, in certain embodiments, the compositions of the present invention may further comprise a superdisintegrant.

[0055] The term "super disintegrants" as used herein refers to a group of disintegrants known to those skilled in the art, which may be used in much smaller amounts than common disintegrants to achieve the same effect of facilitating the disintegration or "break-up" of the dosage form after administration. Suitable examples include, but are not limited to, cross-linked polyvinylpyrrolidone (available commercially under the trade names Kollidon® CL and Polyplasdone® XL), in particular crospovidone®, modified starches, in particular sodium starch glycolate (available commercially under the trade names Primojel® and Explotab®), Starch 1500, modified celluloses, in particular croscarmellose sodium (cross-linked sodium carboxymethylcellulose, available commercially under the trade name Ac-Di-Sol), LHPC (low-substituted hydroxypropylcellulose) and Veegum®.

[0056] Examples suitable for use in the tablets of the present invention include cross-linked polyvinylpyrrolidone, and modified starches, especially sodium starch glycolate.

[0057] According to the present invention, the superdisintegrant is present in the tablet in an amount of 0.1-10% (w / w), preferably 0.5-8% (w / w), more preferably 2.5-6% (w / w) based on the total weight of the composition. The superdisintegrant may be a single superdisintegrant or a combination of superdisintegrants or may be used in combination with one or more conventional disintegrants such as, for example, starch, methylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, pregelatinized starch, clay, cellulose, powdered cellulose, pregelatinized starch, sodium alginate, alginic acid, guar gum, magnesium aluminum silicate, polacrilin potassium, etc.

[0058] Thus, other compositions of the invention may contain the above amounts of iron oxyhydroxide, a selected stabilizing agent in an amount of 1.0-50% (w / w), preferably 5.0-30% (w / w), a selected excipient different from the stabilizing agent in an amount of 1.0-50% (w / w), preferably 5.0-30% (w / w), a superdisintegrant in an amount of 0.1-10%, preferably 0.5-8% (w / w), more preferably 2.5-6% (w / w), and a selected taste enhancer in an amount of 0.1-50 ppm (w / w), preferably 1-10 ppm (w / w), more preferably 1-5 ppm (w / w), and / or a selected flavoring in an amount of 0.01-10% (w / w), preferably 0.1-5% (w / w), more preferably 0.1-1% (w / w), all said weight ranges being relative to the total weight of the composition.

[0059] In yet other embodiments, the compositions of the present invention may further comprise a glidant and / or a lubricant.

[0060] The terms "glidant" and / or "lubricant" as used herein refer to a group of additives used to facilitate tablet manufacture by achieving suitable flow properties, compressibility, etc. Suitable glidants include, but are not limited to, magnesium oxide, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type I, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, polyethylene glycol, talc, zinc stearate, silica derivatives such as colloidal silica (e.g., Aerosil®), pyrogenic silica, sodium silicoaluminate hydrate, colloidal silicon dioxide, and mineral and light mineral oils.

[0061] Preferred glidants include magnesium oxide, magnesium stearate, talc, and colloidal silica.

[0062] In one embodiment, the selected glidant may be present in an amount of 0.01-10% (w / w), preferably 0.1-5% (w / w), most preferably 1-2% (w / w), based on the total weight of the composition.

[0063] Additional additives, particularly for oral dosage forms capable of rapid disintegration in the oral cavity, may contain sialagogues (compounds that stimulate saliva production) to facilitate swallowing. These are generally pharma-ceutically acceptable acids, such as citric acid, malic acid, tartrates, or the compounds Optamint® and Optaflow®. Care must be taken that the use of said acidic compounds, such as citric acid, does not increase iron release, and therefore the amount of said substance must be chosen accordingly. In one embodiment, the selected acid may be present in an amount of 0.01-10% (w / w), preferably 0.1-5% (w / w), most preferably 2-5% (w / w), based on the total weight of the composition.

[0064] As mentioned above, the pharmaceutical composition is in a form suitable for oral administration for the selective removal of inorganic phosphate, in particular as an oral delivery system, either as a film-coated dosage form for complete swallowing or as a disintegrable dosage form (in the mouth or with a small amount of liquid before ingestion).

[0065] Thus, the pharmaceutical compositions of the present invention include any dosage form suitable for oral administration, in particular tablets and pills in dosage forms intended for complete swallowing (e.g. film-coated) or in chewable forms, forms capable of rapid disintegration (in the mouth after ingestion or with a small amount of liquid before ingestion), including dry powders, granules, capsules or sachets containing said granules, wafers, films, lozenges, etc.

[0066] Preferred administration forms include tablets and pills in whole swallowed (eg film coated) or chewable form, granules, and capsules or sachets containing said granules, and lozenges.

[0067] If desired, in the case of film-coated, orally administrable dosage forms, these are swallowed completely and disintegration takes place in the gastrointestinal tract where the active agent for phosphate binding is released, reducing its systemic absorption.

[0068] The term "film coated" as used herein refers to a mixture of pharma- ceutically acceptable excipients that are typically applied to tablets, beads, granules, or particles of active ingredient that are compressed into tablets. Alternatively, it may be combined, mixed, or added to the active ingredient. It is understood that the coating selected must necessarily be compatible with the active ingredient. It is understood that one skilled in the art knows how to handle a coating that disintegrates in the gastrointestinal tract by selecting the excipients that make up the coating, its type, and / or its thickness.

[0069] In a preferred embodiment, a film coating is applied to a pharmaceutical composition containing iron oxyhydroxide and at least one or more excipients in compressed form.

[0070] Suitable polymers for film coating according to the present invention are soluble at a pH of about 1.2 to 5, such as, for example, hydroxypropylmethylcellulose (HPMC), alone and / or in combination with hydroxypropylcellulose (HPC), carboxymethylcellulose, methylcellulose, ethylcellulose, acrylic resins, and polyvinylpyrrolidone and gelatin, or other commercially available film coating formulations, such as Dri-Klear® (Crompton & Knowles Corp., Mahwah, NJ) or Opadry® (Colorcon, West Point Pa.).

[0071] A preferred film coating of the present invention comprises a commercially available film coating product designed for aqueous film coating containing a water-soluble, film-forming resin, hydroxypropyl methylcellulose, and polyethylene glycol (or other suitable plasticizer, e.g., propylene glycol or glycerin), and optionally titanium dioxide (or other colorant or opacifier). The product is commercially available under the trade name Opadry® White (Colorcon, West Point Pa.).

[0072] A suitable blend for coating may contain 0 to about 20% w / w titanium dioxide or colorant, about 5 to 95% w / w hydroxypropyl methylcellulose, and 0 to about 25% w / w polyethylene glycol. A most preferred embodiment contains 10.5% non-aqueous additives, of which 7.5% is Opadry®, based on the total weight of the coating.

[0073] The coating blend may further contain flavourings, taste masking agents and saliva stimulants as defined above in small amounts, for example 0.1-1.0% (w / w), preferably 0.1-0.4%, based on the total weight of the coating blend. Preferred flavourings and / or taste masking agents may be selected from the group of agents defined above. The preferred amount is easily determined by balancing the goal of adding a sufficient amount to mask the taste of the tablet core and provide a distinctive and pleasant taste independent of it, with the goal of making the tablet less similar to sugar confectionery products. The desired strength of flavourings and / or taste masking agents may vary depending on the type of tablet, the intended recipient and the identity of the flavourings and / or taste masking agents.

[0074] The amount of coating deposited on a tablet is generally in the range of about 1.0% to about 6.0% weight gain, preferably 2.0% to 4.0% weight gain, which refers to the weight gain of the coated tablet relative to an uncoated tablet.

[0075] For orally administrable, rapidly disintegrating dosage forms, disintegration occurs immediately after administration, allowing for rapid release of the active agent or forming small particles containing the active agent in the oral cavity. Suitable disintegration rates range from 1 second to 3 minutes. Preferred disintegration times are generally less than 30 seconds as measured by standard European Pharmacopoeia test methods.

[0076] Thus, in one embodiment, the dosage form is a tablet containing iron oxyhydroxide, stabilizers, excipients (different from stabilizers), including, inter alia, one or more sweeteners, taste enhancers, flavorings, superdisintegrants, glidants, antioxidants, etc., and produced by standard tableting techniques such as direct compression and dry granulation. Wet processing techniques must be avoided because, when using organic solvents, typically isopropanol, the solvent, which is not compatible with the product specifications, remains in the granules after drying. When water is used as a solvent for wet granulation, it increases the iron release from the product, which must be avoided in any case for the phosphate adsorbing composition of the present invention. Extrusion techniques cause problems when using high iron loadings, forming small, hard balls that show little phosphate adsorption properties and are therefore not suitable for the present invention.

[0077] During dry granulation, the powdered ingredients are mixed prior to compression, commonly referred to as precompression, to provide hard slugs that are crushed and sieved prior to the addition of the remaining ingredients and final compression.

[0078] Preferably, the compositions of the present invention are prepared by direct compression, which is considered to be the simplest and most economical process for producing tablets.

[0079] In a preferred embodiment of the present invention, the composition of the present invention is prepared by mixing most of the ingredients (more than 50%, preferably more than 70%, most preferably 90-100% of the total weight of the ingredients), e.g. the ingredients shown in Table 1, in the form of an aqueous suspension (amount of dry matter is, e.g., 1-50% (w / w), preferably 10-40% (w / w), more preferably 20-30% (w / w)), and subjecting said suspension to the known spray drying process under conventional conditions of exposure to air or preferably nitrogen at a temperature of 135-200°C, to obtain a free-flowing powder, which is optionally subsequently mixed with further ingredients (e.g. those shown in Table 2) and subsequently directly compressed under a pressure range of 10-20 kN to obtain tablets.

[0080] Preferably, the suspension contains 3-9% (w / w), more preferably 4-8% (w / w), most preferably 6% (w / w) iron.

[0081] Care must be taken to ensure that the diameter and height of the spray-drying column are large enough. Furthermore, the temperature must be chosen within a range in which the excipients and other ingredients are neither melted nor caramelized. All such products will not lead to a dry powder, which is not suitable for the present invention, but to a vitrified mass.

[0082] Preferably, the free-flowing powder before tableting is first compressed by dry pressing to reduce the amount of fine powder (dust) and to homogenize the particle size. The tablets thus obtained achieve a hardness in the range of 25-400N. The pressure is adjusted so that the hardness of the tablets obtained from the compressed mixture is in the range of 50-100N for chewable tablets and 100-200N for coated or swallow tablets. When using said ranges, the disintegration rate of the obtained tablets is within the specifications required by the European Pharmacopoeia.

[0083] It has been surprisingly found that, in particular by the method of the present invention, the amount of excipients required to obtain tablets with suitable properties in terms of, for example, tablet strength, disintegration behavior, etc. is reduced, which makes it possible to produce pharmaceutical compositions, in particular in tablet form, with a high loading of iron oxyhydroxide.

[0084] It has been found that the exact amount of ingredients determines the size and depth of the tablet. Tablets capable of rapid disintegration (in the oral cavity, e.g. chewable tablets or with a small amount of solution before ingestion) may have any geometric shape, e.g. round, square, triangular, etc. Generally, they are round, preferably with a diameter of 15-30 mm, most preferably 20 mm, and a height of 2-8 mm, preferably 4-6 mm. Film-coated tablets for complete swallowing are generally oval, e.g. with a length of about 19 mm, a width of 10 mm, and a height of 8 mm. These examples are merely illustrative and not limiting. A person skilled in the art can select the appropriate shape depending on the amount of the total ingredients.

[0085] Sufficient compression is required to bind the ingredients together during dose administration while allowing easy disintegration in the oral cavity. Typically 10-20 kN is used.

[0086] In yet another embodiment, the pharmaceutical composition is in the form of granules sufficient for disintegration in the oral cavity or rapid dissolution in a small amount of water. The granules are manufactured by high shear granulation or preferably fluid bed granulation or (dry) mixing processes. As mentioned above, wet techniques using solvents should be avoided. The granules may be filled into capsules or sachets for storage and administration to the oral cavity.

[0087] In additional examples, as an alternative to spray drying, the pharmaceutical composition may be provided in the form of a wafer. Wafers can be formed by pressing a powder, or freeze-drying a cake, or evaporating a suspension, emulsion, or gel. Alternatively, the mixed dry material can be flattened or compressed between a press or rollers to form a powder, e.g., The wafer is formed into a sheet that is cut to an appropriate size for insertion into the oral cavity. In one embodiment, the wafer is formed by suspending the active agent, solvent, binder, or other additives in a solvent such as water. A quantity of the suspension is placed into a well in a plastic mold and freeze-dried in the well to remove the water and form the wafer.

[0088] As noted above, the compositions of the present invention are indicated for use in the well-known indications of essentially non-bioabsorbable iron oxyhydroxide, particularly for the selective removal of inorganic phosphate, such as for the treatment of hyperphosphatemia.

[0089] Thus, in a further aspect, the present invention provides a composition for use in the treatment of hyperphosphatemia.

[0090] In yet another aspect, the present invention provides a method for treating hyperphosphatemia comprising administering to a patient in need of such treatment a composition of the present invention. In yet another aspect, the present invention provides the use of a composition of the present invention in the manufacture of a medicament for the treatment of hyperphosphatemia.

[0091] The usefulness of the compositions of the present invention can be observed in standard clinical trials.

[0092] The exact amount of iron oxyhydroxide and composition to be administered will depend on several factors, such as the severity of the disease, the desired duration of treatment, and the like.

[0093] The present invention will now be further described with reference to the following specific, non-limiting examples. EXAMPLES

[0094] Direct compression was performed using a standard tablet press at a pressure of 10-20 kN. Spray drying was performed at temperatures of 135-200°C.

[0095] Tablet Test Methods: Tablet hardness and disintegration time were determined by standard European Pharmacopoeia test methods.

[0096] Example 1: Preparation of a stabilized iron oxyhydroxide premix A stabilized iron oxyhydroxide premix was prepared by mixing an iron oxyhydroxide suspension (prepared according to EP0 868 125 B1) and excipients in the amounts / ratios according to Table 1. The suspension was subjected to spray drying at 135-200°C to obtain a premix in the form of a free-flowing powder. The premix was subjected to direct compression to obtain tablets with the composition shown in Table 1.

[0097] [Table 1] 1) Stabilizers 2) Filler / disintegrant 3) Stabilizers / binders / fillers / disintegrants 4) Super disintegrant 5) Except for a remaining portion of approximately 5% dry weight (combined with other ingredients), there is no more water present in the premix after drying.

[0098] Example 2: Tablet preparation The ingredients according to Table 2 were mixed to obtain a dry blend, which was applied to direct compression method to obtain tablets. [Table 2]

[0099] Example 3: Film coating of tablets Tablets obtained in Example 2 but having only 50% of the content were compressed into rectangular tablets, and then the ingredients shown in the table below were mixed and film-coated (weight increase of 2-5%).

[0100] [Table 3]

[0101] Example 4: Granules The powder obtained as per example 1e was wet granulated by high shear granulation using isopropanol as the granulating fluid by adding the ingredients as per the table below.

[0102] [Table 4]

[0103] Example 5: Preparation of the final ready-to-disperse granules for filling into sachets or stick packs: The ingredients according to the table below were mixed to prepare a dry mix which was then applied for filling into sachets or stick packs.

[0104] [Table 5] *Refreshing flavors like cola, verbena, and blackberry

[0105] Example 6: Preparation of the final ready-to-disperse granules for filling into sachets or stick packs: The ingredients according to the table below were mixed to prepare a dry mix which was then applied for filling into sachets or stick packs.

[0106] Example 7: Preparation of a free-flowing powder 9.6 kg FeOOH (corresponding to 6.0 kg Fe) was suspended in water with the amounts of excipients and adjuvants shown in Table 7a. 100 kg of the suspension was applied to spray drying. The iron content of the obtained powder is shown in 7b.

[0107] [Table 7a] 1) Potato starch 2) Pregelatinized starch, available from Roquette

[0108] [Table 8] 1) Loss on drying measured with a halogen moisture analyzer (constant mass; change in mass is less than 1 mg per 180 seconds)

[0109] Example 8: Compression of the obtained free-flowing powder The products obtained in Examples 7a) to g) were mixed with the ingredients shown in Table 9a and the mixtures obtained were molded into tablets. The Fe content, Fe release at pH 3 and phosphate adsorption of the obtained tablets are shown in Table 9b.

[0110] The amount of Fe released was measured according to the European Pharmacopoeia Chapter 2.9.3 using the standard dissolution equipment and criteria described in the paper. The test medium was water and pH was adjusted to 3 using hydrochloric acid. Samples were taken after 2 hours and titrated for iron content.

[0111] Phosphate adsorption was measured as described in WO2006 / 000547 by dissolving the resulting tablets in a defined amount of phosphate solution of a specific concentration, adjusting the pH to 3, incubating at 37°C for 2 hours, centrifuging, removing the supernatant and measuring the phosphate content by ion chromatography or photometry.

[0112] [Table 9a]

[0113]

Table 9b

Claims

1. A pharmaceutical composition containing high loadings of iron oxyhydroxide in a form suitable for oral administration.

2. A pharmaceutical composition containing high loadings of iron oxyhydroxide in a form suitable for oral administration as a film-coated dosage form for complete swallowing or as an orally disintegrable dosage form.

3. 3. A composition according to claim 1 or 2, which contains at least one or more carbohydrates and / or humic acids.

4. 4. The composition of claim 3, wherein the carbohydrate is selected from the group consisting of monosaccharides, disaccharides, or polysaccharides, such as agarose, dextran, dextrin, dextran derivatives, cellulose and cellulose derivatives, sucrose, maltose, or lactose, preferably sucrose, dextrin, and starch.

5. 5. The composition of claim 1, wherein the iron oxyhydroxide comprises beta iron oxyhydroxide.

6. A composition according to any one of the preceding claims, wherein the iron oxyhydroxide is present in an amount ranging from 10 to 80% (w / w), preferably from 30 to 65% (w / w), relative to the total weight of the composition.

7. 7. The composition according to any one of claims 1 to 6, wherein the carbohydrates and / or humic acids are present in a total amount ranging from 1 to 50% (w / w), preferably from 5 to 30% (w / w), relative to the total weight of the composition.

8. 8. The composition of claim 1 further comprising one or more flavoring agents, sweeteners, taste enhancers, and / or colorants.

9. The composition of claim 8, wherein the sweetener is a natural or non-natural sweetener selected from sugar, polyol, aspartame, sucralose, acesulfamine K, and / or saccharin, and the taste enhancer is selected from glycosides, e.g., neohesperidin dihydrochalcone, glycyrrhizin, glutamate.

10. 10. A composition according to claim 8 or 9, wherein the sweetener is present in an amount of 0.01 to 2.5% (w / w) and the taste enhancer is present in an amount of 0.1 to 10 ppm, each based on the total weight of the composition.

11. 9. The composition according to claim 8, wherein the flavouring agent is present in an amount ranging from 0.01 to 10% (w / w), preferably from 0.1 to 5% (w / w), most preferably from 0.1 to 1% (w / w), relative to the total weight of the composition.

12. 12. The composition of any one of claims 1 to 11, further comprising one or more excipients, such as superdisintegrants, glidants, antioxidants.

13. 13. The composition of claim 12, wherein the superdisintegrant is selected from the group consisting of crosslinked polyvinylpyrrolidone, modified starch, and modified cellulose.

14. 14. The composition according to claim 12 or 13, wherein the superdisintegrant is present in an amount ranging from 0.1 to 10% (w / w), preferably from 0.5 to 8% (w / w), more preferably from 2.5 to 6% (w / w), relative to the total weight of the composition.

15. 13. The composition of claim 12, wherein the glidant is selected from the group consisting of magnesium stearate, silica derivatives such as colloidal silica, pyrogenic silica, sodium silicoaluminate hydrate, colloidal silicon dioxide, talc, and mixtures thereof, preferably magnesium stearate, colloidal silica, or talc.

16. The composition according to claim 12 or 15, wherein the glidant is present in an amount ranging from 0.01 to 10% (w / w), preferably from 0.1 to 5% (w / w), relative to the total weight of the composition.

17. 17. A composition according to any one of claims 1 to 16, comprising iron oxyhydroxide in an amount of 10 to 80% (w / w), at least one or more carbohydrates and / or humic acids in a total amount of 1.0 to 50% (w / w), optionally one or more excipients in a total amount of 1.0 to 50% (w / w), one or more taste enhancers in a total amount of 0.1 to 10 ppm, and / or one or more flavourings in a total amount of 0.01 to 10% (w / w), each based on the total weight of the composition.

18. 18. The composition of claim 17, comprising one or more superdisintegrants in a total amount of 0.1 to 10% by weight (w / w).

19. 19. A composition according to any one of claims 1 to 18 in a form for complete swallowing or in a form capable of rapid disintegration, such as a chewable tablet or pill, a dry powder, granules, a capsule or sachet containing said granules, a wafer, or a lozenge.

20. 20. Use of a composition according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment of hyperphosphatemia.

21. 21. Use of a composition according to any one of claims 1 to 20 for the manufacture of a medicament for the treatment of patients with chronic renal failure.

22. 22. A process according to any one of claims 1 to 21, wherein the composition is made into a tablet by direct compression or dry granulation.

23. 23. A process for preparing a composition according to any one of claims 1 to 22 in the form of a tablet, comprising preparing an aqueous suspension containing at least 90% (w / w) of the components relative to the total weight of the final composition, subjecting the same to spray drying to obtain a free-flowing powder, which is optionally mixed with the remaining components and then compressed to obtain tablets.

24. A tablet obtainable by the process according to claim 23.

25. A tablet comprising iron oxyhydroxide in an amount of 40-65% (w / w), sucrose in an amount of 5-30% (w / w), and starch in an amount of 5-30% (w / w), based on the total weight of the tablet composition excluding the weight of any tablet coating that may be present.

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