MX2008006985A - Film-coated and/or granulated calcium-containing compounds and use thereof in pharmaceutical compositions - Google Patents

Abstract

Calcium-containing compounds have been at least partly film-coated and/or granulated with a water-soluble substance and a water-soluble polymeric substance and use of such coated compounds in pharmaceutical compositions. The at least partly film-coated and/or granulated calcium-containing compounds have proved suitable for the preparation of tablets having a very high load of elemental calcium and a conveniently small size. A drug load of about 96%or more is obtained in tablets of the invention that have sufficient mechanical and organoleptic properties.

Description

COMPOUNDS CONTAINING CALCIUM, GRANULATED AND / OR COATED WITH FILMS AND USE OF THEM IN COMPOSITIONS PHARMACEUTICALS FIELD OF THE INVENTION The present invention relates to calcium containing compounds that have been at least partially film coated and / or granulated with a water soluble substance and polymeric substance and to the use of such coated compounds in pharmaceutical compositions. Calcium-containing compounds, at least partially coated with film and granules, have been found to be suitable for the preparation of tablets having a very high elemental calcium loading and a suitably small size. BACKGROUND OF THE INVENTION The present administration of calcium as supplements or medicinal specialties to be taken orally is frequently characterized by a number of disadvantages or inferior technical properties in addition to an unfavorable acceptance of the consumers. Calcium is most often administered as calcium carbonate since this salt contains a high calcium load. Normally 500 mg of Ca2 + equivalent to 1250 mg of calcium carbonate are administered in one dose. Incorporating 1250 mg of calcium carbonate into a tablet Ref. 193211 being swallowed does not represent a good form of administration, since the tablet is bulky and not easy to swallow. An increasingly used dosage form containing calcium carbonate is "a chewable tablet formulation" since this dosage form presents a more palatable choice for the patient. A further improvement is the tablet melting formulation, which disperses rapidly in the mouth without the aid of chewing. However, chewable tablets and tablet casting formulations, for various reasons, have had inferior technical properties and problems related to unfavorable acceptance by consumers. Due to a desired high content of calcium carbonate it is often necessary to incorporate a considerable amount of excipients to achieve a satisfactory agglomeration to produce a granulate and subsequently a satisfactory compression to form the tablets. Another reason for incorporating a fairly high proportion of excipients as soluble filler materials is also carried out to achieve a palatable dosage form that disperses rapidly in the mouth and does not stick to the teeth. This generates instead large tablets, which the patient or the consumer will find difficult to take. Another disadvantage with current chewable tablets is that they very often contain soluble filler materials, which are very hygroscopic. The tablets thus represent a stability problem when stored in humid conditions. This problem requires the need for unnecessary packing to protect the tablets against moisture, which adds to the cost of the product. In addition there is a need to produce a dosage form, which gives the patient a choice with respect to the administration of the tablet. Older people and young people very often prefer dosage forms that are easily dispersed in water, thus becoming drinkable. Accordingly, there is a need for a "multifunction" dosage form, which can be chewed, dispersed in water or simply melted in the mouth. There is also a need for a rational and industrial manufacturing method for the production of a small and compact calcium dosage form with multifunctional properties, which does not require the use of expensive excipients or the use of expensive packaging materials. The particulate matter or a granular material can be produced by a variety of production processes in pharmaceutical manufacturing including high speed mixing, dry granulation or compaction, extrusion, spray drying and fluid bed processing. The most common method of granulation in pharmaceutical manufacturing is by high speed mixing or high cutting mixing and subsequent drying of the wet granules in a fluid bed. This method produces a dense granulate which is suitable for making small tablets with a high density. The granulation of the fluid bed is much less used since this is a more complicated and more expensive process with respect to the investment, validation process and operating cost. The process of granulation of the fluid bed produces a less dense granulate, which is undesirable when the ordinary tablets to be swallowed must be manufactured. The successful formulation of calcium chewable products demands very specialized raw materials, and more importantly a very delicate production process. The importance of combining the critical characteristics of the raw materials together with a carefully selected production process has been shown for the calcium chewable tablets in the European Patent Application published under No. 1128815 of Nycomed Pharma AS. This document describes a process by which the unwanted large volume of a chewable tablet containing calcium carbonate is reduced. The reduced size of the tablet has been achieved by the careful selection of the physical properties of the calcium carbonate source and a fluid bed granulation and a drying process. The optimal windows for the average particle size and area specific surface were found to be 3 to 40 μm and 0.1 to 1.2 m2 / g, respectively, for the preferred qualities of calcium carbonate. The choice of the particle size range was especially important to achieve a satisfactory chewable and mouth dispersion capacity, while the specific surface area was important to achieve a short or efficient processing time during the granulation and drying phase in a fluid bed. The granulation step of the fluid bed has resulted in a very homogeneous distribution of the binder, which in turn results in rapid dispersion of the tablet when chewed but also in very good consolidation properties during the tabletting step. This last property is very important for the productivity of the machines of formation of tablets of high speed to ensure the maximum production and a minimum demand for cleaning and maintenance of the machining of the tablet. However, the use of fluid bed granulation and drying increases some problems that remain unresolved. These problems relate to the flexibility of the composition of the fluid bed granulate and to the processing problems during the execution of a batch recipe. The formulation and processing problems are They fit in the section below: Trying to make a more compact calcium chewable formulation by reducing the amount of excipients has proven difficult due to unsatisfactory agglomeration resulting in a granulate that contains too much fine material. It has also been found that the subsequent compression of the tablet is difficult due to insufficient tabletting properties resulting in a non-cohesive tablet with a high percentage unsatisfactory for friability.

• Reducing the level of excipients has also reduced the sensory qualities for the chewable tablet formulation resulting in reduced acceptance of the client or patient. • The regular processing problems are the adherence of a powder or granulate to the internal parts of the fluid bed apparatus, to the spray nozzles and to the air filters. Another problem has been fine dust particles that are housed under the product screen in the lower plenum where the inlet air passes to the fluid bed. In addition to the gradual deposition of layers of dust in the expansion chamber this causes a need for regular cleaning. • During the course of a batch recipe of calcium granules there have been problems in ensuring a fluidization satisfactory during the end of the granulation step and the beginning of the drying step. Especially during the summer season where the ability to dehumidify is at its limits there have been problems with insufficient drying and the formation of conglomerates in the product container. This causes a significant problem of the batches of granules, which are not according to the specification with respect to moisture content which is too high. U.S. Patent 5,939,091: "Method for making fast-melt tablets" by Warner Lambert Company discloses compositions and processes for producing rapidly disintegrating and fast-casting tablets containing calcium carbonate. The patent specifies the use of low density alkaline metals with a density in the range of 0.3 g / ml to about 0.55 g / ml since these qualities after spray drying or compaction can be compressed into tablets having a low density and They exhibit rapid disintegration in the oral cavity and a soft perception in the mouth. Tablets produced with calcium carbonate based on a denser quality of 0.85 g / ml are described as not resulting in an acceptable perception to the mouth. However, US 5,939,091 does not describe compositions, which gives a rapid disintegration in high loads of calcium carbonate, and, consequently, does not produce solutions with respect to producing small and dense tablets with rapid disintegration and good sensory properties. WO 2004/047810 Al. "Mannose-based fast dissolvmg tablets" by Purdue Research Foundation gives an overview of current patents and technologies for making tablets that dissolve fast, disintegrate fast or melt fast. List the following table for the technologies used in the preparation of tablets that dissolve fast: WO 2004/047810 Al discloses a laborious method for producing fast-disintegrating tablets with mannose which involves first compressing a mixture of drug and man-made powder to give a tablet with very low mechanical strength and then exposing this brittle tablet to water vapor or high humidity to establish liquid bridges and where the tablets were subsequently dried to give tablets with an increased mechanical strength of 40 Newtons. US 6,149,941: "Taste of active pharmaceutical mgredients" by Merck Patent Gesellschaft describes a process for improving the taste of solid formulations containing one or more active ingredients. The process involves co-drying by sprinkling the active together with at least one polyol where both; the active and the polyol are dissolved or dispersed in the aqueous phase before starting the drying by spray in either a spray drying equipment or a fluid bed apparatus. The patent further discloses that the tabletting behavior of polyols such as mannitol, lactitol, isomaltol and xylitol is poor resulting in low hardness of the tablet, peeling and severe friability of the tablets. It was found on the other hand that sorbitol produces tablets with very good hardness of the tablet and tablets with particular soft surfaces. The use of sorbitol in the compositions of the examples in the patent was in the range of 10 to 33% which gave tablets with improved sensory properties with respect to taste and ability to be chewed. Thus, the prior art suggests that dense tablets containing calcium carbonate do not produce tablets with rapid disintegration in the oral cavity and with an acceptable perception to the mouth. The prior art also indicates that when formulating chewable tablets it is important to choose a polyol such as sorbitol with good molding properties. It can also be indicated that the technologies and Processes that produce tablets with rapidly disintegrating or rapidly melting properties are often laborious and costly where conventional pharmaceutical processing equipment can not be used. Quick melt formulations very often also exhibit unfavorable characteristics such as having to use a high percentage of excipients, being hygroscopic and being very friable and unstable to moisture. BRIEF DESCRIPTION OF THE INVENTION Accordingly, there is a need to produce an improved oral and solid dosage form containing a calcium compound with the following properties: High calcium loading to produce a small, dense tablet • Rapidly disintegrating or rapid properties casting Good sensory properties • Multifunctional properties where the tablet can be chewed, melted in the mouth or dissolved in a glass of water to be taken as a liquid dosage form • Good tablet compression characteristics to produce tablets with a high degree of strength mechanics • A robust tablet formulation that can withstand challenges of normal environmental humidity • The use of standard pharmaceutical equipment and a time short processing. The present invention provides such improved compositions. The present invention is based on the discovery that, when a water-soluble film comprising a water-soluble substance and a polymeric substance is at least partially applied to the calcium-containing compound, then only small amounts of excipients are required to manufacture for example, tablets having suitable properties as those mentioned above. In addition, it is possible to obtain tablets of relatively small size and containing 96% w / w or more of the compound containing calcium; remarkably, a content of the calcium-containing compound of about 97% w / w can be manufactured. Thus, formulations of calcium chewable tablet with excellent sensory properties have been produced with a quantity of excipients, which has been reduced to a level of about 2-16.6% of the weight of the tablet. Casting and chewable formulations containing 500 mg of Ca2 + equivalent to 1250 mg of calcium carbonate have a tablet weight of 1290 to 1500 mg and a tablet diameter of 13 to 15 mm. This has been achieved due to a surprising synergistic effect that has taken place leading to rapid agglomeration with a reduced amount of fine material and, in a subsequent tabletting step, resulting in tablets with very good cohesive properties produced at low tabletting pressures. The synergistic effect is achieved by applying a composition containing a water-soluble substance and a polymeric substance on the calcium-containing compound to obtain a water-soluble film at least partially on the calcium-containing compound. Without being tied to the theories, the plastic properties can also be important in a subsequent stage of tablet formation to ensure good cohesive properties. In addition, the solid components included in the composition must be soluble in water, ie the polymeric substance must also be soluble in water. Accordingly, in a separate aspect, the invention relates to a calcium-containing at least partially film-coated composite, wherein the calcium-containing compound is in the form of particles and / or crystals that are at least partially provided with a coating of soluble film that has binding properties. The present invention also relates to a method for the preparation of an at least partially calcium-containing calcium-containing compound, the method comprising applying a coating composition that comprises one or more water-soluble substances and one or more polymeric substances in a calcium-containing compound. In addition, the present invention relates to a number of compositions, notably the composition of the tablet having one or more, preferably all of the features listed above. Accordingly, in a further aspect, the present invention relates to a composition comprising a calcium-containing compound at least partially coated with film as described herein and one or more pharmaceutically acceptable excipients. In addition, the invention relates to a method for the preparation of such a composition, the method comprising mixing one or more pharmaceutically acceptable excipients with the at least partially film-coated calcium-containing compound. In a still further aspect, the invention relates to a method for improving the taste of a calcium-containing compound, the method comprising applying a film coating containing one or more water-soluble substances and a polymeric substance on a compound which contains calcium in the form of particles and / or crystals to obtain a calcium-containing compound at least partially coated with film as defined herein. In some cases, depending on the manufacturing method, it can be difficult to judge the degree of coating on the compound that contains calcium. However, the coating process is also a granulation process and, consequently, in another aspect, the invention relates to a compound containing calcium, granulate, which was granulated with a granulation composition comprising a substance soluble in water and a polymer substance. The coating refers to a complete or partially complete coverage of the surfaces of the calcium carbonate crystals that take place at the beginning of the agglomeration process and a coating in a fluid bed spray granulator. This complete or partially complete coverage of the combined polymeric binder and the soluble filler causes rapid granulation or agglomeration to take place. Subsequent application of the granulation and coating liquid subsequently will primarily cause an additional coating to take place where the surfaces of the granules will receive a more extensive coating. However, a bond of dust and fine particles to the surfaces of the initial granules will also take place there at the same time. Thus, the manufacturing method is a combined agglomeration and coating process where the primary particles or crystals receive a full or partial coating, the coated particles are then agglomerated and the granules are then coated further. This is evident by the very rapid dispersion of the particles primary when a calcium smelting tablet according to the invention is exposed to an aqueous environment. All the details and the described circumstances concerning the aspect of the coating apply muta tis mutandis to the appearance of the granulate, cf. the attached claims. In a specific embodiment, the present invention provides a chewable compact calcium composition, which disperses very rapidly in the mouth at low levels of excipient and with multifunctional properties comprising; a chewable tablet; a tablet to be swallowed; a foundry tablet formulation and an aqueous dispersible formulation. In a specific embodiment, the composition comprises the following components: (a) a calcium-containing compound (CC) having a surface area of 0.1 to 1.5 m2 / g (b) a combination of a water-soluble substance and a polymeric substance with link properties; the composition is prepared by (c) dissolving the combined water soluble substance and the polymeric substance to produce a granulating liquid and coating (d) applying the granulating liquid and coating in a fluid bed apparatus on the fluidized bed of the compound which contains calcium, and (e) optionally mixing the obtained granulate with other excipients and compressing it into chewable or cast tablets. The granulation step of the fluid bed has resulted in the formation of granules or agglomerates of individually coated particles or crystals of the calcium-containing compound. It has also been observed that the coating layers can include or fix the fine material fraction of the calcium-containing compound in the film surrounding the individual particles or crystals. In a preferred embodiment, the resulting chewable tablets are characterized by the following properties: A dense tablet with apparent tablet densities in the range of 1.4 to 1.9 g / cm 3. • A multifunction fast-melt tablet that can be chewed, can be quickly dispersed within 60 seconds in the mouth without chewing, can be dispersed within 180 seconds in a glass of tap water or can be swallowed. In a specific embodiment as illustrated in the Examples herein using the fluid bed technology, a casting tablet can be produced to rapidly disperse within seconds in the mouth without chewing, and to disperse within 60 seconds in a glass of tap water • The tablets contain a high load of ingredients active up to 96% or 97% of the weight of the tablet. • Tablets are produced at low tablet pressures from 6 to 46 kN. In a specific embodiment, tabletting pressures may be as low as 6 to 20-25 kN or even less than 6 to 16 k. The pressure applied also depends on the tablet machine used and whether it is a production or a pilot scale. • Tablets are robust with a friability of less than 2% and can withstand ordinary packaging machines. • The composition of the tablet does not require special high cost excipients Tablets can be produced on the packaging equipment and ordinary and existing production.

• The tablets are not hygroscopic. The tablets are contemplated to not require special packaging protection. • Process time is short and tablets can be produced at a low cost. The principle of the new formulation of combining a water soluble substance and a polymeric substance with binding properties has also resulted in processing advantages during the fluid bed process including a shorter processing time, less generation of fine particles, a reduction in the adhesion of fine dust to the interior of the product container and to the expansion chamber and probably a reduction in the accumulation of fine dust in the lower plenum due to a faster rate of agglomeration. It has also surprisingly been found that the average particle size of the at least partially film-coated calcium containing compound can be effectively varied over a wide range of particle sizes by carefully controlling the content of the polymeca substance and the amount of granulation liquid employed during the granulation stage. Furthermore, it has surprisingly been found that the principle of the new formulation is much less sensitive to processing difficulties and variation in moisture content and particle size / distribution of the granulate when different sources of calcium with different physical characteristics are used, such as the area surface specific, particle size / distribution and particle shape. As mentioned above, there is a need to improve dosage forms containing calcium-containing compounds to make these smaller, more palatable and also to introduce flexibility with respect to taking the dosage form. As well There is a need to establish a production method that is rational and cost saving and that uses the standard pharmaceutical processing equipment. The invention is based on the discovery that it is possible to at least partially coat a calcium-containing compound with a combination of a water-soluble substance and a polymeric substance. Such a coating appears to be very advantageous since it at least partially encapsulates the calcium-containing compound in such a way that the amount of the fillers normally used and the flavor-improving agents used in the manufacture of the final product can be reduced without leading to a product that has poorer sensory characteristics. BRIEF DESCRIPTION OF THE FIGURES Figures 1A-1B represent calcium carbonate crystals coated and at least partially bonded with film according to example 1 in the invention. Figure 2 illustrates the disintegration / visual dispersion of the tablet in the aqueous medium is recorded together with the time it takes for the tablet to uncouple from the tied rope. Figure 3 shows the tablet compression curves achieved by example 1 and 2. Figure 4 shows the percentage of dissolved calcium with respect to the dissolution time of the tablet.

Figure 5 shows the results of the sensory analysis of example 3 and 4 according to the invention and the reference example 3 and 4. Figure 6 shows the difference statistically between examples 3 and 4 with respect to the time of dispersion by casting. Figures 7A and 7B show SEM photographs in magnifications of 1500 and 5000x. Figure 8 shows the level of resistance to crushing test 6 is less than the slopes for the rest of the tests. Figure 9 shows the impact on the crush resistance of the design. Figure 10 illustrates the sliding time of a hanging tablet. Figure 11 illustrates the disintegration time of the tablet. Figures 12A-12C indicate the areas of the uncoated surface area of the calcium-containing compound. DETAILED DESCRIPTION OF THE LIVING Compositions or combinations containing calcium or calcium containing compounds at least partially coated with film According to this, in one aspect the invention relates to a calcium-containing compound at least partially coated with film, wherein the calcium-containing compound is in the form of particles and / or crystals that are at least partially provided with a water-soluble film coating. It is believed that it is not necessary to coat the entire available surface of the calcium-containing compound to obtain the desired effect, i.e. to obtain compositions having acceptable sensory properties when tested by a professional tasting panel of at least 6 people and / or for get tablets that have a very high calcium load and a convenient small size. To obtain the desired effect it is contemplated that at least 50% such as, for example, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 99% or 100% of the surface area of the calcium-containing compound is covered with the film coating. The film that covers the calcium-containing compound can be a continuous film, i.e. a film that substantially covers the outer surface of the calcium-containing compound. To judge to what extent the surface of the calcium-containing compound is coated with a film coating it is possible to study the SEM images of the composite coated. Other methods can also be used such as ESEM (electron microscopy for environmental exploration), X-ray photoelectron spectroscopy, TOF-SIMS (time-of-flight secondary ion mass spectrometry) and so on. As mentioned above, it is important that the degree of coating is sufficient for the specific purpose. Consequently, the following test can be used to evaluate whether the coating is applied to a sufficient degree. Prepare a tablet by i) mixing the at least partially coated calcium-containing compound with a lubricant such as, for example, magnesium stearate to obtain a mixture wherein the concentration of the at least partially coated calcium-containing compound is 99.5%, weight / weight and ii) compress the mixture thus obtained in tablets, submit the tablet obtained to the method of "Tablet Hanging" described here, and the observed sliding time should be at most 3 minutes such as at most 2 minutes, at most 1 minute, at most 45 seconds or at most 30 seconds. The aforementioned test is especially relevant when the final product is a casting tablet or a chewing tablet: In addition, the aforementioned test is especially suitable for use when the film coating has been made in a fluid bed apparatus. Alternatively, prepare a tablet by i) mixing the at least partially coated calcium-containing compound with a sugar alcohol such as, for example, xylitol and a lubricant such as, for example, magnesium stearate to obtain a mixture wherein the concentration of the at least partially coated calcium-containing compound is at least 80% w / w, the concentration of the sugar alcohol is at least 19.5% w / w, and the concentration of the lubricant is at least 2%, and ii ) compress the mixture thus obtained into tablets, subject the obtained tablet to a sensory test by a professional tasting panel, which must find the sensory properties of the acceptable tablet. However, the coating process is in fact a combination of a coating and an agglomeration process, ie the calcium-containing compound is coated and agglomerated with a highly soluble film with good binding and / or tablet consolidation properties. Thus, the pharmaceutical processes, which can apply the coating and the agglomeration of crystals or particles individually for example with a small size in the range of 5 to 40 μm, they can be used in the present context. Accordingly, it is contemplated that other coating or granulating methods are equally suitable (see Examples here) such as, for example, other wet or melt granulation methods or other coating methods such as spray coating or cast coating. The agglomeration and coating equipment includes continuous and batch continuous beds with top, bottom or tangential spray such as Glatt, Aeromatic and Heinen systems, highly intensive horizontal and vertical mixers such as Fielder or Diosna, continuous mixers such as Hosokawa Schugi, extruders such as double screw extruders or spray drying equipment in combination with internal or secondary fluid bed units of for example Niro or Anhydro. Agglomeration, also called granulation, is a process where the particles join together in larger aggregates, so called agglomerates or granules, where the original particles are still distinguishable. In wet agglomeration, this process is facilitated by a granulation liquid. The liquid joins the particles by a combination of capillary and viscous forces in the wet state. More permanent bonds are formed during the subsequent drying. The goal of the agglomeration is to improve the flow of dust and the handling, to diminish the dusty, fixation of the mixture and consequently to prevent the segregation of the API (active ingredient) . The strength of the agglomerates depends on the bonds formed during drying. The strength of the bonds can be improved by adding a polymer to the granulation liquid, which can also lead to improved tabletting properties. However, the addition of polymer to the granulation fluid can result in prolonged disintegration times, curing of the tablets, decrease in casting properties, etc. The wet agglomeration can be carried out with for example high shear mixer, Schugi Flex-O-Mix agglomerator and fluid bed between other equipment. Fluid bed: The granulation of the fluid bed and the drying take place in a fluid bed granulator consisting of a product container and an expansion chamber for the fluidization of the powder mixture to be granulated. The powder mixture rests on a product screen at the bottom of the product container and is restricted from escaping from the expansion chamber by an exhaust filter on the outlet side of the fluid bed granulator. The air flow required for the fluidization of the powders is generated by a suction fan mounted on the upper portion of the unit. The air used for the fluidization is heated to the desired temperature by an air heater located in the portion of Air intake of the equipment. The powder mixture is flowed through a sufficient volume of air and the granulation liquid is atomized as a fine mist through a rolling head consisting of a multiple of binary nozzles. The rolling head can add the atomized spray of granulation liquid countercurrent to the pulsating particles denoted "upper spray" or co-current to the pulsating bed denoted "lower spray". The wet particles undergo agglomeration or granulation through particle-particle contact. After proper agglomeration is achieved, the spraying operation is discontinued and the material is dried and discharged from the unit. By adjusting the critical characteristics of the formulation and the process parameters for the fluid bed process it is possible to agglomerate, instantize or coat individual particles in a sprayable mixture. Al to Corte Mixer: In this type of equipment, the particles are set in motion by a rotary impeller at a high speed. It also contains a chopper that breaks large aggregates. The binder liquid is added by pouring, pumping or spraying from above. The wet agglomeration in a high-cut mixer typically involves five to six phases: First the materials are mixed dry, where the liquid is subsequently added during mixing. Then the moist mass becomes wet mass. Then the granules are (sifted in wet), dried and sieved again. Schugi: A typical procedure of the Schugi Flex-O-Mix agglomerator involves the following general steps. The dry feed product is fed by gravity to the top of a cylindrical chamber containing a rotating inner shaft (approximately 1000-4400 RPM) with attached blades. At the point where the dry feed product enters the chamber, a granulation liquid is introduced to the powder by atomization. The dry feed powder and the granulation liquid mix violently and intimately causing particle collisions and subsequent particle growth. The sides of Schugi's cylindrical chamber are made of a flexible material, so that during operation a device can periodically tighten the chamber causing the dust increase to be removed. Subsequently the particles are immediately fed to a dryer to remove excess moisture. The film comprises a substance soluble in water and a polymeric substance, notably a substance soluble in polymeric water. Normally, the polymer substance has binding properties, which is useful since the coating process also enables the formation of agglomerates to provide a granulate. The solubility in water of the polymeric substances is about 10 mg / ml or more such as, for example, about 25 mg / ml or more, about 50 mg / ml or more, about 75 mg / ml or more, about 100 mg / ml or more, about 150 mg / ml or more, about 200 mg / ml or more, about 250 mg / ml or more, or about 300 mg / ml or more. The water-soluble substance in the coating is important in that it confers water solubility on the coating and contributes to the rapid disintegration and / or dlution observed for the tablets based on the at least partially calcium-coated compound containing the film according to the invention . The solubility in water of the one or more water-soluble substances is about 10 mg / ml or more such as, for example, about 25 mg / ml or more, about 50 mg / ml or more, about 75 mg / ml or more or approximately 100 mg / ml or more. The table below gives solubilities in water for water-soluble substances (also denoted water-soluble filler materials) for use according to the invention.

Normally, the soluble filler material should have a solubility greater than 1 g / 100 ml. Examples of water-soluble substances suitable for use according to the invention are polyols and carbohydrates, and mixtures thereof. Other examples of suitable water-soluble substances are organic acids, pharmaceutically acceptable salts of organic acids including alkali metal and alkaline earth metal salts (for example carbonates, citrates, acetates, fumarates, etc., exemplified in the examples with citric acid and ascorbate). sodium), amino acids (for example glycine), inorganic salts including sodium chloride, etc.

Typically, the polyol is a sugar alcohol. In the specific embodiments, the sugar alcohol is selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, lactitol, erythritol, inositol, isomait, isomaltulose and mixtures thereof. The water soluble substance can also be carbohydrate selected from the group consisting of mono-, disaccharides, oligosaccharides, polysaccharides, and mixtures thereof. Examples of monosaccharides suitable for use according to the invention are glucose, mannose, fructose, galactose, and mixtures thereof. Examples of disaccharides suitable for use according to the invention are lactose, maltose, sucrose, trehalose, tagatose, and mixtures thereof; and examples of polysaccharides and oligosaccharides suitable for use according to the invention are dextrose, oligofructose, cyclodextrins, maltodextrins, and mixtures thereof. Typically, the water-soluble substance is present in the at least partially calcium-coated calcium containing compound at a concentration of 0.1% w / w at about 50% w / w such as, for example, 0.5% w / w at about 50% w / w, 0.75% w / w at about 50% w / w, from about 1% w / w to about 40% w / w, from about 1.5% w / w to about 30% w / w, or from about 2% w / w to about 20% w / w.

In specific embodiments, the concentration of the water soluble substance in the at least partially film-coated calcium containing compound may be in a range of lower concentration such as from about 0.1% w / w to about 10% w / w as , for example, from about 0.5% w / w to about 10% w / w, from about 1% w / w to about 10% w / w, or from about 2% w / w to about 5% w / w. As mentioned above, the polymeric substance used in the coating of the calcium-containing compound must have good tablet binding and / or binding properties. Such characteristics are important in the further manufacture of the compound containing calcium at least partially coated with obtained film, especially in the manufacture of tablets. The good binding and / or consolidation properties of the tablet may also be plastic properties. Such properties make it possible to substantially avoid breaking or otherwise destroying the film coating, thus, the properties obtained by the film coating are also present in the final product. Furthermore, it is advantageous if the polymer substance has binding properties and therefore enables the agglomeration of the calcium-containing compound (optionally together with one or more pharmaceutically acceptable excipients). Examples of such polymeric substances with binding properties are among the pharmaceutically acceptable binders. Accordingly, in a specific embodiment, the polymeric substance is a pharmaceutically acceptable binder. The polymeric substances can be selected from different types of povidones, copovidones, cellulose-type polymers, inulin and oligosaccharides, starches and high molecular weight polysaccharides. Specific examples can be found under the heading "Pharmaceutically acceptable excipients" and in the examples herein. Examples of pharmaceutically acceptable binders which are suitable for use according to the present invention are povidones including K-90, K-30, K-25, K-17 and K-12; copovidone; polyethylene glycol-polyvinyl alcohol (for example Kollicoat IR), agar; jelly; gum arabic; agglutinates including sodium alginate and polyethylene glycol alginate; starches or modified starches including potato starch, corn starch, rice starch, pre-gelatinized starch; carbohydrates including inulin, polydextrose, dextrin, maltodextrins; cellulose and cellulose derivatives including sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC), microcrystalline cellulose, cellulose derivatives such as substituted hydroxypropylcellulose, and mixtures thereof. The concentration of the polymeric substance used in the at least partially calcium-containing calcium-containing compound can vary depending on the particular polymeric substance employed. In general, the concentration is in a range from about 0.09% w / w to about 10% w / w such as from about 0.2% w / w to about 10% w / w, from about 0.5 w / w to about 5% weight / weight The calcium-containing compound is selected from the group consisting of calcium carbonate, calcium citrate, calcium lactate, calcium phosphate including tricalcium phosphate, calcium gluconate, calcium bisglycine, calcium citrate maleate, hydroxyapatite including solvates of the same, and mixtures thereof. In specific modalities, the calcium-containing compound is calcium carbonate or a calcium phosphate (including dicalcium phosphate and tricalcium phosphate), or mixtures thereof. Of particular interest is calcium carbonate. The specific surface area of the calcium-containing compound used is of particular interest in those cases where the granulation of the fluid bed is involved in the manufacturing process. Consequently, in such cases, the specific surface area of the calcium-containing compound such as, for example, calcium carbonate is from about 0.1 to about 3 m2 / g such as. { 5br example from about 0.1 to about 2.75 m2 / g, from about 0.1 to about 2.5 m2 / g, from about 0.1 to about 2 m2 / g, from about 0.1 to about 1.8 m2 / g, from about 0.1 to about 1.5 m2 / g g, from about 0.1 to about 1.6 m2 / g, from about 0.1 to about 1.4 m2 / g or from about 0.1 to about 1.3 m2 / g. With respect to calcium carbonate, the specific surface area is usually from about 0.1 to about 1.2 m2 / g. As mentioned hereinbefore, it is generally recognized that the particle size of the calcium-containing compound is of importance for the sensory properties of the final product. Consequently, in a specific embodiment, the average particle size of the calcium-containing compound such as, for example, calcium carbonate is from about 0.1 microns to about 100 microns such as from about 0.1 microns to about 80 microns, about 0.5 microns to about 60 μm, from about 1 μm to about 50 μm or from about 2 μm to about 40 μm. In a further embodiment, the average particle size of the calcium carbonate is from about 3 to about 40 μm. The examples herein demonstrate that a particular suitable coating obtained is when the water-soluble substance is xylitol and the polymeric substance is a povidone or co-povidone, or mixtures thereof. Furthermore, in a specific embodiment the coating essentially contains the water soluble substance, notably a sugar alcohol, and the polymer substance, notably a polyvinyl pyrrolidone. The calcium-containing compound at least partially coated with film can be combined with one or more active substances such as, for example, a nutrient and / or a therapeutically active substance. Of particular interest are compositions in whthe calcium containing compound at least partially coated film is present in combination with a vitamin such as, for example, vitamin D including vitamin D2 and D3, vitamin B or vitamin K, and derivatives from the same . In another aspect of the invention a coating of The film is applied to a combination of a compound containing calcium and one or more additional substances. The one or more additional substances may be another active substance such as that mentioned above, or may be one or more pharmaceutically acceptable excipients or additives. As seen from the examples herein, a specific embodiment of the invention is a composition at least partially coated with film comprising a compound containing calcium and one or more polyols such as those mentioned hereinbefore. Additives such as one or more flavoring agents, hiding the taste, agents that enhance artificial sweeteners sensory properties, acidulants, sweeteners including sweeteners and intense may also be present in the composition is at least partially provided with a film coating . In general, the concentration of such additional substances present in an at least partially film coated composition is at most about 20% w / w such as, for example, at most about 15% w / w, at most about 10%. % weight / weight, at most approximately 7.5% weight / weight, at most approximately 5% weight / weight or in a range from approximately 0.5 to approximately 5% weight / weight. With regard to artificial sweeteners the concentration is usually even lower such as at most about 1% w / w or at most about 0.01% w / w. In other words, normally the calcium-containing compound constitutes at least 80% w / w such as at least 85% w / w or at least about 90% w / w of the total weight of the composition at least partially coated with film. In a specific embodiment, the at least partially film-coated combination according to the invention further comprises one or more pharmaceutically acceptable excipients. In addition to the possibility that a composition comprising the aforementioned substances together with the at least partially calcium-containing compound can be provided with a film coating, it is also possible to add such substances to the coating composition. In such cases, the film coating will also contain such substances. To this end, sucralose has been used in some of the Examples herein as an example of an intensive sweetener that has been dissolved in the film coating composition (which is the same to the granulation liquid) prior to the coating process eg in the fluid bed. Other excipients that can be added to the granulation liquid and coating are colors, flavors, acidulants, surfactants and emulsifiers. Typically the percentage of dry matter in the coating composition (for example a solution) has been in the range of 40-70% w / w. In those cases where the fluid bed is used, the coating and granulation processing time is typically short in the range of 6-20 minutes such as in the range of 10-20 minutes including preheating / mixing, coating / granulation, drying and cooling. Compositions, especially pharmaceutical compositions, comprising compounds, combinations or compositions containing calcium at least partially coated with film, As mentioned above, the compounds, combinations or at least partially calcium-containing compositions coated with film, described above, they are especially suitable in the preparation of the pharmaceutical compositions. Accordingly, in a separate aspect, the invention relates to a composition comprising a calcium-containing compound at least partially coated with film and one or more pharmaceutically acceptable excipients. A composition according to the invention can used in the manufacture of a pharmaceutical or nutritional composition. The composition can have any suitable form such as, for example, it can be in the form of particles such as for example powders, granules, granules, beads, pellets, etc. or it can be in a dosage form such as, for example, tablets, capsules, sachets, etc. The composition can also be in liquid form or it can be presented in dry form pretending to be dispersed in a suitable medium before ingestion. In a particularly interesting embodiment of the invention, the composition is in the form of a tablet, notably a smelting tablet or a chewing tablet. As mentioned above, the compound, combination or composition contains calcium at least partially coated with film, it is particularly suitable for use in the preparation of high load calcium products. Accordingly, in one embodiment the concentration of the calcium-containing compound is 50% w / w or more such as, for example, 55% w / w or more, 60% w / w or more, 65% w / w or more, 70% w / w or more, 75% w / w or more, 80% w / w or more or 85% w / w or more in the composition (pharmaceutical composition). Notably, the composition is in the form of a tablet and the concentration of the calcium-containing compound in the uncoated form is 80% w / w or more, 85% w / w or more, 90% w / w or more, 95% w / w or more, 96% w / w or more or 97% w / w or more. Porosity and density of the tablet The density of the tablet was found to be an important parameter in the development since a high value for the apparent density of the tablet gave an increase to small and compact tablets with a low volume of the tablet. At the same time it is equally important that the tablet has a sufficient porosity to facilitate the dispersion of the tablet in the aqueous phase which is in the mouth or in a glass of water. In the Examples herein, tablet density and porosity were calculated by measuring the true density of the tablet and the volume of the same tablet by an AccuPyc 1330 instrument and a GeoPyc 1360 instrument respectively, both from Micromeretics.

The focus of development work has also been to make smaller and more compact tablets. As seen from the examples here, this has been adequately achieved. Accordingly, the invention also provides tablets containing the at least partially calcium-coated compound, combination or composition containing calcium, wherein the tablet has a bulk density of at most about 2.2 g / cm3 such as, for example, at most about 2.0 g / cm3, at most about 1.8 g / cm3, or in a range of about 1.4 g / cm3 to about 2.2 g / cm3. In more specific embodiments, the tablet has a bulk density of 1.4 g / cm 3 or more such as, for example, about 1.5 g / cm 3 or more or in a range of about 1.4 g / cm 3 to about 1.9 g / cm 3 or about 1.5 g / cm3 at approximately 1.7 g / cm3. It should be emphasized that these density ranges are based on calcium carbonate as the calcium-containing compound. Other calcium salts or combinations of calcium salts will create other density ranges based on the differences in the true and apparent densities of these compounds. The cast and chewable tablet formulations described in some of the Examples have tablet densities in the range of 1.4 to 1.9 g / cm 3. Typically a casting and chewable calcium formulation according to the invention will have a tablet density of 1.5 - 1.7 g / cm3. A tablet according to the invention with this density has at the same time a high satisfactory value for the tablet porosity in the range of 30 to 40% with typical values of 32 to 36%. The possibility of obtaining small tablets does not affect the possibility of maintaining adequate porosity, ie a porosity that is important when the tablets are cast tablets or chewing tablets. Accordingly, the tablet can have a porosity of from about 10 to about 50% such as, for example, from about 15 to about 40% or from about 20 to about 40%. In specific embodiments, the tablet has a porosity of about 30 to about 40%. Another measure of a small tablet is the volume of the tablet per 500 mg of elemental calcium contained in a tablet according to the invention. Accordingly, the volume of a tablet according to the invention is usually at most 1.5 cm3 such as, for example, at most about 1.25 cm3, at most about 1 cm3, at most about 0.8 cm3, at most approximately 0.7 cm3 or at most approximately 0.65 cm3 per 500 mg of elemental calcium contained in the tablet. Disintegration and dispersion of the tablet The disintegration and dispersion of the tablet have been investigated by three different methods to characterize this important property. First a disintegration test has been carried out according to the European Pharmacopoeia (Ph.Eur.) Version 5.02 for all formulations. The Ph.Eur. states that chewable tablets do not have to meet with the test but also defines three other dosage forms that are relevant to the description of the invention: sun tablets are tablets that claim to be dissolved in water before application; Dispersible tablets are tablets that claim to be dispersed in water before administration and gold-dispersible tablets which are tablets intended to be placed in the mouth where they are dispersed before being swallowed. The requirement with respect to disintegration time for soluble tablets, which can be dispersed and gold-which can be dispersed according to the Ph.Eur. is that these dosage forms should disintegrate within 3 minutes. A tablet according to the invention normally has a disintegration time as measured according to the Ph.Eur. of at most approximately 30 minutes such as, at most approximately 20 minutes, at most approximately 15 minutes, at most approximately 10 minutes, at most approximately 5 minutes, at most approximately 4 minutes or at most approximately 3 minutes. In specific embodiments, a tablet according to the invention complies with the Ph.Eur. Typically a calcium smelting tablet according to the invention will disintegrate within 60 to 90 seconds. The inventors have developed another method that is especially suitable to simulate the situation inside the mouth. The method is called the "Hanging Tablet" method. In this method a hole is drilled in the middle of the tablet and a nylon rope is attached to the tablet. The tablet is then dropped into a tank of water and kept suspended in the water at 37 ° C by the help of the rope. The visual disintegration / dispersion of the tablet in the aqueous medium is recorded together with the time it takes for the tablet to uncouple from the tied rope. The image enclosed in Figure 2 best illustrates the method. The disintegration time of the Ph. Eur. Is a little more indefinite compared to the "Hanging Tablet" method with respect to measuring the disintegration time in the mouth. There may still be a conglomerate of the tablet material resting on the screen in the disintegrating apparatus even if the tablet has been completely dispersed. When the tablet has been completely dispersed it means that all the primary particles of calcium carbonate have been completely wetted and released from each other. A tablet, which is suspended from a thread in the "Hanging Tablet" method, will be uncoupled from the yarn when the tablet has been completely wetted or dispersed with a collapse resulting from the internal structure in the tablet. So, this method is more similar to what will happen in the mouth if there is a sufficient amount of saliva to extract from the matrix and disperse the primary particles of calcium carbonate. Typically, a tablet according to the invention has a sliding time (or dispersion time) as measured by the "Pendant Tablet" method as described herein for at most about 180 seconds, such as at most about 150 seconds, at most about 100 seconds, at most about 60 seconds, at most about 45 seconds or at most about 30 seconds. In the specific embodiment, the dispersion time by the "Hang Tablet" method is typically less than 30 seconds for the compositions according to the invention. In addition, the dispersion time correlates adequately with the actual perceived dispersion time in the mouth as described below. Dispersion of tablets such as, for example, cast iron tablets in the mouth A sensory panel of six selected assessors was used to determine the time of dispersion by melting in the mouth. The average time for the tablet to melt in the mouth and to swallow the contents was recorded for the formulations selected according to the invention. The statistical differences were detected using ANOVA with 95% confidence level and the Tukey HSD test with a level of importance of 5% to discriminate between the means. Two compositions according to the invention were tested against a reference based on a chewable calcium tablet according to the European application EP-A-1128815 of Nycomed Pharma. Both of the formulations according to the invention came out with a significantly shorter melt dispersion time when compared against the reference tablet. The formulation with the best cast characteristics was dispersed after 52 seconds. The results have been represented in Figure 6. Dissolution rate As it appears from the Examples herein, the use of a compound, combination or composition containing at least partially calcium coated with film according to the invention for the manufacture of tablets can lead to tablets that release the calcium-containing compound very quickly. Accordingly, at least 60% of the calcium-containing compound is released from the tablet within 30 minutes, at least 70% of the calcium-containing compound is released from the tablet within 30 minutes, at least 80% of the calcium-containing compound is free from the tablet within 30 minutes, at least 60% of the compound that contains calcium is released from the tablet within 20 minutes, at least 70% of the calcium-containing compound is released from the tablet within 20 minutes, at least 80% of the calcium-containing compound is released from the tablet within 20 minutes, at least 60% of the calcium-containing compound is released from the tablet within 10 minutes, at least 70% of the calcium-containing compound is released from the tablet within 10 minutes, at least 80% of the calcium-containing compound is released from the tablet within 10 minutes as measured by a dissolution test in vi tro according to the Ph.Eur. / USP (pallets, 50 rpm dissolution medium: 1000 ml of 0.1 M HCl containing 0.04% cetrimide, 37 ° C) In the Examples here, the dissolution analysis was carried out according to the Ph.Eur. / USP with the dissolution apparatus 2 (vane apparatus) and with a blade speed of 50 rpm. The dissolution medium was 0.1 M HCl with the addition of the cationic surfactant cetrimide, 0.04% (weight / volume). The concentration level of 0.04% (weight / volume) of cetrimide in 0.1 N HCl defines the critical concentration of micel. Cetrimide is added to reduce surface tension The dissolution rates for Examples 1 and 2 according to the invention were typically very fast and approximately 90% had already been dissolved after ten minutes. In contrast, dissolution rates for two reference examples were very slow and only 17 to 42% weight / weight dissolved after 10 minutes. Other ingredients in a composition comprising a compound, combination or composition which has at least partial coating with a film according to the invention. As mentioned above, other ingredients may be incorporated than the compound, combination or composition containing calcium at least partially coated with film in a composition of the invention. Thus, one or more active substances such as, for example, a nutrient and / or therapeutically active substance may be present including a vitamin such as, for example, vitamin D including vitamin D2 and D3, vitamin B or vitamin k, and derivatives from the same. In addition, one or more pharmaceutically acceptable additives or excipients may be incorporated (suitable examples are described below). One or more flavoring agents, flavor-hiding agents, agents that improve sensory properties, acidifiers, sweeteners including artificial sweeteners and intense sweeteners in the composition according to the invention may also be present. Preparation of a compound, combination or composition which has at least partial calcium content with the invention film and pharmaceutical compositions that contain the compounds, combinations and compositions that contain calcium The present invention also provides a method for the preparation of a calcium-containing compound at least partially coated according to the invention, the method comprising applying a coating composition comprising one or more water-soluble substances and a or more polymeric substances in a compound containing calcium. For this purpose, it is important to note that in order to obtain satisfactory results, the coating composition and / or the granulation liquid used contain a mixture or a solution of the two components. When applied in one and the same coating composition or granulation liquid, the synergistic effect is achieved and this enables the preparation of very small Ca containing tablets with suitable properties. As mentioned hereinabove, the two components are remarkably soluble in water to provide a water soluble film and are normally dissolved in an aqueous medium, notably water, before application. As seen from the examples herein, the coating composition or the granulation liquid may also contain other substances such as, for example, an artificial sweetener. Normally, the water soluble substance and the polymeric substance are dispersed or dissolved in a solvent such as an aqueous solvent or an organic solvent. In a specific embodiment, the solvent is an aqueous solvent.

As mentioned hereinbefore, one or more active substances, one or more pharmaceutically acceptable excipients and / or one or more additives may be contained in the coating composition. In one embodiment, the sweeteners including the intense sweeteners, colors, flavors, acidulants, flavors or the like are added to the solvent. In general, the application of the coating composition is carried out by spraying, melting or spray drying by the use of fluid bed, spray drying, melt granulation, extrusion, high cut mixing, or rotoprocessing. Modes Regarding Fluid Bed Processing As appears from the Examples herein, the specific embodiment relates to a method, wherein the coating composition is applied by the use of fluidized bed. For this purpose the following has been observed: The compositions according to the invention are made by coating and agglomeration of fluid bed with top spray in a Glatt GPCG 3 pilot scale model with the general fixed points for the processing parameters as follows: Batch size 3-5 kg (3 - 3.5 kg) Inlet temperature of 45-90 ° C (45 and 80 ° C) granulation Amount of granulation liquid 200-800 grams (200 - 400 grams) Spray speed 40-120 g / min (40 - 100 g / min) Spray atomization pressure 1.5 bar Drying inlet temperature 80-90 ° C (80 ° C) End point temperature 45 ° C Drying Temperature End point of 42 ° C cooling Escoralita IB from Scora atrigant SA, France has been used in all tests unless otherwise specified. In cases where a soluble filler (water-soluble substance) has been added to the compound containing dry calcium before processing in the fluid bed then the polyol or the carbohydrate has been sieved at 210 μm (70 mesh). Alternatively, the soluble filler can be milled to break up conglomerates and agglomerates. Mixtures of calcium carbonate powder and xylitol were mixed in a Kenwood Major with a mixing intensity of 4 to 2 minutes before transfer to the GPCG 3 fluid bed. The fluid bed granulates after fluid bed processing were separated into 1.4 mm (12 mesh) before mixing with the flavor granulate and magnesium stearate and finally the formation of tablets with 14 mm normal concave punches. The quality of the calcium carbonate used in all the tests was Escoralita IB or main stream of Escoralita IB if not specified otherwise. This quality is suitable for the fluidization of the fluid bed and the coating since it consists of crystals with discrete cubic or cubic shape with a particle size in the range of 5-20 μm and with a low value for the specific surface area in the range from 0.2 to 0.6 g / m2. Specific examples can be found under the title "Calcium carbonate" and in the examples here. The invention involves the coating and agglomeration of particles or crystals of the calcium-containing compound. The coating consists of a highly soluble film that at least partially covers the surfaces of the calcium-containing compound as depicted in Figures 1A-1B. Figure IA represents calcium carbonate crystals coated and agglomerated at least partially with film according to example 1 in the invention. Calcium carbonate alone without any filler excipients added here has been coated and agglomerated with a coating solution consisting of copovidone (eg PVP VA64) and xylitol. The image with magnification of 1500x indicates at least partially a coating on the calcium carbonate crystals. The granules contain very few fine particles and granules up to 400 μm in size can be seen in the image. It can be seen that sub-micron particles are embedded or fixed on the glass or on the surfaces of the calcium carbonate particle. The chemistry of embedded submicron particles was checked by scattering energy spectroscopy during SEM photography. The analysis revealed that the sub-micron particles had a higher carbon density compared to an average reading of a larger surface area that includes surfaces between the sub-micron particles. The sub-micron particles were also seen to melt at higher magnifications due to the heat generated from the electron beam in the microscope. Figures 7A and 7B show SEM photographs in magnifications of 1500 and 5000x. Figure IB represents a granulate according to the European application EP-A-1128815 of Nycomed Pharma which consists of calcium carbonate (74.5%), sorbitol (23.3%) and copovidone (2.2%) where a 28% solution of copovidone It has been used during the granulation stage on a Glatt GPCG 3 fluid bed pilot scale. The link mechanism can be seen in the form of a fine mesh or mesh consisting of PV64 VA64, which binds the calcium carbonate crystals jointly. A considerable amount of calcium carbonate fine material can be seen in conjunction with the larger irregular sorbitol particles. Thus, the use of copovidone alone in the granulation liquid results in a different binding mechanism in the granules where there is no evidence that a coating effect takes place during the granulation stage of the fluid bed. There is also no evidence of submicron particles embedded in the surfaces of the calcium carbonate crystal. As mentioned here above, the approach to The formulation work was to make a chewable tablet smaller and more compact or preferably a cast formulation with very good sensory properties. The formulation should agglomerate properly, suitably compressed at low tabletting pressures to give tablets with a low friability value below 2% w / w. The target was a tablet weight of approximately 1400 mg comprising 1250 mg of calcium carbonate and with a tablet diameter of 14 mm. Fluid bed granulation tests revealed that the composition of the granulation liquid (i.e. the coating composition) was critical to achieve satisfactory agglomeration and also to facilitate compression of the tablets at low tablet pressures that exhibited a value low for friability below 2%. Agglomeration without success was the result when the calcium carbonate alone without any excipient was granulated with a 28% solution of copovidone or with a 50% solution of xylitol. Compression of the tablet without success was also the result when the tablets were made of these granules. Surprisingly, it was found that a synergistic effect appeared at two levels when povidone K30 or copovidone as examples of polymer substance (with binding properties) were combined with xylitol as an example of the water-soluble substance (i.e. the soluble filler material) in the granulation liquid (i.e. coating composition). Firstly, in the granulation stage of the fluid bed a very fast agglomeration was achieved with very little fine material and with narrow particle size distributions as follows: D (v, 0.1) = 30 - 90 μm D (v, 0.5) = 130 - 350 μm D (v, 0.9) = 280 - 800 μm The particle size analysis was performed on a Malvern Mastersizer S long bench apparatus where D (v, 0.1), D (v, 0.5) and D ( v, 0.9) give the particle sizes for which 10%, 50% and 90% of the particles by volume have sizes below the given values. The narrow distributions of particle sizes achieved in the examples entailed were characterized by a low space value below 2.0. The space value is calculated as [D (v, 0.9) - D (v, 0.1)] / D (v, 0.5). It has been found that a narrow size distribution and an average particle size that matches the average particle size and the particle size distribution of vitamin D3 is important to ensure satisfactory homogeneity of vitamin D3 in the secondary granulate or the final mixture of tablet formation in the case that You want to incorporate vitamin D into tablets. Subsequently, a synergistic effect was observed when the granulates based on the combination of a polymeric binder and a filler soluble in the granulation liquid were compressed into tablets. Very good compression curves were achieved unlike formulations where only one of the components had been used in the granulation liquid. Compression Curves Compression curves were carried out on a rotary tablet forming machine (Manesty B3B), which was instrumented with a compaction force monitor to measure tabletting pressures. The tablet compression curves were plotted by plotting the crushing strength in Newtons (N) against the corresponding tablet forming pressure in kilo Newtons (kN). The average crushing strength of five tablets was measured at tabletting pressures of 10, 14, 18, 22 and 26 kN. A satisfactory compression curve was characterized by a linear curve over the entire range of tabletting pressures and in which tablets with satisfactory friability and crush resistance could be produced at low tabletting pressures. A number of formulations described in the Examples entailed achieved this with crushing strengths in the range of 30-60 N and with friability values below 2% for tablets produced at low tablet pressures of 6 to 14 kN. Sensory evaluation of calcium tablet formulations The sensory panel consisted of seven selected assessors and was used to detect differences between chewable and cast tablet formulations with respect to lemon flavor intensity, tablet solubility in the mouth and the adhesiveness or stickiness of the tablet residues on the teeth. The intensity of each attitude was characterized by plotting the score on a visual analogue scale. The tests were carried out in a sensory laboratory in controlled environments. Each evaluation of a particular sample was carried out twice by each assessor. Statistical differences were detected using ANOVA with 95% confidence level and the Tukey HSD test with an importance level of 5% to discriminate between the means. Data recording and statistical analysis were carried out using Compusense 4.0 and Statgraphics 4.0, respectively. Two compositions according to the invention were tested in all three parameters against two examples of reference or comparatives. The two reference examples were based on two commercial qualities of directly compressible calcium carbonate, which was claimed to have improved sensory qualities when incorporated into the chewable tablets. The results are shown in Figure 5, which shows the results of the sensory analysis of example 3 and 4 according to the invention and reference example 3 and 4. The two examples according to the invention were statistically significant differently than when compared to the two reference examples with respect to an increased lemon flavor intensity, more soluble and reduced adhesiveness in the mouth. Definition of selected terms used herein The term "coated" is intended to mean a homogeneous layer that at least partially covers the individual crystal or particle, which has been subjected to the coating and agglomeration process. A visual description of the coated and agglomerated calcium carbonate crystals is given in Figure IA. The term "particulate material" is intended to be synonymous with granular material or simply granulate. The term "formulated" is intended to relate to the selection of excipients, carriers, vehicles, solvents, co-solvents, preservatives, coloring agents, agents flavors and so on in the preparation of a medicament using the composition. In the present context, the term "pharmaceutically acceptable excipient" is intended to denote any material, which is inert in the sense that it substantially has no therapeutic and / or prophylactic effect per se. A pharmaceutically acceptable excipient can be added to the substance of the active drug in order to make it possible to obtain a pharmaceutical formulation, having acceptable technical properties. In the present context, the term "liberated" means dissolved, when referred to in relation to dissolution tests in vi tro. Compound with calcium The calcium-containing compound contained in a particulate material made according to the invention is a physiologically tolerable calcium-containing compound that is therapeutically and / or prophylactically active. Calcium is essential for a number of key functions in the body, such as ionized calcium and a calcium complex (Campell AK.Clin Sci 1987; 72: 1-10). Cellular behavior and growth are regulated by calcium. In association with troponin, calcium controls contraction and muscle relaxation (Ebashi S. Proc R Soc Lond 1980; 207: 259-86).

The selected calcium channels are a universal characteristic of the cell membrane and the electrical activity of the nervous tissue and the discharge of neurosecretory granules are a function of the balance between calcium, intracellular and extracellular levels (Burgoyne RD, Biochim Biophys Acta 1984; 779 : 201-16). The secretion of hormones and the activity of enzymes and key proteins are dependent on calcium. Finally, calcium as a calcium phosphate complex confers stiffness and strength in the skeleton (Boskey AL, Springer, 1988: 171-26). Because bones contain over 99% of the total calcium in the body, skeletal calcium also serves as the main long-term calcium reservoir. Calcium salts such as, for example, calcium carbonate is used as a source of calcium especially for patients suffering from or at risk of osteoporosis. In addition, calcium carbonate is used as an acid neutralizing agent in antacid tablets. As mentioned above, calcium has a number of important functions within the mammalian body, particularly in humans. In addition, in many animal models, chronic intake of low calcium causes osteopenia. Osteopenia affects cancellous bone more than cortical bone and may not be completely reversible with calcium supply. If the animal is growing the reduced calcium intake leads to prevent growth. In the premature human infant, the higher the calcium intake, the greater the increase in skeletal calcium increase that, if high enough, can equal gestational calcium retention. During growth, chronic calcium deficiency causes rickets. Calcium supplements in healthy pre- and post-puberty children leads to increased bone mass. In adolescents, the higher the calcium intake, the higher the retention of calcium, with the highest retention occurring shortly after menarche. Taken together, these data suggest that in children and adolescents who are considered to have adequate calcium intake, maximum bone mass can be optimized by supplementing the diet with calcium. The mechanisms involved in the optimization of calcium deposition in the skeleton during growth are unknown. They are probably innate properties of the mineralization process that ensures optimal calcification of the osteoid if calcium supplies are high. The factors responsible for preventing growth in calcium deficiency states are also unknown but clearly involve growth factors that regulate skeletal size. In adults, the supply of calcium reduces the rate of age-related bone damage (Dawson-Hughes B. Am J Clin Nut 1991; 54: S274-80). Calcium supplements are important for individuals who can not or will not achieve optimal calcium intake from food. In addition, calcium supplementation is important in the prevention and treatment of osteoporosis, etc. In addition, calcium can have anticancer actions within the colon. Several preliminary studies have shown that diets high in calcium or taking calcium supplements are associated with reduced rectal colon cancer. There is growing evidence that calcium in combination with acetylsalicylic acid (ASA) and another non-steroidal anti-inflammatory drug (NSAIDS) reduces the risk of colorectal cancer. Recent research studies suggest that calcium may relieve premenstrual syndrome (PMS). Some researchers believe that interference in calcium regulation is an underlying factor in the development of PMS symptoms. In one study, half of the women in a group of 466 people of pre-menopausal women from across the US were monitored during three menstrual cycles and given 1200 mg of calcium supplements daily throughout the cycle. The final results showed that 48% of the women who took the placebo had symptoms related to PMS. Only 30% of those who received calcium tablets did so. Calcium salts such as calcium carbonate, for example, are used in tablets and due to the high dose of calcium required, such tablets are often in the form of chewable tablets. It is a challenge to formulate for example chewable tablets containing a calcium salt, whose tablets have a pleasant taste and an acceptable mouthfeel without the characteristic dominant flavor or chalk sensation. A calcium-containing compound for use according to the invention can be for example calcium bisglycine, calcium acetate, calcium carbonate, calcium chloride, calcium citrate, calcium citrate malate, calcium cornate, calcium fluoride. , calcium glubionate, calcium gluconate, calcium glycerophosphate, calcium hydrogen phosphate, calcium hydroxyapatite, calcium lactate, calcium lactobionate, calcium lactogluconate, calcium phosphate, calcium pidolate, calcium stearate and tricalcium phosphate , or mixtures thereof. Other sources of calcium may be calcium salts soluble in water, or complexes such as for example calcium alginate, EDTA-calcium and the like or organic compounds containing calcium such as for example calcium organophosphates. The use of bone meal, dolomite and other unrefined sources of calcium is discouraged because these sources may contain lead. and other toxic pollutants. However, such sources may be relevant if they are purified to a desired degree. The calcium-containing compound can be used singly or in combination with other calcium-containing compounds. Of specific interest is calcium bisglycine, calcium acetate, calcium carbonate, calcium chloride, calcium citrate, calcium citrate malate, calcium cornate, calcium fluoride, calcium glubionate, calcium gluconate, calcium glycerophosphate , calcium hydrogen phosphate, calcium hydroxyapatite, calcium lactate, calcium lactobionate, calcium lactogluconate, calcium phosphate, calcium pidolate, calcium stearate and tricalcium phosphate. Mixtures of different calcium-containing compounds can also be used. As appears from the examples herein, calcium carbonate is especially suitable for use as a calcium-containing compound and a calcium carbonate has a high calcium content. Of particular interest is calcium carbonate. Typically, a tablet made according to the invention contains an amount of the calcium-containing compound corresponding to from about 100 to about 1000 mg of Ca such as, for example, from about 150 to about 800 mg, from about 200 to about 700. mg, from approximately 200 to about 600 mg or about 200 to about 500 mg of Ca. Calcium carbonate Calcium carbonate can be in three different crystal structures: calcite, aragonite and vaterite. Mineralogically, these are specific mineral phases, which are related to the different arrangement of the calcium, carbon and oxygen atoms in the crystal structure. These different phases influence the shape and symmetry of the crystal shapes. For example, calcite is available in four different forms: scalenohedral, prismatic, spherical and rhombohedral, and aragonite crystals can be obtained as for example discrete or accumulated needle-like shapes. Other forms are also available such as, for example, cubic forms (Scoralita ÍA + B de Scora). As shown in the examples herein, a particular suitable quality of calcium carbonate is calcium carbonate having an average particle size of 60 μm or less such as, for example, 50 μm or less or 40 μm or less. In addition, an interesting quality of calcium carbonate has a volumetric density below 2 g / ml. The 2064 Merck calcium carbonate (available from Merck, Darmstadt, Germany) having an average particle size of 10-30 μm, a volumetric density apparent from 0.4 to 0.7 g / ml, and a specific surface area of 0.3 m2 / g; The 2069 Merck calcium carbonate (available from Merck, Darmstadt, Germany) having an average particle size of about 3.9 μm, and an apparent bulk density of 0.4 to 0.7 g / ml; Escoralita ÍA (available from Scora Watrigant SA, France) has an average particle size of 5 to 20 μm, an apparent bulk density of 0.7 to 1.0 g / ml, and a specific surface area of 0.6 m2 / g; Escoralita IB (available from Scora Watrigant SA, France) has an average particle size of 10 - 25 μm, an apparent bulk density of 0.9 to 1.2 g / ml, and a specific surface area of 0.4 to 0.6 m2 / g; Escoralita ÍA + B (available from Scora Watrigant SA, France) has an average particle size of 7 - 25 μm, an apparent bulk density of 0.7 to 1.2 g / ml, and a specific surface area of 0.35 to 0.8 m2 / g; Pharmacarb LL (available from Chr. Hansen, Mahawah New Jersie) L has an average particle size of 12 - 16 μm, an apparent bulk density of 1.0 to 1.5 g / ml, and a specific surface area of 0.7 m2 / g; Sturcal H has a mean particle size of about 4 μm, an apparent bulk density of 0.48 to 0.61 g / ml; Sturcal F has an average particle size of approximately 2.5 μm, an apparent bulk density of 0.32 to 0.43 g / ml; Sturcal M has a mean particle size of 7 μm, an apparent bulk density of 0.7 to 1.0 g / ml, and a specific surface area of 1.5 m2 / g; Mikhart 10, SPL, 15, 40 and 65 (available from Provencale, Provencale, France); Mikhart 10 has an average particle size of 10 μm, Mikhart SPL has an average particle size of 20 μm, Mikhart 15 has a mean particle size of 17 μm Mikhart 40 has an average particle size of 30 μm, an apparent bulk density of 1.1 to 1.5 g / ml; Mikhart 65 has an average particle size of 60 μm, an apparent bulk density of 1.25 to 1.7 g / ml; Hubercal Elite 500 (available from J.M. Huber Corp., USA) has an average particle size of 5.8 μm and a specific surface area of 1.8 m2 / g; Hubercal Elite 500 (available from J.M. Huber Corp., USA) has an average particle size of 8.2 μm and a specific surface area of 1.3 m2 / g. Omyapure 35, (available from Omya S.A.S, Paris, France) has an average particle size of 5-30 μm, and a specific surface area of 2.9 m2 / g; Socal P2PHV (available from Solvay, Brussels, Belgium) has an average particle size of 1.5 μm, an apparent bulk density of 0.28 g / ml, and a specific surface area of 7.0 m2 / g; Calci Mash 250 Heavy, Calci Mash 250 Extra Heavy and Calci Purée GCC HD 212 with an average particle size of 10-30 μm, an apparent bulk density of 0.9 - 1.2 g / ml, and a specific surface area of 0.7 m2 / g (available from Particle Dynamic Inc., St. Louis Montana). The content of the calcium-containing compound in a tablet made according to the present invention is in a range of about 40% w / w to about 100% w / w such as, for example, from about 45% w / w to about 98% w / w, from about 50% w / w to about 95% w / w, from about 55% w / w to about 90% w / w or at least about 60% w / w, at least about 65% weight / weight, at least about 70% weight / weight, at least about 75% weight / weight, at least about 80% weight / weight or at least about 85% weight / weight. Typically, the dose of calcium for therapeutic or prophylactic purposes is from about 350 mg (eg newborn) to about 1200 mg (lactating women) daily. The amount of the calcium-containing compound in the tablets can be adjusted so that The tablets are suitable for administration 1-4 times a day, preferably once or twice a day. As mentioned above, the granulate obtained by the method according to the invention can be used as such, but it is also very suitable for further manufacture in solid dosage forms such as for example tablets, capsules or sachets. A person skilled in the art will know how to adjust the composition and the various process parameters to obtain a product containing desired calcium. In one embodiment of the invention, the granulate obtained by the present method is intended to be manufactured into tablets. It is often necessary to add one or more pharmaceutically acceptable excipients (e.g. lubricants) to prevent adhesion and / or increase the flowability of the granulate obtained. Accordingly, the method may also comprise a step of mixing the obtained granulate with one or more pharmaceutically acceptable excipients. In the case that it is desired to include other active substances than the calcium-containing compound, the method may also comprise a step of adding one or more substances therapeutically, prophylactically and / or diagnostically active to the obtained granulate. Such substances include one or more nutrients such as, for example, one or more vitamins or minerals. In a specific modality, the additional active substance is a vitamin D such as, for example, vitamin D3, vitamin D2 or derivatives thereof. VI tamin D or other active substances A particulate material as well as a tablet obtained according to the invention may comprise an additional therapeutically and / or prophylactically active substance. Of particular interest are one or more vitamin D compounds. Non-limiting examples are dry vitamin D3, 100 CWS available from Roche and vitamin D3 dry 100 GFP available from BASF. A particulate material or a tablet made according to the invention may comprise an additional therapeutically and / or prophylactically active substance, or may contain one or more nutrients such as, for example, one or more vitamins or minerals. Of specific interest are, for example, vitamin B, vitamin C, vitamin D and / or vitamin k, and derivatives thereof, and minerals such as zinc, magnesium, selenium, and the like. Of particular interest are one or more vitamin D compounds such as, for example, vitamin D2 (ergocalciferol) and Vitamin D3 (cholecalciferol) including dry vitamin D3, 100 CWS available from Roche and vitamin D3 dry 100 GFP available from BASF. In addition to its action on calcium and skeletal homeostasis, Vitamin D is involved in the regulation of several major systems in the body. The actions of vitamin D are medicated in the genome by a complex formed by l, 25- (OH) 2 vitamin D mainly produced in the kidney, with the vitamin D receptor (VDR). The latter is widely distributed in many types of cells. The 1,25- (OH) 2 vitamin D / VDR complex has important regulatory roles in cell differentiation and in the immune system. Some of these actions are probably dependent on the ability of certain tissues other than the kidney to produce l, 25- (OH) 2 vitamin D locally and to act as a paracrine (Adams JS et al Endocrinology 1996; 137: 4514-7). In humans, vitamin D deficiency results in rickets in children and osteomalacia in adults. The basic abnormality is a delay in the speed of osteoid mineralization as it is broken down by the osteoblast (Peacock M. London Livingstone, 1993: 83-118). It is not clear whether this delay is due to a failure of a mechanism dependent on 1,25- (OH) 2 vitamin D in the osteoblast or to reduced supplies of calcium and secondary phosphate for malabsorption or a combination of both. Accompanying the delay of mineralization, there is a reduced supply of calcium and phosphate, severe secondary hyperparathyroidism with hypocalcaemia and hypophosphatemia and increased bone turnover. Insufficient vitamin D, the preclinical phase of vitamin D deficiency, also causes a reduced supply of calcium and secondary hyperparathyroidism, although to a more gentle degree than as it is found with deficiency. If this condition remains chronic, then osteopenia results. The biochemical process underlying this state of calcium insufficiency is probably the inappropriate level of l, 25- (OH) 2 vitamin D due to a reduction in its 25-OHD substrate (Francis RM et al., Eur J Clin Invest 1983; : 391-6). The state of vitamin D insufficiency is most commonly found in older people. With age there is a decrease in serum vitamin D 25-OH due to decreased exposure to sunlight and possibly decreased skin synthesis. In addition, in older people the condition is exacerbated by a decrease in calcium intake and a paradoxical decrease in calcium absorption. The reduction in renal function with age that leads to the production of reduced renal 1,25- (OH) 2 vitamin D may be a contributing factor. There are a number of studies of the effects of vitamin D supply on bone damage in the elderly. Some are without calcium supply and others are supplied with calcium. It appears from the studies that although the supply of vitamin D is necessary to reverse the deficiency and insufficiency, it is even more important up to where the skeleton is affected to provide calcium supply because the main skeletal defect is calcium deficiency. In the literature based on clinical evidence, recent findings suggest trends of need for higher doses of vitamin D for older patients (Compston JE, BMJ 1998).; 317: 1466-67). A quasi-randomized open-label study of annual injections of 150,000-300,000 IU of vitamin D (corresponding to approximately 400-800 IU / day) showed a significant reduction in overall fracture velocity but not in hip fracture velocity in treated patients (Heikinheimo RJ et al., Calcif Tissue lnt 1992; 51: 105-110). As shown above, a combination of calcium and vitamin D is of interest: The Recommended Daily Allowance (RDA) of calcium and vitamin D3 is as follows (European Commission, Report on osteoporosis in the European Community, Action for prevention, Office for official Publications of the European Communities, Luxembourg 1998): Group Age (years) Calcium (mg) * Vitamin D3 (μg) Just 0-0.5 > 400 10-25 born 0.5-1. 0 360-400 10-25 Children 1.0-3. 0 400-600 10 4.0-7. 0 450-600 0-10 8.0-1C) 550-700 0-10 Men 11-17 900-1000 0-10 18-24 900-1000 0-15 25-65 700-800 0-10 65+ 700-800 10 Women 11-17 900-1000 0-15 18-24 900-1000 0-10 25-50 700-800 0-10 51-65 800 0-10 65+ 700-800 10 Pregnant 700-900 10 Infants 1200 10 * RDA of calcium varies from country to country and is being re-evaluated in many countries Vitamin D is very sensitive to moisture and is subject to degradation. Therefore, vitamin D is often administered in a protective matrix. Consequently, when preparing the tablets that contain a vitamin D it is very important that the compression forces applied during the tablet-forming stage do not diminish the protective effect of the matrix and therefore impair the stability of vitamin D. To this end, the combination of several ingredients in a granulate or tablet made according to the invention has proven to be very suitable in those cases where vitamin D is also incorporated into the composition since it is possible to employ a relatively low compression force during tabletting and still achieve a tablet with strength adequate mechanics (resistance to crushing, friability, etc.). In a specific embodiment, the invention provides a tablet comprising i) a compound containing calcium as an active substance, ii) a vitamin D, and iii) optionally one or more pharmaceutically acceptable actives or excipients. More specifically, the tablet may comprise i) at least 200 mg of the calcium-containing compound (normal range 200-1500 mg) ii) at least 5 μg of vitamin D (normal range 5-100 μg -1 μg = 40 IU), and iii) optionally one or more active or excipients pharmaceutically acceptable In a specific embodiment, the invention provides a tablet comprising i) from about 50% w / w to about 90% w / w of the calcium-containing compound, ii) from about 0.00029% w / w to about 0. 0122% w / w of a vitamin D, and iii) optionally one or more pharmaceutically acceptable actives or excipients with the proviso that the total amount of ingredients corresponds to approximately 100% w / w. In particular, the tablet may comprise i) from about 50% w / w to about 90% w / w of the calcium-containing compound, ii) from about 5 to about 40% w / w of a sweetening agent, iii) from about 0.12% weight / weight to approximately 4. 9% weight / weight of a vitamin D including a protective matrix, iv) optionally one or more pharmaceutically acceptable actives or excipients with the proviso that the total amount of ingredients corresponds to approximately 100% w / w. Other active ingredients Examples include isoflavones, vitamin k, vitamin C, vitamin B6 and oligosaccharides such as inulin and oligofructose. Isoflavones exhibit a weak oestrogenic effect and can thus increase bone density in post-menopausal women. Isoflavones are available under the trade name Novasoy 400 from ADM Nutraceutical, Illinois, USA. The Novasoy 400 contains 40% isoflavones and will typically be used in an amount sufficient to provide 25 to 100 mg isoflavone / dosage. Isoflavones can be included in the second granulate; however as Novasoy 400 is a relatively cohesive powder it is preferred that it be included in the first granulate to ensure that it is evenly distributed. Vitamin K (more especially vitamin Ki) can improve the biochemical markers of bone formation and bone density and low concentrations of vitamin K, have been associated with low bone mineral density and bone fractures. Vitamin K is available from Roche as Vitamin K Dry, 5% SD, a dry substance containing 5% vitamin Ki. Typically vitamin K, will be used in an amount sufficient to provide 0.05 to 5 mg of vitamin Kj / dosage. Vitamin C and vitamin B6 (available from Roche, Takeda and BASF among others) function as co-factors in the formation of collagen, the main component of the organic matrix of bone. Vitamin C and vitamin B6 will typically be used in sufficient amounts to provide 60 to 200 mg of vitamin C / dosage and 1.6 to 4.8 mg of vitamin B6 / dosage respectively. Oligosaccharides have been shown to facilitate and increase calcium absorption and can typically be used in amounts sufficient to provide 0.3 to 5 g of oligosaccharide / dosage. In general it is desirable that a total of at least 5 g of oligosaccharide be administered daily to facilitate the admission of calcium and to obtain a prebiotic effect. Where an active component which forms a minor part of the overall granulate, for example vitamin D, is used, it is generally preferred to produce a premix of such a component and the granulate before mixing the premix and the remaining required amount of the granulate. This ensures uniform distribution of the minor component in the granulate. Pharmaceutically acceptable excipient substances In the present context, the term "pharmaceutically acceptable excipient" is intended to denote any material, which is inert in the sense that it substantially has no therapeutic and / or prophylactic effect per se. A pharmaceutically acceptable excipient can be added to the substance of the active drug in order to make it possible to obtain a pharmaceutical composition, having acceptable technical properties. The calcium-containing compound is normally mixed with one or more pharmaceutically acceptable excipients before compression into tablets. Such excipients include those normally used in the formulation of solid dosage forms such as, for example filler, binders, disintegrators, lubricants, flavoring agents, coloring agents, including sweeteners, pH adjusting agents, buffering agents, stabilizing agents. , etc. The following are examples of suitable excipients for use in a tablet according to the present invention.

Sweeteners Examples of suitable sweeteners include dextrose, erythritol, fructose, glycerin, glucose, inositol, isomait, isomaltulose, lactitol, lactose, maltitol, maltose, mannitol, sorbitol, sucrose, tagatose, trehalose, xylitol, etc. Sorbitoles for example Neosorb P100T, Sorbidex P166B0 and Sorbogem Crystalline Sorbitol ends available from Roquette Freres, Cerestar and SPI Polyols Inc. respectively. Maltisorb P90 (maltitol) available from Roquette Freres, Xilitol CM50, Fructofin CM (fructose) and Lactitol CM50 available from Danisco Sweeteners, Isomait ST-PF and Palatinose (Isomaltulose), Gaio Tagatose and Mannitol available from Palatinit, Arla Foods and Roquette, Freres respectively. Sorbitol has a sweetening effect (compared to sucrose) of 0.55; maltitol having a sweetening effect of = 1; the xylitol having a sweetening effect of 1, the isomait having a sweetening effect of < 0.5, etc. The sweetening effect can be of value in connection with choosing the individual sweetening agents. Thus, if a decreased tablet weight and volume is desired, it is appropriate to choose a sweetening agent that has a high sweetening effect. Artificial endulces Acesulfam of potassium, alitama, aspartame, cyclamic acid, cyclamate salt (eg calcium cyclamate, sodium cyclamate), neohesperidin dihydrochalcone, neohesperidin hydrochloride, saccharin, saccharin salt (eg, ammonium saccharin) , saccharin calcium, saccharin potassium, saccharin sodium), sucralose, thaumatin and mixtures thereof.

Flavors Chabacano, Lemon, Lime / Lemon, Lime, Orange, Tangerine, such as Chabacano 501.110 AP0551, Lemon 501.051 TP0551, Lemon 501.162 AP0551, Lime / Lemon 501.053 TP0551, File 501.054 TP0551, Orange 501.071 AP0551, Orange TP0551, Orange 501.434 P0551, Tangerine 501.AP0551, Lemon Durarome 501.282 TDI 1091 available from Firmenich, Kerpen, Germany or Juicy Lemon Flavor T3602 available from TasteTech, Bristol, England or Permseal Lemon Lime Flavor 11029-31, Lemon Flavor Permseal 12028-31, Ultradseal Lemon Flavor 96918-71 Available from Givaudan Schweiz AG, Kemptthal, Schweiz or Lemon Flavor Powder 605786, Lemon Flavor Powder 605897 available from Frey + Lau Gmbh, Henstedt-Ulzburg, Germany Agen Disintegrators Alginic acid - alginates, calcium carboxymethylcellulose, sodium carboxymethylcellulose, crospovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), cellulose derivatives such as hydroxypropylcellulose under substitution (for example LH 11, LH 20, LH 21, LH 22, LH 30, LH 31, LH 32 available from Shin-Etsu Chemical Co.) and microcrystalline cellulose, polacrilin potassium or sodium, polyacrylic acid, polycarbophil, polyethylene glycol, polyvinyl acetate, polyvinyl pyrrolidone (for example Polividon® CL, Polividon® CL-M, Colliding® CL, Polyplasdone® XL, Polyplasdone® XL-10); sodium carboxymethyl starch (for example Primo-gel® and Explotab®), croscarmellose sodium (i.e. cross-linked sodium carboxymethylcellulose salt, for example Ac-Di-Sol®), sodium starch glycolate, starches (e.g. , potato starch, corn starch, rice starch), pre-gelatinized starch. Those skilled in the art will appreciate that it is desirable for compressible tablets to disintegrate within 30 minutes, more desirable within 15 minutes, more desirable within 5 minutes; therefore, the preferably used disintegrator results in the disintegration of the tablet within 30 minutes, more preferably within 15 minutes, more preferably within 5 minutes. Effervescent agent (for example the mixture of sodium hydrogen carbonate (carbonates, alkali metals, alkaline earth metals) and citric acid (tartaric acid, fumaric acid, etc.)). Slippers and lubricants Glidants and lubricants can be incorporated such as stearic acid, metal stearates, talc, waxes and glycerides with high melting temperatures, hydrogenated vegetable oils, colloidal silica, sodium stearyl fumarate, polyethylene glycols and alkyl sulfates.

Suitable lubricants include talc, magnesium stearate, calcium stearate, stearic acid, oils hydrogenated vegetables and the like. Preferably, magnesium stearate is used. Rei luisers A di luentes A glutinants Dextrins, maltodextrins (for example Lodex® 5 and Lodex® 10), dextrose, fructose, glucose, inositol, erythritol, isomait, lactitol, lactose (for example, spray-dried lactose, o-lactose) , ß-lactose, Tabletose®, various grades of Pharmatose®, Microtose or Fast-Floc®), maltitol, maltose, mannitol, sorbitol, sucrose, tagatose, trehalose, xylitol, substituted hydroxypropylcellulose (for example LH 11, LH 20, LH 21, LH 22, LH 30, LH 31, LH 32 available from Shin-Etsu Chemical Co.), microcrystalline cellulose (e.g., various grades of Avicel®, such as Avicel® PH101, Avicel® PH102 or Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tai® and Solka-Floc®), modified starches or starches (for example potato starch, corn starch, rice starch, pre-gelatinized starch), polyvinylpyrrolidone (eg example Kollidon 25, 30 and 90F from BASF and Plasdone K-12, K17, K-25, K-30 and K-90 from ISP) , copovidone which is a vinylacetate / polyvinylpyrrolidone copolymer (eg PVP VA64 from BASF and Plasdone S-630 from ISP), agar (eg sodium alginate), calcium hydrogen phosphate, calcium phosphate (for example basic calcium phosphate, calcium hydrogen phosphate), calcium sulfate, carboxyalkylcellulose, dextrates, dibasic calcium phosphate, gelatin, gum arabic, hydroxypropyl cellulose, hydroxypropylmethylcellulose, magnesium carbonate, magnesium chloride, methylcellulose, polyethylene glycol, polyethylene oxide, polysaccharides eg dextran, soy polysaccharide, sodium carbonate, chloride of sodium, sodium phosphate. Some of the aforementioned substances also belong to the group of polymeric substances suitable for use according to the invention (see also the paragraph below). In particular, this applies to modified starches or starches (for example potato starch, corn starch, rice starch, pre-gelatinized starch), polyvinylpyrrolidone, copovidone or vinyl acetate copolymer / polyvinylpyrrolidone, agar (for example sodium alginate and polyethylene glycol alginate), carboxyalkylcellulose, gelatin, gum arabic, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polysaccharides for example inulin, dextran, soy polysaccharide. Surfactants Improvers Surfactants can be used such as Nonionic (eg, polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, sorbitan monoisostearate, monolaurate sorbitan, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan thiolate, glyceryl monooleate and polyvinylalcohol) ammonium (eg, sodium docusate and sodium lauryl sulfate) cationic (eg. benzalkonium, benzethonium chloride and cetpmida) Fatty acids, fatty alcohols and fatty esters, for example: ethyl oleate, sodium oleate, lauric acid, methyl laurate, oleic acid, sodium caprate dioctyl sulfosuccinate, potassium sulfosuccinate of dioctyl, dodecyltrimethylammonium bromide, hexadecyltrimethylammonium bromide, trimethyltetradecylammonium bromide, polyoxyethylene ethers (pol? ox? et? leno-9-lauryl ether, sodium dodecyl sulfate, sodium dioxide sulfosuccinate, sodium laurate, Sodium 5-methoxysalicylate, sodium salicylate, bile salts, for example: sodium deoxycholate, deoxicolic acid, sodium cholate, colic acid, sodium glycocholate io, sodium glycodeoxycholate, sodium taurocholate, sodium taurodeoxycholate; cytoadhesives, for example: lectmas (for example Lycopersicon Esculentum Agglutinin, Wheat Germ Agglutinin, Diogal Nettle Agglutinin). N-acylated amino acids (especially N- [8- (2-hydroxy-4-methoxy) benzoyl] amino caprylic acid (4-MOAC), 4- [4- (2-hydroxybenzoyl) amino] butyric acid, N-caprylate - [8- (2-hydroxybenzoyl) amino] sodium, phospholipids, for example: hexadecylphosphocholine, dimyristoylphosphatidylglycerol, lysophosphatidylglycerol, phosphatidylinositol, 1,2-di (2,4-octadecadienoyl) -sn-glycerol-3-phosphorylcholine and phosphatidylcholine ( for example didecanoyl-L-phosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine), lysophosphatidylcholine are of particular interest, cyclodextrins, for example: β-cyclodextrin, dimethyl-β-cyclodextrin, β-cyclodextrin, hydroxypropyl β-cyclodextrin, methyl cyclodextrin; dimethyl-β-cyclodextrin is of particular interest: derivatives of fusidic acid, for example: sodium taurodihydrofusidate, sodium glycidohydrofusidate, sodium phosphate dihydrofusidate, especially sodium taurodihydrofusidate or is of particular interest; others: sodium salts of for example glycyrrhizic acid, acid capric, alkanes (for example azacycloalkanes), amines and amides (for example N-methyl-pyrrolidone, Azone), amino acids and modified amino acid compounds (for example acetyl-L-cysteine), polyols (for example propylene glycol, hydrogels), sulfoxides (for example dimethylsulfoxide), terpenes (for example carvone), ammonium glycyrrhizinate, hiluronic acid, isopropyl myristate, n-lauryl-beta-D-maltopyranoside, saponins, DL-octanonylcarnitine chloride, palmitoyl-DL-carnitine chloride, DL-stearoylcarnitine chloride, acylcarnitines, ethylene diamine hydrochloride, phosphate dihydrofusidate, sodium CAP); especially n-lauryl-beta-D-maltopyranoside is of particular interest, alpha 1000 peptide, MW peptide < 1000 comprising at least 6 mol% of aspartatic and glutamic acid, decomposed royal jelly, prebiotic, butyrate, butyric acid, vitamin D2, vitamin D3, hydroxy-vitamin D3, 1.25-dihydroxy-vitamin D3, spirulina, proteoglycan, soyahydrolisate, lysine , lactic acid, di-fructose-anhydride, vilitol Ca- (lactate), casein hydrolyzate in particular a caseinoglycomacropeptide, negative ionization of CaC03, acetylsalicylic acid, vitamin K, creatine. Film forming agents (polymeric substances) Hydrofilic film formers such as polyvinylpyrrolidone, copovidone, hydroxypropylmethylcellulose (HPMC) (for example HPMC E5, HPMC E15), hydroxyethylcellulose, hydroxypropyl cellulose, polydextrose and maltodextrin, Sepifilm ™ and Sepifilm ™ LP available from Seppic S.A., Pharmacoat® available from Shin-Etsu Chemical Co. Admi tives of acetylated monoglyceride film, acetyl tributyl, acetyl tributyl citrate, acetyltriethyl citrate, benzyl benzoate, calcium stearate, castor oil, cetanol, chlorobutanol, colloidal silicon dioxide, dibutyl phthalate, dibutyl sebacate, diethyl oxalate, diethyl malate, diethyl maleate, diethyl malonate, diethyl fumarate, diethyl phthalate, diethyl sebacate, diethyl succinate, dimethyl phthalate, dioctyl phthalate, glycerin, glycerol tributyrate, glycerol triacetate, glyceryl behanate, glyceryl monostearate, hydrogenated vegetable oil, lecithin, leucine, magnesium silicate, magnesium stearate, magnesium, polyethylene glycol, propylene, glycol, polysorbate, silicone, stearic acid, talc, titanium dioxide, triacetin, tributyl citrate, triethyl citrate, zinc stearate, wax. The following non-limiting examples are intended to illustrate the present invention. Examples The examples were processed according to the detailed description of the invention. Granulation of the fluid bed and drying take place in a fluid bed spray granulator consisting of a product container and an expansion chamber for the fluidization of the powder mixture to be granulated. The details regarding the adjustments are mentioned here above. The powder mixture rests on a product screen at the bottom of the product container and is restricted from escaping from the expansion chamber by an exhaust filter on the outlet side of the fluid bed granulator. The air flow required for the fluidization of the powders is generated by a suction fan mounted on the upper portion of the unit. The air used for fluidization is heated to the desired temperature by an air heater located in the air inlet portion of the equipment. The powder mixture is flowed through a sufficient volume of air and the granulation liquid is atomized as a fine spray through a rolling head consisting of a multiple of binary nozzles. The rolling head can add the atomized spray of granulation liquid countercurrent to the pulsating particles denoted "upper spray" or co-current to the pulsating bed denoted "lower spray". The wet particles undergo agglomeration or granulation through particle-particle contact. After proper agglomeration is achieved, the spraying operation is discontinued and the material is Dry and discharge from the unit. By adjusting the critical characteristics of the formulation and the process parameters for the fluid bed process it is possible to agglomerate, instantize or coat individual particles in a sprayable mixture. Unless otherwise specified, the compositions were standardized with respect to the weight of the tablet, concentration and type of intense sweetener, amount and type of flavor, amount of magnesium stearate and tablet pressures used to facilitate comparison between formulations The tabletting pressure was adjusted in each case to obtain a satisfactory value for friability below 2%. Tablet compression curves were carried out for most of the formulations to investigate the compression behavior as a function of the formulation variables for example the type and amount of polymer substance and water soluble substance in the coating layer of the calcium carbonate crystals. The water-soluble substance, such as xylitol and other polyols and carbohydrates, was divided in most formulations into two amounts for the granulation liquid and the dry powder mixture before of the coating and agglomeration of the fluid bed respectively. Granules and tablets were characterized with respect to volumetric density, particle size and distribution, tabletting pressure, crushing strength, friability, tablet density, tablet porosity, disintegration and dissolution. The disintegration and dissolution were carried out according to Ph. Eur. As described in the previous text. The dissolution test was carried out only for example 1, 2, 3, 4, reference example 3 and reference example 4.

Examples 1, 2, reference examples 1 and 2 * the term "binder" used in connection with the granulation liquid (or film coating composition) is equivalent to the term "polymeric substance" ** the term "filler" used in connection with the granulation liquid (or composition of film coating) is equivalent to the term "water soluble substance" *** The tests were not carried out due to defective tablets Reference example 1 shows a formulation where a 28% solution of copovidone has been used as the granulation liquid during the granulation of the fluid bed and the drying. The formulation did not agglomerate satisfactorily resulting in a granulate with too much fine material and a low value for the average particle size. Compressing the granulate into tablets at a high pressure of forming tablets of 18 kN proved to be difficult resulting in tablets with a very low crushing resistance and very friable tablets with a very high value for friability. The granulation with a 50% solution of xylitol in reference example 2 resulted in a very poor granulate which was not fully compressed and with a friability value of 100%. Example 1 according to the invention is calcium carbonate, which has been granulated without any added filler material and with a granulation liquid consisting of 28% copovidone and 19.7% xylitol. Surprisingly the combination of the polymer binder material and the filler soluble in the granulation liquid has resulted in a very good agglomeration with a high value of 82 μm for Dio and an average particle size of 219 μm for the granulate. Example 2 according to the invention shows the calcium carbonate with a small addition of xylitol to the powder mixture before the granulation of the fluid bed and the coating and where a granulation liquid consisting of 28% copovidone has been used and 29.7% xylitol. A free-flowing granulate with little fine material and an average particle size of 225 μm was achieved. Equally surprising are the very good tablet compression curves achieved by example 1 and 2 as shown in Figure 3. The linear compression curves can be seen for the two examples with satisfactory friability values below 2% at low tablet pressures in the range of 10 to 14 kN. Examples 1 and 2 of tablet are further characterized with a low value for tablet densities giving rise to a small tablet where a high satisfactory value has been retained for the tablet porosities. The very short disintegration time of 3 minutes, the short sliding time of the hanging tablet of 60 seconds and the rapid dissolution rate of 90% weight / weight dissolved after 10 minutes show that the two formulations have tablet melting characteristics .

Examples 3, 4, reference examples 3 and 4 Two reference examples were used (reference 3 and 4) based on the commercial and granular qualities of calcium carbonate to comparatively measure these formulations against the formulations according to the invention. * the term "binder" used in connection with the granulation liquid (or film coating composition) is equivalent to the term "polymeca substance" ** the term "filler" used in connection with the granulation liquid (or film coating composition) is equivalent to the term "water soluble substance" Examples 3 and 4 according to the invention and the example 3 and 4 of reference have been made with the same amount of sabopzante, intense sweetener and tablet lubricant for compare these with respect to tablet characteristics and sensory properties. Examples 3 and 4 according to the invention are characterized as dense tablets with apparent tablet densities in the range of 1.5 to 1.7 g / cm 3, which facilitates the formulation of small tablets. The tablets are also characterized by a sufficiently high value for porosity, which is in the range of 30 to 38%. It can also be seen that Example 3 and 4 produce tablets with a satisfactory crushing and friability resistance of 40-50 N and 0.5 to 1.2%, respectively, at low tableting pressures of 9 to 10 kN. The tablets are further characterized with a rapid disintegration time of 1-3 minutes and a rapid dissolution rate where 90% w / w dissolves after 10 minutes. The travel time of the pendant tablet for example 4 is only 24 seconds, which gives evidence of the excellent melting characteristics of this formulation. Reference example 3 is a tablet based on Lycatab Mineral CC 190 from Roquette Freres. This quality is based on a Escoralita quality from Scora Watrigant SA, France, which has been granulated with 10% corn starch. This quality produces dense tablets but the time of disintegration is above 30 minutes and calcium dissolution is only 17% w / w after 10 minutes, which does not satisfy the in vi tro requirements for a calcium-containing smelting tablet. Reference example 4 is a tablet based on Formaxx CaC03 from Merck KgaA, Germany consisting of 70% calcium carbonate, which has been produced by a drying process. Only 980 mg of calcium carbonate could be incorporated into this tablet to achieve a tablet weight of 1420 mg since this granulate only contains 70% calcium carbonate. It is also a less dense tablet due to the high porosity of the spray-dried material. Reference example 4 exhibits inferior properties with respect to the rate of disintegration and dissolution when compared to the examples according to the invention. Both of the reference examples have high values for the sliding time of the pendant tablet, which indicates that these formulations do not have casting properties. The four formulations were compared to each other by a sensory analysis as described under the detailed description of the invention. The four formulations contained the same amount and type of flavor, intense sweetener and tablet lubricant except for the level of sweetener in Example 4 due to the higher content of sorbitol in this formulation. Figure 5 displays the results of a sensory analysis carried out with the four formulations. Examples 3 and 4 are marked with an asterisk in Figure 5 where both examples are statistically different in all three attitudes at a 95% confidence level of the two reference examples marked with two asterisks. Examples 3 and 4 according to the invention came out better with respect to lemon flavor although the four formulations contained the same amount of flavor. The reason for this is due to the improved disintegration / dispersion and flavor release in the mouth for example 3 and 4. Examples 3 and 4 according to the invention were tested against a reference based on a calcium chewable tablet of according to the European application EP-A-1128815 of Nycomed Pharma. Both of the formulations according to the invention came out with a significantly shorter melt dispersion time when compared against the reference tablet. Example 4 had the best melting characteristics with a melt dispersion time of 52 seconds. There was also a statistically difference between examples 3 and 4 with respect to the melt dispersion time. The results have been shown in Figure 6. Thus it has been shown that the compositions according to the invention have superior tablet characteristics and improved sensory properties compared to the commercial qualities of calcium carbonate, which have been recommended for use in chewable tablets. It has further been shown that the calcium smelting formulations according to the invention have a significantly shorter casting time when compared to a calcium tablet based on European application EP-A-1128815 to Nycomed Pharma. These superior properties have been achieved despite the fact that the tablets are dense and therefore also offer tablet volumes and reduced tablet sizes / diameters.

Examples 5, 6, 7, 8 and 9 A series of examples were carried out to vary the ratio between the polymeric substance (also denoted binder material) and the water soluble substance (also denoted soluble filler). The material of the polymeric binder, which in this case was Povidone K-30, was added in concentrations of 3.8, 9.8, 15.8, 21.8 and 27.9% w / w to the granulation liquid where the amount of xylitol was adjusted to have a content of constant dry matter of 50% weight / weight in the granulation liquid. * the term "binder used in connection with the granulation liquid (or film coating composition) is equivalent to the term" polymeric substance "** the term" filler used in connection with the granulation liquid (or coating composition of film) is equivalent to the term "water-soluble substance" You can see that the average particle size increases while increasing the concentration of the binder in the granulate. The granulates are further characterized by low values for the space values indicating narrow particle size distributions. From the table it can be seen that as little as 0.5% povidone K-30 per tablet weight produces tablets with acceptable friability and crush resistance. The crushing strength increases and the friability values decrease while the concentration of the binder in the granulates increases. It can also be seen that the disintegration and the sliding time of the pendant tablet increase while the binder content in the tablet increases. This is due to the presence of a more viscous film around the calcium carbonate crystals, which reduces the entry of water to a slight degree. The best melting properties for the previous series of examples are observed with binder contents (povidone K-30) of 6 to 26 mg, which is equivalent to 0.4 to 1.8% w / w of binder in the tablet formulations.

Examples 10, 11, 12, 13, 14 and 15 The flexibility of the type of filler material in the coating of calcium carbonate crystals has been investigated in the following examples. [01 * the term "binder" used in connection with the granulation liquid (or film coating composition) is equivalent to the term "polymer substance" ** the term "filler" used in connection with the granulation liquid (or composition of film coating) is equivalent to the term "water soluble substance" From the results it can be seen that a number of filler materials can be employed as a component in the coating of the calcium carbonate crystals. Satisfactory agglomeration is achieved with average particle sizes in the range of 200 to 307 μm and with low space values indicating narrow particle size distributions. It can be seen that the formulations produce dense tablets in the range of 1.57 to 1.66 g / cm 3 and with sufficiently high values for the porosity in the range of 32 to 36%. The values for the disintegration time and the sliding time of the pendant tablet are slightly higher than those achieved for xylitol which indicates that xylitol is one of the preferred filler materials in the film that covers the carbonate crystals of calcium. The relatively high crushing strengths of 70 to 117 N and very low friability values of 0.1 to 0.4% are achieved at low tablet pressures of 8 to 10 kN.

Examples 16, 17, 18 and 19 Different qualities of calcium carbonate and different types of wet binder material in the coating of calcium carbonate crystals have been investigated in the following examples * the term "binder" used in connection with the granulation liquid (or film coating composition) is equivalent to the term "polymeca substance" ** the term "filler" used in connection with the granulation liquid (or composition of film coating) is equivalent to the term "water soluble sustarcia" From the results it can be seen that different binder materials can be used as a component in the coating of the calcium carbonate crystals. Example 17 contains propylene glycol alginate, which is only present at a 0.09% concentration in the tablet. It is, however, a very viscous binder in low concentrations, which explains the high value for the sliding time of the pendant tablet. Examples 18 and 19 show that different qualities of calcium carbonate with a specific surface area of up to 1.5 m2 / g can be used with good results with respect to the granulate and the characteristics of the tablet.

Examples 20, 21, 22, 23 and 24 A series of examples was carried out to vary the amount of water soluble substance (also denoted soluble filler). The soluble filler was added in amounts of 4.2, 2.2, 1.1 and 0.6% w / w to the tablet where the amount of polymeric binder was maintained at two levels of 16 and 26 mg per tablet respectively. * the term "binder" used in connection with the granulation liquid (or film coating composition) is equivalent to the term "polymeric substance" ** the term "filler" used in connection with the granulation liquid (or composition of film coating) is equivalent to the term "water soluble substance" The granulates are additionally characterized by low values for the space values indicating narrow particle size distributions. From the table it can be seen that as little as 7.5 mg or 0.6% xylitol per tablet produces tablets with an acceptable friability and crushing resistance. Furthermore, it can be seen that tablet formulations are characterized by high tablet densities due to the low levels of soluble filler material in the tablets. Accordingly, the use of a combination of a water-soluble substance and a polymeric substance to coat or partially coat a calcium-containing compound enables the preparation of tablets with a surprisingly high content of the compound with Ca. In the present example, the tablet is designed as a chewable tablet, but has characteristics that also enable normal oral administration, ie swallowing the tablet. In this case, the Ca content will be even higher (97% w / w) due to the fact that for the swallowable tablets the flavor can be omitted. The tablet casting characteristics are achieved for the entire series of formulations with disintegration time and sliding time of the pendant tablet in the range of 57-123 seconds and 25-65 seconds respectively.

It is surprising that the characteristics of tablet melting function are retained at these low levels of excipient where the active ingredient is present in an amount exceeding 96% (eg 24).

Examples 25, 26 and 27 A series of examples were carried out to use other calcium salts and especially calcium salts based on organic acids. Combinations of calcium carbonate with calcium lactate and calcium citrate have also been formulated to have a sufficient amount of calcium in each tablet. Examples 25, 26 and 27 contain 350, 400 and 200 mg respectively of calcium per tablet. * the term "binder" used in connection with the granulation liquid (or film coating composition) is equivalent to the term "polymeca substance" ** the term "filler" used in connection with the granulation liquid (or film coating composition) is equivalent to the term "water soluble substance" It is seen from the table above that tablet melting tablets are achieved with acceptable friabilities and crushing strengths at low tabletting pressures. The tablet casting characteristics are evident with disintegration and sliding times of the pendant tablet of 50-92 seconds and 35-95 seconds respectively. It can be seen that the tablet density is dependent on the particular calcium salt or the combination of calcium salts used where the tablets based on organic calcium salts are less dense than the tablets based mainly on calcium carbonate.

Example 28 Wet granulation in a high shear mixer 28A. Design The compositions to be evaluated in this experiment are as follows The calcium carbonate is mixed with a part of the soluble filler. The mixture is moistened with a solution / suspension of the rest of the water-soluble substance and the polymer substance with binding properties, the solution / suspension is roela on the powder mixture by the use of an injector. The purpose of spraying is to obtain particles and / or calcium carbonate crystals, substantially coated with the film. The wet powder mass is kneaded wet for 1 to 10 minutes.

The mass of granulated powder is transferred to a fluidized bed dryer where it is dried at a water content below 1.0%. The dried granulate is passed through a 1.5 mm screen and mixed with the remaining excipients for final granulation. The final granulate is compressed to chewable tablets. 28B. Pilot scale experiment An example has been carried out in a pilot scale high speed mixer, in order to show that other granulation processes can be used to produce the tablet softening formulations according to the invention. The granulation was carried out in a Fielder PMA 25 with a batch size of 6 kg. The main impeller and blade were adjusted for mixing speeds of 400 RPM and 3000 RPM respectively. 300g of the granulation liquid with a dry matter content of 60% was applied to the powder mixture with a spray speed of 80 g / min and a spray atomization pressure of 1.5 bar. The wet granulated product was subsequently passed through a 12 mesh screen and 3 kg was transferred to a pilot bed (Glatt GPCG) at pilot scale for drying.

The product was dried at 80 ° C to a final moisture content of 0.1%. The dried granulate was then mixed with the eleven flavor granulate and magnesium stearate and normal 14 mm convex tablets were produced.

* The term "binder" used in connection with the granulation liquid (or film coating composition) is equivalent to the term "polymer substance" ** The term "filler" used in connection with the granulation liquid (or film coating composition) is equivalent to the term "water soluble substance"). The example above shows that calcium-softened tablets can be used with granulation technologies other than fluidized bed technologies. Calcium softened tablets have been achieved with a low value for friability and an acceptable crush resistance at a tableting pressure of 38 kN. The softening characteristics of the tablets were evident with a disintegration time of 83 sec and a sliding time by hanging the tablets of 50 sec. The tablet formulation based on the high shear granulation has a high density of 1.72 g / cm3 and a porosity of 30.1%. The density is higher and the porosity is somewhat lower compared to the formulations based on fluidized bed / coating granulation in this invention. This was expected due to the fact that a high shear mixer produces a denser granulate during wet kneading at high shear rates in the mixer.

EXAMPLE 29 Scale preparation of production of granules containing calcium carbonate Granules having a composition per unit dose were prepared within the following ranges: The granulation tests were carried out in a Glatt fluidized bed granulator using a multi-head injector (2.3 mm). The size of the batch was 250 kg. The calcium carbonate was transferred to the product container and the xylitol, the povidone 30 and the artificial sweetener were dissolved in the water. The powder bed was heated to a temperature of 35-40 ° C before starting the granulation. The air intake temperature was maintained at 80 ° C during the entire test until the cooling step. The temperature of the product was maintained at 35-40 ° C during the granulation step where an atomization air pressure of about 4.5 bar was used to atomize the granulation liquid. During drying, the temperature of the product rose to 50-52 ° C where after the intake temperature of the air was lowered to 20 ° C beginning the cooling step. Upon reaching a product temperature of 40-45 ° C the cooling stopped and the granulate was discharged from the fluidized bed. There were 6 tests. Tests 1-4 were configured in a 22 factorial design where the xylitol / povidone 30 level and the spray rate (of the granulation liquid) were the indeent variables. In test 5 the level of xylitol was increased and the level of povidone 30 was reduced compared to the factorial design. In test 6, the level of xylitol was reduced and the level of povidone 30 was increased compared to the factorial design.

Composition of the tests 1-6 in mg / enabledta In order to determine the degree of coverage (coating) of the calcium carbonate crystals, so that they are solids in the granulation liquid, measurements of XPS (X-Ray Photoelectron Spectroscopy) were made in Tests 1 in the prepared granules. 2 and 4.

The results show those surfaces of the granulates that are covered are given below: Percentage of the surface of the coated granules It is observed that even a long granulation time, which should result in a more homogeneous distribution, does not ensure complete coverage of the calcium carbonate crystals by the binder (Povidone 30) and the water soluble filler (xylitol). The particle size distribution of the granules is measured by laser diffraction (Malvern) [μm]: Density per unit volume of granules [g / ml] A statistical analysis of the tests which are part of the factorial design shows a significant statistical effect for the spray speed. An increase in spray speed results in an increase in D50 and Dio. The analysis also shows a significant statistical effect for the low amounts of xylitol, which results in the increase in densities per unit volume. This also applies to the combination of low amounts of xylitol and high spray speeds.

EXAMPLE 30 Preparation of Calcium Carbonate-containing Tablets The final granulates were prepared by mixing Durarome® flavor granules and magnesium stearate with the? -fluous ones obtained in Example 29 and the extra excipients of the granules were added.

The tablets were prepared from the final granulates. The tablets were compressed in a 16 station B3B (Manestry) using normal 14 mm concave punches and the following compression forces: 0.6 tons, 1.0 tons, 1.4 tons, 1.8 tons and 2.2 tons. The crush resistance-compression force profiles were obtained; see Figure 8, as well as the disintegration time, the porosity of the tablets (compression strength of 1 ton).

Technical data of the tablets (compression strength of 1 ton): The statistical analysis of lots 1-4 which enter a factorial design of 22 does not show significant effects, which points towards a very robust tabletting process. This is also illustrated by the technical data of the tablets and the crush resistance-compression force profiles in Figure 8. Tests 5 and 6 are not part of the factorial design, however, from a practical point of view neither the Disintegration time nor the porosity of the tablets for these two tests deviates significantly from the design results. From Figure 8, it is observed that the level of resistance to crushing of the test 6 is lower than the slope for the rest of the tests. This is probably caused by the lower amount of xylitol in that formulation (see Example 29).

Example 31 Test of the alternative polymeric compounds The agar and the Kollicoat IR in different concentrations were evaluated according to the following design: Composition of the granules (by lot) Calcium carbonate was transferred to the product container in a fluidized bed (Glatt) GPCG 3 with an upper spray pattern and the xylitol and the polymeric compound were dissolved in the water. The calcium carbonate was converted into granules using the process parameters mentioned below: Flow rate of the granulation liquid: 120 g / min.

Intake temperature of the granulation air 80 ° C Ingress temperature of drying 80 ° C Drying at the temperature of the end point: 45 ° C Cooling to the end point temperature: 42 ° C. After cooling the granulates were passed through a 1400 μm sieve to remove all too large particles. Magnesium stearate was mixed to obtain the final granulates. The granulates are compressed to tablets using punches with 14 mm flat beveled edges with a bisection line. The results of the tests can be seen in the results table.

Results In general it was shown that the resistance to crushing increases by that of the polymer concentration This was also the case for the sliding time for the hanging tablets. As can also be seen from the results table, it is necessary to carefully select the process and formulation parameters in order to obtain satisfactory products.

Example 32 Test of alternative soluble compounds Citric acid, glycoin, sodium chloride and sodium ascorbate were evaluated according to the following design: Composition of the granules (by lot): The calcium carbonate was transferred to the product vessel in a GPCG 3 fluidized bed (Glatt) with an overhead spray pattern and the soluble compound and Povidone 30 dissolved in the water. The calcium carbonate was converted into granules using the following process parameters: Flow rate of the granulation liquid: 120 g / min.

Admission temperature of the granulation air: 80 ° C Admission temperature of drying: 80 ° C Drying at the end point temperature: 45 ° C Cooling to the end point temperature: 42 ° C. After cooling the granulates were passed through a 1400 μm sieve to remove all too large particles. The final granulates were obtained by mixing the magnesium stearate with the sifted granules: Final composition of the granulates (by lot) From the table of results, it can be seen that the use of a soluble compound in combination with the polymer results in tablets having softening properties.

Results In order to achieve satisfactory products it is necessary to carefully select the process and formulation parameters. By combining the formulation parameters of Examples 31 and 32 it will be possible to obtain satisfactory products as long as the appropriate process parameters are chosen.

EXAMPLE 33 Wet Granulation in a Flexomix System of Schugi 33A. Design The compositions to be evaluated in this experiment are as follows: The calcium carbonate is mixed with a part of the soluble filler and passed through the Flexomix system at a flow rate between 100 kg / h-5000 kg / h. The mixture is moistened with a solution / suspension of the rest of the water-soluble substances and the polymeric substance with adhesion properties; through the use of injectors at a flow rate of 4 kg / h to 700 kg / h. The RPM of the mixing blades is set between 1000 and 4500. The mass of granulated powder is transferred to a continuous fluidized bed dryer where it is dried at a water content below 1.0%. The dried granulate is passed through a 1.5 mm screen and mixed with the remaining excipients for final granulation. The final granulate is compressed to chewable tablets. 33B. Granulation in a Fexomix of Schugi, test of the variables of amount of soluble compound, polymer and Schugi.

Preparation of the granules: A powder of calcium carbonate was transferred to a hopper. A granulation liquid consisting of water and the excipients was prepared, see the design table for the composition, in a jacketed container. The granulation was carried out in a Schugi Flexomix FX-1600 with a batch size of approximately 30 kg and a knife position of +2. The rotation speed of the mixer shaft was varied between 3500 rpm and 4500 rpm. Powder feed was controlled by the use of a K-tron pre-feeder T-65, with a stirrer and a constant weight feeder WF300 from K-tron. The granulation liquid was added to the powder by atomization by means of two injectors. The wet granulate was transferred to a horizontal fluidized bed dryer and dried at a final temperature of the specified product.

Design : The granulates were mixed with flavor granules and 0.50 by magnesium stearate, by using an Erweka Tumbling mixer at 27 rpm for 5 minutes, batch size of approximately 5 kg. The tablets were manufactured using a Korsch PH106 instrumented rotary press and 14 mm flat, round bevelled punches. the mass target of the tablets was adjusted to give an amount of 1250 mg of calcium carbonate per tablet. The compression force was adjusted for resistance to crushing of about 40 N, 70 N and 100 N, for each granulate in order to achieve a profile of crushing strength / compression force.

Composition of the tablets The tablets are characterized by their resistance to crushing, the disintegration and sliding time of the hanging tablets. The impact on the crush resistance of the design described above is shown in Figure 9, the sliding time of a hanging tablet in Figure 10 and the disintegration time in Figure 11. The robustness of the formulations is illustrated by the comparison of the replicas (tests 4-8) with variations, tests 1-3, in the amount of xylitol and PVP (tablet compositions) and the flow rate of the liquid and the rpm (current design). The lack of major differences in resistance to crushing, travel time and time of Disintegration between tests 1-6 underlines the robustness of the tablets based on the technology Schugi-Flex-O-Reaction mixture. 33c. Granulation in Schugi's Flexomix, omitting the polymer in the formulation The preparation and characterization of the tablets was carried out as described in Example 33C with the following test and composition design: Composition of the tablets The compression experiment showed that it was not possible to obtain tablets of acceptable quality because the capsules or tablets were too soft. Example 34 Illustration of the coated and uncoated surfaces of a granular calcium containing compound using xylitol as the soluble compound and PVP 30 as the polymer in the granulation liquid The granulates prepared according to example 29 were evaluated by XPS, see example 29 by the results. It was recorded that between 20.9% and 26.9% of the visible surfaces of the calcium-containing compound in the granulates were not coated by the constituents of the dry matter of the granulation liquid. ESEM (Electronic Scanning Electron Microscopy) was used to investigate the appearance of these uncoated surfaces.

In Figures 12A-12C, the arrows designated by A are indicating the areas of the uncoated surface area of the calcium-containing compound. These areas are often characterized by sharp edges or rather flat areas or patterns similar to straight lines on the surface. The Arrows designated by B are pointing to the coated areas. These areas are characterized by rounded surfaces or patterns similar to waves or irregular areas. In view of the results of Example 29. These results show that it is not necessary to have 100% coating or coverage of the compound containing Ca with the ingredients in the coating composition or the granulation liquid. Other planned investigations are described in the following examples. Example 35 Wet granulation with a double extruder The compositions to be evaluated in this experiment are as follows: The calcium carbonate is mixed with a part of the water-soluble substance and transferred to the start section of a twin-extruder MIC 27GL / 28D, from Leistritz, 8.4 kW. The mixture is moistened by adding to the extruder a solution / suspension of the rest of the water-soluble substance and the polymeric substance with adhesion properties. The powder feed is adjusted to 100 g / min and the screw speed is 100 rpm.

The die is not required.

The mass of granulated powder is transferred to a fluidized drip dryer where it dries to a water content below 1.0%. The dried granulate is passed through a 1.5 mm screen and mixed with the remaining excipients for final granulation. The final granulate is compressed to chewable tablets.

EXAMPLE 36 Hot melt granulation in a double extruder The compositions to be evaluated in this experiment are as follows: A mixture of the water soluble substance and the polymer substance with adhesion properties is transferred to the start section of a double extruder Lestritz MIC 27GL / 28D, 8.4 kW with a temperature profile adjusted to the following: The powder feed is adjusted to suit the current formulation and the screw speed is adjusted to 100 rpm. The calcium carbonate is transferred to the double extruder in section 3. The feed of the powder is fine at 100 g / min. The die is not used. The mass of granulated powder is cooled and then the The granulate is passed through a 1.5 mm sieve and mixed with the remaining excipients for final granulation. The final granulate is compressed to chewable tablets.

EXAMPLE 37 Hot melt granulation in a double extruder The compositions to be evaluated in this experiment are as follows: A mixture of soluble filler, binder polymer and calcium carbonate is transferred to the start section of a Leistritz MIC 27GL / 28D double extruder, 8.4 kW with a temperature profile set to the following: The powder feed was adjusted to suit the Current formulation and screw speed was set at 100 rpm. The die is not required. The mass of granulated powder is cooled and then the granulate is passed through a 1.5 mm screen and mixed with the remaining excipients for the final granulation. The final granulate is compressed to chewable tablets.

Example 38 Hot melt granulation in a double extruder The compositions to be evaluated in this experiment are as follows: A mixture of the water-soluble substance and the polymer substance with adhesion properties is moistened with water and then transferred to the initial section of a Leistritz MIC 27GL / 28D double extruder, 8.4 kW with a temperature profile set to the following: The powder feed is adjusted to suit the current formulation and the screw speed is set at 100 rpm. The calcium carbonate is transferred to the double extruder in section 3. The powder feed is adjusted to 100 g / min. The die is not required. The granulated powder mass is cooled and then the granulate is passed through a 1.5 mm screen and mixed with the remaining excipients for final granulation. The final granulate is compressed to chewable tablets. Example 39 Hot melt granulation in a double extruder The compositions to be evaluated in this experiment are as follows: A mixture of the water-soluble substance and the polymer substance with adhesion properties wetted with water is mixed with the calcium carbonate and then transferred to the start section of a Leistritz double extruder MIC 27GL / 28D, 8.4 kW with a profile of temperature adjusted to the next.

The powder feed is adjusted to suit the current formulation and the screw speed is set at 100 rpm. The die is not required. The granulated powder mass is cooled and then the granulate is passed through a 1.5 mm screen and mixed with the remaining excipients for final granulation. The final granulate is compressed to chewable tablets.

EXAMPLE 40 Granulation in a spray dryer The compositions to be evaluated in this experiment are as follows The water-soluble substance dissolves in a solvent, the polymeric substance with binding properties dissolves / disperses in the solution and finally the calcium carbonate is dispersed in the solution / dispersion, the final content of the solids in the suspension is from 10% to 90%. The spraying is carried out using an injector introduced in a dry flow of air having a temperature between 120 ° C and 300 ° C. The resulting granulate is optionally dried by the use of a fluidized bed at a water content below 1.0%. The dried granulate is passed through a 1.5 mm screen and mixed with the remaining excipients for final granulation. The final granulate is compressed to chewable tablets. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (48)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A method for the preparation of a calcium-containing compound at least partially coated with a film or granulate, characterized in that it comprises i) dissolving or dispersing a or more water-soluble substances and one or more polymeric substances in a solvent, to obtain a coating and / or granulation composition, and ii) applying the coating and / or granulation composition of step i) on a compound containing calcium in the form of particular and / or crystals, to obtain the calcium-containing compound at least partially coated with a film and / or granules.
2. 2. A method according to claim 1, characterized in that the solvent is an aqueous or organic solvent.
3. 3. A method according to claim 2, characterized in that the solvent is an aqueous solvent.
4. 4. A method according to any of the preceding claims, characterized in that the polymer substance has binding properties.
5. 5. A method of compliance with any of the preceding claims, characterized in that the polymer substance is soluble in water.
6. 6. A method according to any of the preceding claims, characterized in that the one or more water-soluble substances have a solubility in water of about 10 mg / ml or more, such as, for example, about 25 mg / ml, approximately 50 mg / ml or more, approximately 75 mg / ml or more or approximately 100 mg / ml or more.
7. 7. A method according to any of the preceding claims, characterized in that the one or more water-soluble substances are selected from the group consisting of polyols and carbohydrates.
8. 8. A method according to claim 7, characterized in that the polyol is a sugar alcohol.
9. 9. A method according to claim 8, characterized in that the sugar alcohol is selected from the group consisting of xylilol, sorbitol, mannitol, malitol, lactilol, erythritol, inositol, isomait, isomaltulose and mixtures thereof.
10. 10. A method according to claim 8, characterized in that the carbohydrate is selected from the group consisting of mono, disaccharides, oligosaccharides, polysaccharides, and mixtures thereof.
11. 11. A method according to claim 10, characterized in that the carbohydrate is a monosaccharide selected from the group consisting of glucose, mannose, fructose, galactose, and mixtures thereof.
12. 12. A method according to claim 10, characterized in that the carbohydrate is a disaccharide selected from the group consisting of lactose, maltose, sucrose, trehalose, tagalose, and mixtures thereof.
13. 13. A method according to claim 10, characterized in that the carbohydrate is an oligosaccharide or a polysaccharide selected from the group consisting of cyclodextrins, mixtures, and mixtures thereof.
14. A method according to any of claims 1-6, characterized in that the water-soluble substance is selected from the group consisting of organic acids including amino acids, carbonic acid, citric acid, acetic acid, fumaric acid, etc., pharmaceutically acceptable salts of the organic acids including the alkali metal salts and the alkaline earth metal salts of carbonates, citrates, acetates, fumarates, etc., salts of inorganic acids including alkali metal salts of hydrochloric acid, sulfuric acid, nitric acid and the like.
15. 15. A method according to any of the preceding claims, characterized in that the concentration of the water soluble substance in the at least partially coated and / or granulated calcium containing compound is at least about 0.1% w / w, such as, for example, in a range from 0.3% w / w to approximately 50% w / w, from approximately 0.5% w / w to approximately 50% w / w, from approximately 0.6% w / w to approximately 50% w / w, from 1 % w / w about 50% w / w, such as, for example, from about 0.5% to about 40% w / w, from about 1% w / w to about 40% w / w, from about 0.5% to about 30 % w / w, from about 1% w / w to about 30% w / w, from about 1.5% w / w to about 30% w / w, from about 0.5% to about 20% w / w, from about 1% w / w / pa about 20% w / w, or from about 2% to about 20% w / w.
16. 16. A method according to any of the preceding claims, characterized in that the concentration of the water soluble substance in the at least partially coated or grained calcium containing compound is from about 0.5% w / w to about 10% w / w , from about 1% w / w to about 10% w / w such as, for example, from about 0.5% w / w to about 5% w / w, from about 1% w / w to about 5% w / w or from about 2% w / w to about 5% w / w.
17. 17. A method according to any of the preceding claims, characterized in that the polymeric substance is a pharmaceutically acceptable binder.
18. 18. A method according to any of the preceding claims, characterized in that the polymeric substance is selected from the group consisting of povidones including K-90, K-30, K-25, K-17 and K-12; copovidones; polyethylene glycol-polyvinyl alcohol; agas; jelly; gum arabic; alginates that include sodium alginate and propylene glycol alginate; modified starches or starches including potato starch, corn starch, rice starch, pre-gelatinized starch; carbohydrates that include inulin, polydextrose, dextrin, maltodextrins; cellulose and cellulose derivatives including sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), microcrystalline cellulose, cellulose derivatives, such as low substituted hydroxypropylcellulose, and mixtures thereof.
19. 19. A method according to any of the preceding claims, characterized in that the calcium-containing compound is selected from the group consisting of calcium carbonate, calcium citrate, lactate of calcium, calcium phosphate including tricalcium phosphate, calcium gluconate, calcium bisglycine, calcium maleate citrate, hydroxyapatite, including derivatives thereof and mixtures thereof.
20. 20. A method according to any of the preceding claims, characterized in that the calcium-containing compound is calcium carbonate.
21. 21. A method according to claim 20, characterized in that, the specific surface area of the calcium carbonate is from about 0.1 to about 3 m2 / g, such as, for example, from about 0.1 to about 2.75 m2 / g, from about 0.1 to about 2.5 m2 / g, from about 0.1 to about 2 m2 / g, from about 0.1 to about 1.8 m2 / g, from about 0.1 to about 1.6 m2 / g, from about 0.1 to about 1.4 m2 / g or from about 0.1 to approximately 1.3 m2 / g.
22. 22. A method according to claim 21, characterized in that the specific surface area of the calcium carbonate is from about 0.1 to about 1.2 m2 / g.
23. 23. A method according to any of claims 20-22, characterized in that the average particle size of the calcium carbonate is from about 0.1 μm to about 100 μm, such as from about 0.1 μm to about 80 μm, from about 0.5 μm to about 60 μm, from about 1 μm to about 50 μm or from about 2 μm to about 40 μm.
24. 24. A method according to claim 23, characterized in that the average particle size of the calcium carbonate is from about 3 to about 40 μm.
25. 25. A method according to any of the preceding claims, characterized in that the water-soluble substance is xylylol and the polymeric substance is a povidone or copovidone, or mixtures thereof.
26. 26. A method according to any of the preceding claims, characterized in that, in step i), one or more sweeteners, including intense sweeteners, colors, flavors, acidulants, flavors or the like are added to the solvent.
27. 27. A method according to any of the preceding claims, characterized in that the application of the coating and / or granulation composition is carried out by spraying, melting or spray drying.
28. 28. A method of compliance with any of the preceding claims, characterized in that the coating and / or granulation composition is applied by the use of granulation the fluidized bed, spray drying, melt granulation, extrusion, high shear mixing, or rotoprocessing.
29. 29. A method according to claim 28, characterized in that the coating and / or granulation composition is applied by the use of a fluidized bed.
30. 30. A method for the preparation of a composition comprising the calcium-containing compound at least partially coated with a film or granulate, as defined in any of claims 1-29, characterized in that it comprises a step of mixing one or more excipients pharmaceutically acceptable with the calcium-containing compound coated with at least partially or granulated film.
31. 31. A method according to claim 30, characterized in that the composition obtained is in the form of particles.
32. 32. A method according to claim 31, characterized in that the composition is used in the preparation of a pharmaceutical or nutritional composition.
33. 33. A method according to claim 32, characterized in that the pharmaceutical or nutritional composition is in the form of tablets, capsules, pills, beads, granules, granules, powders, etc.
34. 34. A method according to claim 33, for the preparation of tablets, characterized in that it comprises mixing one or more pharmaceutically acceptable excipients, such as, for example, one or more lubricants, glidants, and optionally, one or more flavors or agents of improving the taste to the calcium-containing compound at least partially coated with a film or granulate and compressing the resulting mixture into tablets.
35. 35. A method according to any of claims 30-34, characterized in that the concentration of the calcium-containing compound in the pharmaceutical or nutritional composition is 50% w / w more such as, for example 55% w / w more, 60 % p / p more, 65 p / p more, 70 p / p more, 75 p / p more, 80 p / p more 85 or more.
36. 36. A method according to claim 34 or 35, characterized in that the composition is in the form of tablets and the concentration of the compound containing calcium is 80% w / w more, 85% w / w more, 90% p / more or 95% p / p or more.
37. 37. A method according to any of claims 34-36, characterized in that the tablets have a bulk density at more than about 2.2 g / cm3, such as, for example, at most about 2.0 g / cm3, at more approximately 1.8 g / cm3, or in an interval from about 1.4 g / cm3 to about 2.2 g / cm3.
38. 38. A method according to any of claims 34-37, characterized in that the tablets have a bulk density of 1.4 g / cm3 or more, such as, for example, about 1.5 g / cm3 or more or in a range from about 1.4 g / cm3 to about 1.9 g / cm3 or from about 1.5 g / cm3 to about 1.7 g / cm3.
39. 39. A method according to any of claims 34-38, characterized in that the tablets have a porosity of from about 5 to about 50% such as, for example, from about 5 to about 45%, from about 5 to about 40% , from about 10 to about 40%, from about 15 to about 40% or from about 20 to about 40%.
40. 40. A method according to any of claims 34-39, characterized in that the tablets have a porosity from about 30 to about 40%.
41. 41. A method according to any of claims 34-40, characterized in that the tablets have a disintegration time when measured according to Ph. Eur., At most 30 minutes, such as, at most approximately 20 min, at most approximately 15 min, at more about 10 min, at most about 5 min, at most about 4 min or at most about 3 min.
42. 42. A method according to any of claims 34-41, characterized in that at least 60% of the calcium-containing compound is released from the tablets within 30 minutes, at least 70% of the calcium-containing compound is released from the tablets within 30 minutes, at least 80% of the calcium-containing compound is released from the tablets within 30 minutes, at least 60% of the calcium-containing compound is released from the tablets within 20 minutes , at least 70% of the calcium-containing compound is released from the tablets within 20 minutes, at least 80% of the calcium-containing compound is released from the tablets within 20 minutes, at least 60% of the compound contains calcium is released from the tablets within 10 minutes, at least 70% of the calcium-containing compound is released from the tablets within 10 minutes and at least 60% of the calcium-containing compound is released from the tablets in a term of 30 minutes, which It is measured by an in vitro dissolution test according to Ph.Eur. / USP (paddle wheel, 50 rpm dissolution medium: 1000 ml of 0.1 M HCl containing 0.04% cetrimide, 37 ° C).
43. 43. A method of compliance with any of the claims 34-42, characterized in that the tablets have a sliding time when measured by the "hanging tablet method" as described herein of at most about 60 sec, such as at most about 45 sec or at most about 30 sec. sec.
44. 44. A method according to any of claims 34-42, characterized in that the volume of the tablets is at most 1.5 cm3 such as, for example, at most approximately 1.25 cm3, at most approximately 1 cm3, at more about 0.8 cm3, at most about 0.7 cm3, or at most about 0.65 cm3 per 500 mg of the elemental calcium contained in the tablets
45. 45. A compound containing at least partially coated or granulated calcium, characterized in that, it can be obtained as defined in accordance with any of claims 1-28.
46. 46. A pharmaceutical or nutritional composition, characterized in that it comprises a compound containing at least partially coated or granulated calcium, which can be obtained as defined according to any of claims 1-29.
47. 47. A pharmaceutical or nutritional composition, characterized in that it can be obtained as defined in accordance with any of claims 30-44.
48. 48. A method to improve sensory properties of a calcium-containing compound, the method characterized in that it comprises applying a coating or a granulation composition containing one or more water-soluble substances and a polymeric substance on a calcium-containing compound in the form of particles and / or crystals, to obtain a calcium-containing compound at least partially coated with a film or granulate, or the pharmaceutical or nutritional composition, as defined in any of claims 1-44.