HK1180212A - Pre-compacted calcium-containing compositions - Google Patents

Description

Precompacted calcium-containing composition

This application is a divisional application filed under application number 200680046402.9 (PCT/DK 2006/000695) on 7/12/2006 entitled "Pre-compacted calcium-containing composition".

Technical Field

The invention relates to a pre-compacted material comprising a polycrystalline porous calcium-containing compound and a sugar alcohol. For polycrystalline nature and porosity, SEM photography can be used to identify the structure of the calcium-containing compound. The invention also relates to methods of making the pre-compacted material and solid dosage forms. The method comprises agglomerating the calcium-containing compound and the pharmaceutically acceptable sugar alcohol by roller compaction. The pre-compacted material obtained by roller compaction is suitable for further processing of the pre-compacted material into compositions, such as pharmaceutical or nutritional compositions, including dosage forms such as tablets, capsules, sachets and the like, including chewable tablets.

Background

Previously, it has been described that the specification of the calcium-containing compound and the method of preparing the pharmaceutical composition containing the calcium-containing compound are very important for obtaining chewable tablets with acceptable taste and mouthfeel (WO 00/28973). In contrast to WO 00/28973, the process of the present invention does not use a step of binding the granules together by wet granulation, which means that it is advantageous to use the process of the present invention when it is desired to incorporate moisture sensitive materials. An example of such a substance is vitamin D, which is usually included in a pharmaceutical dosage form together with a calcium salt. The present invention provides a simple, cost-effective alternative for obtaining such dosage forms without the need for, for example, a step involving wet granulation.

To this end, the inventors have previously found that roller compaction is a suitable method for preparing a pre-compacted calcium-containing material comprising a regularly shaped calcium-containing compound and a sugar alcohol. However, not all sugar alcohols are equally suitable. Therefore, it is advantageous to use sugar alcohols having a suitable microstructure. A particularly suitable specification is sorbitol having a specific small average particle size below 50 μm. These findings are described in co-pending PCT application No. PCT/DK 2005/000338. US 6,475,510 describes a method of producing bite-dispersion tablets. Calcium carbonate is mentioned in example 6. However, the specification of the calcium carbonate to be used is not described in detail, and a wax-like material such as Precirol is also used. In the material of the present invention, since the specification of the calcium-containing substance is carefully selected, it is not necessary to add such a wax-like material. Thus, in a particular embodiment, the material of the invention is free of Precirol or any other waxy material mentioned in column 5, lines 31-39 of US 6,475,510 (i.e., a mono-, di-or tri-C10-C30 fatty acid glyceride, especially glyceryl palmitostearate or glyceryl behenate; a high molecular weight (C10-30) straight chain fatty alcohol such as stearyl alcohol or cetyl alcohol; and mixtures of high molecular weight fatty acids and esters; or combinations thereof; especially, the waxy material is stearyl alcohol or cetyl alcohol, or glyceryl palmitostearate or glyceryl behenate.).

However, there is a demand for the use of rolling for other calcium-containing compounds like regular shaped calcium-containing compounds, and further for other kinds of sugar alcohols like sugar alcohols having binding properties and microstructures. In particular, the use of xylitol is very important, since xylitol has a positive influence on the sensory properties of the final product, e.g. a chewable tablet.

Disclosure of Invention

The present invention is based on the finding that it is possible to prepare a pre-compacted calcium-containing material comprising a sugar alcohol without placing any specific requirements on the sugar alcohol, as long as the calcium-containing compound itself fulfils the specific requirements with respect to crystal structure and porosity.

More specifically, the inventors have found that it is only possible to obtain a pre-compacted material suitable for use in the manufacture of e.g. a tablet dosage form if the calcium-containing compound has a polycrystalline and porous structure.

Polycrystalline structure refers to a material consisting of grains of a crystalline material, which grains are randomly oriented with respect to each other (seewww.icknowledge.com/glossary/p.html，www.wordnet.princeton.edu/perl/webwinOr is orwww.en.wikipedia.org/wiki/polycrystalline). The polycrystalline structure results in a crystal having an irregular structure, as compared with a cube (a crystal of a regular shape) having a smooth surface. Such irregular structures are also referred to herein as perforated structures.

In the present context, the term "precompacted" refers to the initial compaction of the material ("having a particle size below about 100 μm") with the aim of obtaining a flowable granulate, which can be further compressed into tablets in a later production process.

As mentioned above, in the present invention, the roller compaction method of powder is used as an alternative to the existing granulation or agglomeration method, i.e., wet granulation or direct compression method using a dry binder in preparing tablets. The present inventors have previously found that the roller compaction process is a very gentle process, without compromising the possibility of obtaining a product with an acceptable mouthfeel without at the same time a significant chalky-like taste or sensation. However, the findings are limited to regular shaped calcium-containing compounds and sugar alcohols having binding properties and a microporous structure.

Generally, roller compaction is used to increase the bulk density of a particular substance or composition, for example to convert bulk materials into smaller volume materials, which are more readily used in the manufacture of pharmaceutical compositions. However, roller compaction is not generally used as a mild granulation process to maintain or not destroy important properties of the material (i.e. the calcium-containing compound) in order to obtain an acceptable taste, mouthfeel, etc.

In order to produce tablets that are smaller but still have acceptable taste and mouthfeel, the present inventors have found that the use of a pharmaceutically acceptable sugar alcohol in the agglomeration process is particularly suitable. However, the present inventors have previously found that in order to obtain suitable properties of the compacted compound comprising a calcium-containing compound, two main factors are of great importance, namely the properties of the calcium-containing compound itself as discussed above and the choice of sugar alcohol to be used as binder in the agglomeration process. However, the present invention eliminates the limitation on the selection of the sugar alcohol as long as the calcium-containing compound has a polycrystalline and porous structure.

Thus, one aspect of the invention relates to a pre-compacted material comprising one or more calcium-containing compounds having a polycrystalline porous structure and one or more sugar alcohols.

As demonstrated in the examples herein (see example 3), it is not sufficient that the calcium-containing compound has only an irregular shape in order to be able to prepare a suitable pre-compacted material. Example 3 demonstrates that the irregularly shaped calcium-containing compound Dicafos PA (see fig. 6A) does not have sufficient properties to successfully roll with a sugar alcohol. Therefore, the porous nature of the calcium-containing compound is also important.

Typically, the concentration of the calcium-containing compound in the pre-compacted material of the invention is about 60% w/w or more, such as about 65% w/w or more, about 70% w/w or more, about 75% w/w or more, about 80% w/w or more, about 85% w/w or more, about 90% w/w or more or about 95% w/w or more.

Contrary to what the inventors expect, experiments conducted by the inventors have shown that calcium-containing compounds that are available in the specification for direct compression do not automatically serve as a good starting point for roller compaction. As can be seen from examples 3 and 6 herein, the DC specification must also be porous in order to be able to prepare a suitable pre-compacted material and subsequently further process it into, for example, a tablet.

As described above, it is particularly advantageous to pre-compact the calcium-containing compound together with one or more sugar alcohols. It can be seen from the examples herein that a relatively wide range of concentrations can be used without changing the overall properties of the pre-compacted material in the compressed tablet. Furthermore, the examples herein show that the structure (e.g. crystalline, microstructure, porosity, etc.) of the sugar alcohol has less impact on the technical properties of the product when the calcium-containing compound has the desired polycrystalline and porous properties.

Sugar alcohols suitable for use in the pre-compacted material of the present invention include xylitol, sorbitol, mannitol, maltitol, lactitol, erythritol, inositol, isomalt (isomalt) and mixtures thereof.

The concentration of the one or more sugar alcohols in the pre-compacted material of the invention is typically about 5% w/w or more, such as about 7.5% w/w or more, about 10% w/w or more, about 15% w/w or more, about 20% w/w or more, about 25% w/w or more, about 30% w/w or more, about 35% w/w or more or about 40% w/w.

As mentioned above, the most important properties are the polycrystalline and porous nature of the calcium-containing compound. These properties can be seen in SEM pictures, with reference to the examples herein. As long as these properties are present, the calcium-containing compound may be selected from calcium carbonate, calcium citrate, calcium lactate, calcium phosphates including tricalcium phosphate, calcium gluconate, calcium bisglycinate (bisglycinate), calcium citrate maleate, hydroxyapatite including solvates thereof, and mixtures thereof.

According to the examples herein, it is clear that particularly suitable calcium-containing compounds are calcium carbonate and calcium phosphate.

Thus, in one embodiment, the calcium-containing compound is calcium carbonate, e.g. Sturcal, including e.g. Sturcal L. In another embodiment, the calcium-containing compound is a calcium phosphate, including tricalcium phosphate, dicalcium phosphate, or monocalcium phosphate. Suitable specifications (quality) include tricalcium phosphate (Ca)₅(PO₄)₃OH) and dicalcium phosphate (CaHPO)₄）。

In another embodiment, the calcium-containing compound is in a directly compressible form.

Particular embodiments of the present invention include pre-compacted materials including Sturcal L and xylitol, Sturcal L and mannitol, Sturcal L and maltitol, Tricafos P and xylitol, Tricafos P and mannitol, Tricafos P and maltitol, Tricafos A and xylitol, Tricafos A and mannitol, and Tricafos A and maltitol.

Sturcal may also be of D, H, LS, M or X specification or a mixture thereof, and Tricafos may be of S or R specification or a mixture thereof. Furthermore, Dicafos may be AN specification.

In another embodiment, the pre-compacted material of the invention further comprises a sugar alcohol other than xylitol, mannitol or maltitol.

In these cases, the total concentration of the one or more sugar alcohols in the final composition is from about 5% w/w to about 40% w/w, such as about 5% w/w, about 10% w/w, about 25% w/w or about 40%.

Using roller compaction as a means to agglomerate calcium-containing compounds to obtain a pre-compacted material suitable for use in the preparation of e.g. chewable tablets with acceptable taste and mouthfeel, there are two key parameters in the calcium-containing compounds, i.e. polymorphism and porosity.

A description of the calcium-containing compound is given in the following paragraphs. However, as mentioned herein before, the calcium-containing compound used in the compaction process of the invention is polycrystalline and porous, e.g. a calcium salt such as calcium carbonate with a specific specification. In a preferred aspect, the calcium salt is calcium carbonate and apparently has a shape and average particle size corresponding to that of Strucal L, or is a calcium phosphate such as Dicafos a or Tricafos P.

However, the calcium-containing compounds described above may be used in admixture with other calcium-containing compounds, such as those described in the following paragraphs, in particular calcium citrate, calcium lactate, calcium phosphates including tricalcium phosphate, calcium gluconate, calcium bisglycinate (bisglycinate), calcium citrate maleate, hydroxyapatite including solvates thereof, and mixtures thereof.

In a particular case, the pre-compacted material of the invention contains the above-mentioned polycrystalline and porous calcium-containing compound as well as another calcium-containing compound (i.e. irrespective of its crystalline nature and porous structure). In a particular embodiment, the pre-compacted material of the invention further comprises a calcium-containing compound having a non-porous structure. In these cases, the weight ratio between the non-porous calcium-containing compound and the polycrystalline porous calcium-containing compound is typically at most 0.4, such as at most 0.35, at most 0.3, at most 0.25, at most 0.2, at most 0.15, at most 0.1 or at most 0.05.

More specifically, the polycrystalline porous calcium-containing compound may be Sturcal L, Tricafos P, or Dicafos A, or mixtures thereof, and the non-porous calcium-containing compound may be Scoralite or CafosDB, or mixtures thereof.

In case calcium-containing compounds of different structure and properties are present, the concentration of the non-porous calcium-containing compound is typically from about 5% to about 40%, e.g. 40% w/w or less, 25% w/w or less, 10% w/w or less or 5% w/w or less.

Generally, the content of polycrystalline and porous calcium-containing compound in the pre-compacted material is in the range of from about 40% to about 100% w/w, such as from about 45% to about 98% w/w, from about 50% to about 95% w/w, from about 55% to about 90% w/w, or at least about 60% w/w, at least about 65% w/w, at least about 70% w/w or at least about 75% w/w.

The pre-compacted material obtained by roller compaction may contain 100% w/w of the calcium-containing compound, or it may contain about 50% to about 90% w/w, such as about 70% to about 80% w/w, of the total amount of calcium-containing compound contained in the tablet. Thus, a part of the total amount of calcium-containing compound may be added after the roller compaction.

The precompacted material of the invention may also contain one or more pharmaceutically acceptable excipients or additives, one or more substances having therapeutic, prophylactic and/or diagnostic activity. A description of pharmaceutically acceptable excipients suitable for use in the present invention is given herein.

One active substance of particular interest is vitamin D.

In another aspect, the invention relates to the use of the previously compacted material described above for the preparation of a formulation, including a pharmaceutical or nutraceutical formulation. In a particular embodiment of the invention, solid dosage forms comprising the pre-compacted material of the invention are contemplated.

The dosage form of the present invention comprises pre-compacted material, optionally together with one or more pharmaceutically acceptable excipients.

Particular embodiments of interest are those wherein the dosage forms of the invention are in the form of tablets (including chewable, suckable and swallowable tablets), capsules, sachets and the like.

Typically, the concentration of the polycrystalline porous calcium-containing compound in the composition of the invention (e.g. in a tablet) is 50% w/w or more, such as about 55% w/w or more, about 60% w/w or more, about 65% w/w or more, about 70% w/w or more, about 75% w/w or more, about 80% w/w or more, about 85% w/w or more or about 90% w/w or more.

Furthermore, roller compaction of the composition comprising the calcium-containing compound and the sugar alcohol to obtain the pre-compacted material of the invention results in a pre-compacted material having a flowability such that when the pre-compacted material is optionally mixed with up to 10% w/w, such as up to about 7.5% w/w or up to about 5% w/w of a glidant to prepare a tablet using a tablet press at a speed of at least 300 tablets per minute, the deviation in weight of the obtained tablet meets the requirements set forth by ph. The tablet press may be operated at, for example, 1000 tablets/minute or more, e.g., 2000 tablets/minute, 3000 tablets/minute, 4000 tablets/minute, 5000 tablets/minute, 6500 tablets/minute, 700 tablets/minute, 8000 tablets/minute, or the like. The residence time during tablet preparation is at most about 1 second.

In a particular embodiment, the pre-compacted material of the invention comprises about 60 to 95% w/w of the calcium-containing compound and about 5 to about 40% w/w of the pharmaceutically acceptable sugar alcohol, provided that the sum does not exceed 100% w/w.

In another specific embodiment, the precompacted material of the invention comprises from about 60 to about 94% w/w, such as from about 65% to about 80% w/w of a calcium-containing compound, from about 5 to about 35% w/w, such as from about 15 to about 30% w/w, of a pharmaceutically acceptable sugar alcohol and from about 1 to about 15% w/w of one or more pharmaceutically acceptable excipients and/or active substances, as long as the sum of the ingredients is equal to 100% w/w.

More specifically, the pre-compacted material of the invention preferably comprises about 65% to about 80% w/w, such as about 70% to about 75% w/w, of the calcium-containing compound and about 15% to about 25% w/w, such as about 20 to about 25% w/w, of sorbitol or isomalt or a mixture thereof.

The precompacted material of the present invention may be used as is, but it is typically processed into a suitable solid dosage form. One or more pharmaceutically acceptable excipients may be added for the preparation of the dosage form. Dosage forms are for oral administration, e.g., in the form of single unit or multiple unit dosage forms, e.g., in the form of tablets, capsules, sachets, spheres, pellets, or the like.

In a preferred embodiment, the solid dosage form of the invention is in the form of a tablet.

The solid dosage forms of the invention may contain one or more calcium-containing compounds in an amount corresponding to about 300 to about 1200mg of calcium, for example about 400 to about 600mg of calcium. Generally, the total concentration of the one or more calcium-containing compounds in the dosage form is in the range of from about 40% to about 99% w/w, such as from about 45% to about 98% w/w, from about 50% to about 95% w/w, from about 55% to about 90% w/w, or at least about 60% w/w, at least about 65% w/w, at least about 70% w/w.

In particular embodiments, the dosage form comprises a total concentration of pre-compacted material from about 65% to about 100% w/w, such as from about 70% to about 98% w/w, from about 75% to about 95% w/w, from about 80% to about 95% or from about 85% to about 95% w/w.

In another embodiment, the solid dosage form of the invention comprises from about 60% to about 95% w/w of the calcium-containing compound, and from about 5% to about 40% w/w of a pharmaceutically acceptable sugar alcohol, as long as the sum does not exceed 100% w/w. Alternatively, the solid dosage form comprises from about 60 to about 94% w/w, such as from about 65% to about 80% w/w of a calcium-containing compound, from about 5 to about 35% w/w, such as from about 15 to about 30% of a pharmaceutically acceptable sugar alcohol, and from about 1 to about 15% w/w of one or more pharmaceutically acceptable excipients and/or active substances, provided that the sum of the amounts of ingredients equals 100% w/w.

SEM photographs of fractured surfaces of solid dosage forms show that the surfaces of the deformed particles of sugar alcohol are in intimate contact with the surface of the one or more calcium-containing compounds.

In a preferred aspect, the solid dosage form is in the form of a chewable, suckable and/or swallowable tablet. Important for chewable tablets is taste, and these tablets of the invention must have an acceptable taste in terms of sweetness, aroma and chalk-like characteristics when tested by at least 6 professional/skilled sensory test panel.

The solid dosage form of the present invention may contain a sweetener selected from the group consisting of: dextrose, fructose, glycerol, glucose, isomalt, lactitol, lactose, maltitol, maltose, mannitol, sorbitol, sucrose, tagatose, trehalose, xylitol, alitame (alitame), aspartame, acesulfame (acesulfam potassium), cyclamic acid, cyclamate (e.g., calcium cyclamate, sodium cyclamate), neohesperidin dihydrochalcone, thaumatin (thaumatin), saccharin (saccharan), saccharin salts (e.g., ammonium saccharin, calcium saccharin, potassium saccharin, sodium saccharin), and mixtures thereof.

The invention also relates to a method for preparing a pre-compacted material as defined above, which method comprises roller compaction of a composition comprising a polycrystalline porous calcium-containing compound and one or more pharmaceutically acceptable sugar alcohols. Details regarding the main aspects of the invention (i.e. the pre-compacted material) may be applied to this and other aspects of the invention with necessary modifications.

Another aspect of the invention is to combine the production of pre-compacted material with the production of tablets. The powder mixture can be converted directly into solid dosage forms, i.e. tablets, by using small rolls on a roller compactor (pocket roller).

Another aspect of the invention is a method for preparing a tablet containing a calcium-containing compound, the method comprising:

i) preparing a pre-compacted material as defined herein,

ii) optionally in admixture with one or more pharmaceutically acceptable excipients or additives and/or one or more active substances, and

iii) compressing the material into tablets

Generally, the compression force used for tabletting in step iii) is adjusted according to the diameter of the tablet and the desired height such that when the tablet has a diameter of about 16mm or is in the shape of a capsule (9.4 x 18.9 mm) and the height obtained is at most about 10mm, such as at most about 9mm, at most about 8mm or at most about 7mm, at most about 6mm or at most about 5mm, the compression force applied is at most about 80kN, such as at most 70kN, at most 60kN, at most 50kN, at most about 40kN, at most about 30kN or at most about 20 kN.

In particular, the present invention relates to a process for preparing a tablet comprising:

i) calcium carbonate, calcium phosphate or a mixture thereof,

ii) sorbitol and/or isomalt (which may comprise maltitol and/or xylitol in other embodiments),

iii) vitamin D, and

iv) optionally one or more pharmaceutically acceptable excipients.

The tablet may contain:

i) from about 50% to about 95% w/w calcium carbonate,

ii) from about 5 to about 40% w/w sorbitol and/or isomalt,

iii) from about 0.01 to about 1% w/w vitamin D, and

iv) optionally one or more pharmaceutically acceptable excipients, provided that the total amount of ingredients corresponds to about 100% w/w.

Calcium-containing compounds

The calcium-containing compound comprised in the pre-compacted material manufactured according to the invention is a physiologically tolerable calcium-containing compound having therapeutic and/or prophylactic activity.

Calcium, in the form of ionized calcium and calcium complexes, is essential for many important functions in the body (Campell AK. Clin Sci 1987;72: 1-10). The behavior and growth of cells are regulated by calcium. Calcium, together with troponin, controls contraction and relaxation of muscle (Ebashis. Proc R Soc Lond 1980;207: 259-86).

Calcium selective channels are a common feature of cell membranes, and electrical activity of neural tissue and firing of neurosecretory granules are a function of the balance between intracellular and extracellular calcium levels (Burgoyne RD. Biochim Biophys Acta 1984;779: 201-16). Secretion of hormones and the activity of key enzymes and proteins is calcium dependent. Finally, calcium imparts rigidity and strength to bone in the form of calcium phosphate complexes (Boskey AL. Springer,1988: 171-26). Since bone contains more than 99% of the total calcium in the body, calcium in bone also serves as the primary long-term calcium reservoir.

Calcium salts such as calcium carbonate or calcium phosphate are used as a calcium source, particularly 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 in the body of mammals, particularly humans. Furthermore, chronic low calcium intake causes osteopenia (osteopenia) in many animal models. Osteopenia affects cancellous bone more than cortical bone and may not be completely reversible upon calcium supplementation. If the animal is growing, reduced calcium intake will result in stunted growth. In a premature human neonate, the higher the calcium intake, the greater the increase in bone calcium accretion, if high enough, may be equal to pregnancy calcium retention. During growth, chronic calcium deficiency causes rickets. Bone mass is increased in healthy children supplemented with calcium both before and after puberty. The higher the intake of calcium in adolescents, the more calcium is retained, with the highest retention occurring immediately after menarche. Taken together, these data indicate that peak bone mass is optimized by calcium supplementation in the diet in children and adolescents considered to ingest sufficient amounts of calcium. The mechanism involved in the optimal accumulation of calcium in bone during growth is not known. It is likely that the intrinsic nature of the mineralization process ensures optimal calcification of osteoids in situations where calcium supply is high. The factors that cause growth arrest in calcium deficient conditions are also unclear, but growth factors that regulate bone size are clearly involved.

In adults, calcium supplementation reduces the rate of bone loss associated with aging (Dawson-Hughes B. am J Clin Nut 1991;54: S274-80). Calcium supplementation is important for individuals who cannot or will not obtain optimal calcium intake from food. In addition, calcium supplementation is important for the prevention and treatment of osteoporosis.

In addition, calcium may have an anticancer effect in the colon. Several preliminary studies have shown that a high calcium diet or intake of calcium supplements is associated with reduced colorectal cancer. There is increasing evidence that calcium, together with acetylsalicylic Acid (AS) and other non-steroidal anti-inflammatory drugs (NSAIDS), reduces the risk of colorectal cancer.

Recent studies have shown that calcium may be able to alleviate premenstrual syndrome (PMS). Some researchers believe that disruption of calcium regulation is a potential factor in the development of PMS syndrome. In one study, three menstrual cycles were followed for half of the 446 premenopausal female groups from the entire united states and 1200mg calcium was supplemented daily throughout the cycle. The final results showed that 48% of women taking placebo had PMS-related syndrome. While the proportion of women receiving calcium tablets is only 30%.

Calcium salts such as calcium carbonate are used in tablets, which are usually in the form of chewable tablets due to the high doses of calcium required. It is a challenge to formulate, for example, chewable tablets containing calcium salts while providing the tablets with a pleasing taste and an acceptable mouthfeel without the characteristic noticeable taste and sensation of chalk.

The calcium-containing compound used in the present invention may be, for example, bisglycinate (bisglycinate), calcium acetate, calcium carbonate, calcium chloride, 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 tartrate, calcium stearate and tricalcium phosphate. Other calcium sources may be water soluble calcium salts or complexes such as calcium alginate, calcium-EDTA and the like or organic compounds containing calcium such as organic calcium phosphates. The use of bone meal, dolomite and other unrefined calcium sources is discouraged because these sources may contain lead and other toxic contaminants. However, if these sources are purified to the desired extent, they may also be suitable.

The calcium-containing compounds may be used alone or in combination with other calcium-containing compounds.

Of particular interest are bisglycinate (bisglycinate), calcium acetate, calcium carbonate, calcium chloride, 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 tartrate, calcium stearate and tricalcium phosphate. Mixtures of different calcium-containing compounds may also be used. As shown in the examples herein, calcium carbonate and calcium phosphate are particularly suitable for use as the calcium-containing compound, and calcium carbonate, tricalcium phosphate (Ca)₅(PO₄) OH) and beta-tricalcium phosphate (Ca)₃(PO₄) Has a high calcium content, however dicalcium phosphate (CaHPO)₄) Has a lower calcium content but can be used at high density specifications.

Of particular interest are calcium carbonate and calcium phosphate.

In general, tablets prepared according to the invention contain an amount of the calcium-containing compound corresponding to from about 100 to about 1000mg Ca, such as from about 150 to about 800mg, from about 200 to about 700mg, from about 200 to about 600mg or from about 200 to about 500mg Ca.

Calcium carbonate

Calcium carbonate can be in three different crystal structures: calcite, aragonite and vaterite (vaterite). Mineralogically, they are specific mineral phases that involve a unique arrangement of calcium, carbon and oxygen atoms in the crystal structure. These unique phases affect the shape and symmetry of the crystalline form. For example, calcite can have four different shapes: scalenohedron, prismatic, spherical and orthorhombic, the aragonite crystals may be obtained in the form of, for example, isolated or clustered needles. Other shapes exist, such as cube-shaped (Scoralite 1A + B from Scora).

As shown in the examples herein, a particularly suitable calcium carbonate specification is calcium carbonate having an average particle size of 60 μm or less, for example 50 μm or less or 40 μm or less.

Furthermore, the calcium carbonate of interest is of a size having a bulk density below 2 g/mL.

Calcium carbonate 2064Merck (available from Merck, Darmstadt, Germany) has an average particle size of 10-30 μm, an apparent bulk density of 0.4 to 0.7g/mL and 0.3m²Specific surface area per gram;

calcium carbonate 2069Merck (available from Merck, Darmstadt, Germany) has an average particle size of about 3.9 μm, an apparent bulk density of 0.4 to 0.7 g/mL;

scoralite1A (obtained from Scora Watrigant SA, France) had an average particle size of 5-20 μm, an apparent bulk density of 0.7 to 1.0g/mL and 0.6m²Specific surface area per gram;

scoralite1B (obtained from Scora Watrigant SA, France) had an average particle size of 10-25 μm, an apparent bulk density of 0.9 to 1.2g/mL and an apparent bulk density of 0.4-0.6m²Specific surface area per gram;

scoralite1A + B (obtained from Scora Watrigant SA, France) having an average particle size of 7-25 μm, an apparent bulk density of 0.7 to 1.2g/mL and an apparent bulk density of 0.35-0.8m²Specific surface area per gram;

pharmacarb LL (available from Chr. Hansen, Mahawah New Jersee) has an average particle size of 12-16 μm, an apparent bulk density of 1.0 to 1.5g/mL and an apparent bulk density of 0.7m²Specific surface area per gram;

sturcal H (obtained from Specialty Minerals, Bethlehem, Pensylvania) has an average particle size of about 4 μm, an apparent bulk density of 0.48 to 0.61 g/mL;

sturcal F (available from Specialty Minerals, Bethlehem, Pensylvania) has an average particle size of about 2.5 μm, an apparent bulk density of 0.32 to 0.43 g/mL;

sturcal M (obtained from Specialty Minerals, Bethlehem, Pensylvania) has an average particle size of 7 μ M, an apparent bulk density of 0.7 to 1.0g/mL and a 1.5M²Specific surface area per gram;

sturcal L (available from Specialty Minerals, Bethlehem, Pensylvania) having an average particle size of about 7 μm, an apparent bulk density of 0.78 to 0.96g/mL, consisting of scalenohedral shaped crystals;

socal P2PHV (obtained from Solvay, Brussels, Belgium) has an average particle size of 1.5 μm, an apparent bulk density of 0.28g/mL and 7.0m²Specific surface area/g, SocalP2PHV is composed of scalenohedral shaped crystals;

mikhart10, SPL, 15, 40, and 65 (available from Provencale, France);

mikhart10 had an average particle size of 10 μm,

mikhart SPL had an average particle size of 20 μm,

mikhart15 had an average particle size of 17 μm,

mikhart40 had an average particle size of 30 μm, an apparent bulk density of 1.1 to 1.5 g/mL;

mikhart65 had an average particle size of 60 μm, an apparent bulk density of 1.25 to 1.7 g/mL;

hubercal Elite500 (obtained from J.M. Huber Corp., USA) has an average particle size of 5.8 μm and 1.8m²Specific surface area per gram;

hubercal Elite500 (obtained from J.M. Huber Corp., USA) has an average particle size of 8.2 μm and 1.3m²Specific surface area per gram;

omyapure35 (obtained from Omya S.A.S., Paris, France) had an average particle size of 5-30 μm and 2.9m²Specific surface area per gram;

calci Pure250Heavy, Calci Pure250Extra Heavy and Calci Pure GCC HD212 has a mean particle size of 10-30 μm, an apparent bulk density of 0.9 to 1.2g/mL and an apparent bulk density of 0.7m²Specific surface area per gram (obtained from Particle Dynamic inc., st. louis Montana).

Calcium phosphate

DI-CAFOS A（CaHPO₄) (available from Chemische Fabrik Buddenheim KG, Buddenheim, Germany) has an average particle size of about 70 μm, a bulk density of about 1.3g/mL and a polycrystalline porous nature;

DI-CAFOS PA（CaHPO₄) (available from Chemische Fabrik Buddenheim KG, Buddenheim, Germany) has an average particle size of less than 7 μm and a bulk density of about 0.9 g/mL;

TRI-CAFOS P（Ca₅(PO₄)₃OH) (available from Chemische Fabrik BuddenheimKG, Buddenheim, Germany) has an average particle size of less than 6 μm, a bulk density of about 0.25g/mL and a polycrystalline porous nature;

TRI-CAFOS S（Ca₅(PO₄)₃OH) (available from Chemische Fabrik BuddenheimKG, Buddenheim, Germany) has an average particle size of about 70 μm and a bulk density of about 0.5 g/mL;

CAFOS DB（Ca₃(PO₄)₂) (available from Chemische Fabrik Buddenheim KG, Buddenheim, Germany) has an average particle size of less than 5 μm and a bulk density of about 0.6 g/mL;

other specifications, provided they have polycrystalline and porous properties, may also be suitable for use in the present invention.

The content of the calcium-containing compound in the tablets prepared according to the invention is in the range of about 40% to about 100% w/w, such as from about 45% to about 98% w/w, from about 50% to about 95% w/w, from about 55% to about 90% w/w, or at least about 60% w/w, at least about 65% w/w, at least about 70% w/w or at least about 75% w/w.

In general, the dosage of calcium for therapeutic or prophylactic purposes ranges from about 350mg per day (e.g., newborn) to about 1200mg per day (lactating women). The amount of the calcium-containing compound in the tablet may be adjusted such that the tablet is suitable for administration 1-4 times a day, preferably 1-2 times a day.

As mentioned above, the granulate obtained by the process of the invention may be used directly, but it is also very suitable for further manufacture into solid dosage forms such as tablets, capsules or sachets.

Those skilled in the art will know how to adjust the composition and various processing parameters to obtain the desired calcium-containing product.

In one embodiment of the invention, it is intended that the granulate obtained by the process of the invention is processed into tablets. Typically, it is necessary to add one or more pharmaceutically acceptable excipients (e.g. lubricants) to avoid sticking or to increase the flowability of the particles obtained. Thus, the method may further comprise the step of mixing the obtained granulate with one or more pharmaceutically acceptable excipients.

In case it is desired to include other active substances than the calcium-containing compound, the method of the invention may further comprise the step of adding one or more therapeutically, prophylactically and/or diagnostically active substances to the obtained granulate.

Such materials include one or more nutrients such as one or more vitamins or minerals. In a particular embodiment, the further active substance is a D-group vitamin, for example vitamin D₃Vitamin D₂Or a derivative thereof.

D vitamins or other actives

Prepressing obtained by the inventionThe solid material as well as the tablets may contain other substances with therapeutic and/or prophylactic activity. Of particular interest are one or more D vitamin compounds. A non-limiting example is dry vitamin D from Roche₃100CWS and Dry vitamin D from BASF₃100GFP。

The pre-compacted material or tablet prepared according to the invention may contain other substances with therapeutic and/or prophylactic activity or it may contain one or more nutrients such as one or more vitamins or minerals. Of particular interest are, for example, vitamin B, vitamin C, vitamin D and/or vitamin K, as well as minerals such as zinc, magnesium, selenium and the like.

Of particular interest are one or more D-group vitamin compounds, such as vitamin D₂(ergocalciferol) and vitamin D₃(Cholcitonin) including dry vitamin D from Roche₃100CWS and Dry vitamin D from BASF₃100GFP。

In addition to its effects on calcium and bone homeostasis, vitamin D is involved in the regulation of several important systems in the body. The action of vitamin D on the genome is via 1,25- (OH) produced mainly in the kidney₂The formation of complexes of vitamin D with Vitamin D Receptors (VDRs). The latter are widely distributed in many types of cells. 1,25- (OH)₂The vitamin D/VDR complex has important regulatory functions in cell differentiation and immune system. Some of these effects may depend on local production of 1,25- (OH) by tissues other than the kidney₂The ability of vitamin D to function as paracrine (Adams JS et al, Endocrinology 1996;137: 4514-7).

In humans, vitamin D deficiency leads to rickets in children and osteomalacia in adults. The basic abnormality is a delay in the rate of osteoid mineralization, as it is laid down by osteoblasts (Peacock M. London Livingstone,1993: 83-118). It is not clear that this delay is due to 1,25- (OH) in osteoblasts₂Vitamin preparationFailure of the D-dependent mechanism is also due to the reduced supply of calcium and phosphorus caused by malabsorption, or due to the combined action of the two. With a delay in mineralization, there is a reduced calcium and phosphorus supply, severe secondary hyperparathyroidism with hypocalcemia and hypophosphatemia, and an increase in bone turnover.

Vitamin D insufficiency, the preclinical manifestations of vitamin D deficiency, also leads to reduced calcium supply and secondary hyperparathyroidism, albeit to a milder extent than that found in vitamin D deficiency. If this condition is maintained, chronic osteopenia may result. This hidden biochemical process in a calcium deficient state may be 1,25- (OH)₂Inappropriate levels of vitamin D are due to a reduction in its substrate, 25-OHD (Francis RM et al, Eur J Clin Invest 1983;13: 391-6). Vitamin D deficient states are most commonly found after middle age. With age, 25-OH vitamin D in serum is reduced due to a reduction in sun exposure and possibly due to a reduction in skin synthesis. In addition, after middle age, the disorder is exacerbated by a decrease in calcium uptake and an abnormal decrease in calcium absorption. Kidney 1,25- (OH) caused by decrease in renal function with aging₂Reduction of vitamin D production may also be a contributing factor. There have been many studies on the effect of vitamin D supplementation on bone loss after middle age. Some of them had no calcium added, others had calcium added. Studies have shown that although the addition of vitamins is necessary to reverse deficiencies and inadequacies, it is more important to consider the extent to which calcium supplementation is provided to the bone, since most bone defects are calcium deficiencies. In the literature based on clinical trials, recent findings indicate that higher doses of vitamin D tend to be required for patients after middle age (Compston JE. BMJ 1998;317: 1466-67). A published quasi-randomized study with annual injections of 150.000-300.000IU of vitamin D (equivalent to about 400-.

As shown above, the combination of calcium and vitamin D is valuable. Calcium and vitamin D₃The daily Recommended Allowance (RAD) is as follows (European Committee, Report on osteoporosis in the European Community: preventive action for prevention in the European Community office of office from office publications of the European Community, Luxembourg 1998):

RDA of calcium varied in different countries and was re-evaluated in many countries.

Vitamin D is very sensitive to moisture and is easily degraded. Thus, vitamin D is typically placed in a protective matrix. Therefore, when preparing tablets containing vitamin D, it is of utmost importance that the compression force applied during the tabletting step does not reduce the protective effect of the matrix and thereby impair the stability of the vitamin D. For this reason, combining various different ingredients in the granulate or tablet prepared according to the invention has proved to be very suitable in those cases where vitamin D is also incorporated in the formulation, since it enables the use of relatively low compression forces during tabletting and still enables tablets with suitable mechanical strength (crushing strength, friability, etc.) to be obtained.

In a particular embodiment, the present invention provides a tablet comprising:

i) a calcium-containing compound as an active substance,

ii) vitamin D, and

iii) optionally one or more pharmaceutically acceptable excipients or active substances.

More specifically, the tablet may contain:

i) at least 200mg of a calcium-containing compound (typically in the range of 200 and 1500 mg)

ii) at least 5 μ g of vitamin D (typically in the range 5-100 μ g, 1 μ g =40 IU), and

iv) optionally one or more pharmaceutically acceptable excipients or active substances.

In a particular embodiment, the present invention provides a tablet comprising:

i) from about 50% to about 90% w/w of a calcium-containing compound,

ii) from about 0.00029% to about 0.0122% w/w of vitamin D, and

iii) optionally one or more pharmaceutically acceptable excipients or active substances, as long as the total amount of the ingredients corresponds to about 100% w/w.

In particular, the tablet may comprise:

i) from about 50% to about 90% w/w of a calcium-containing compound,

ii) from about 5 to about 40% w/w sweetener

iii) from about 0.12% to about 4.9% w/w vitamin D comprising a protective matrix,

iv) optionally one or more pharmaceutically acceptable excipients or active substances, as long as the total amount of the ingredients corresponds to about 100% w/w.

Pharmaceutically acceptable excipients

In the present context, the term "pharmaceutically acceptable excipient" refers to any inert substance, inert in the sense that it does not itself have any therapeutic and/or prophylactic effect. Pharmaceutically acceptable excipients may be added to the active drug substance in order to be able to obtain pharmaceutical compositions with acceptable technical properties. Although pharmaceutically acceptable excipients may have some effect on the release of the active drug substance, materials used to achieve modified release are not included in this definition.

The calcium-containing compound and the sugar alcohol may also be mixed with one or more pharmaceutically acceptable excipients before or after the roller compaction. Such excipients include excipients commonly used in the formulation of solid dosage forms, such as fillers, binders, disintegrants, lubricants, flavoring agents, coloring agents, including sweetening agents, pH adjusting agents, stabilizing agents, and the like.

Generally, the disintegrant is selected from: croscarmellose sodium (a cross-linked polymer of sodium carboxymethylcellulose), polyvinylpyrrolidone, starch NF, polacrilin sodium or potassium, and sodium starch glycolate. Those skilled in the art will recognize. For a compressible tablet, disintegration within 30 minutes is desirable, more desirably within 10 minutes, and most desirably within 5 minutes; thus, the disintegrant used preferably results in disintegration of the tablet within 30 minutes, more preferably within 10 minutes, most preferably within 5 minutes.

Examples of disintegrants that can be used are e.g. cellulose derivatives, including microcrystalline cellulose, low substituted hydroxypropyl cellulose (e.g. LH 22, LH 21, LH 20, LH 32, LH 31, LH 30); starches, including potato starch; cross-linked sodium carboxymethylcellulose (i.e. cross-linked polymers of sodium carboxymethylcellulose), e.g.(ii) a Alginic acid or alginates; insoluble polyvinylpyrrolidones (e.g. polyvinylpyrrolidone)XL-10); sodium carboxymethyl starch (e.g. sodium carboxymethyl starch)And

fillers that may be includedThe/diluent/binder is for example polyol, sucrose, sorbitol, mannitol, erythritolTagatoseLactose (e.g. spray-dried lactose, alpha-lactose, beta-lactose,of various different classesMicrotose orMicrocrystalline cellulose (e.g. of various grades)Such asPH101、PH102 orPH105、P100、Andhydroxypropyl cellulose, L-hydroxypropyl cellulose (low substituted) (e.g. L-HPC-CH31, L-HPC-LH11, LH 22, LH 21, LH 20, LH 32, LH 31, LH 30), dextrin, maltodextrin (e.g. L-HPC-CH31, LH 32, LH 31, LH 30)5 and10) starch or modified starch (including potato starch, corn starch and rice starch), sodium chloride, sodium phosphate, calcium sulfate, calcium carbonate.

In the pharmaceutical preparations prepared according to the invention, microcrystalline cellulose, L-hydroxypropyl cellulose, dextrin, maltodextrin, starch and modified starch may be particularly suitable.

In a particular embodiment, the calcium-containing compound may be roller compacted with one or more pharmaceutically acceptable binders, or the binder may be added after roller compaction. Suitable binders include those commonly used in the pharmaceutical arts, although binders commonly used in wet granulation may not function to the same extent in the substantial absence of liquid during agglomeration.

More specifically, examples include

Cellulose derivatives including methylcellulose, hydroxypropyl cellulose (HPC, L-HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), sodium carboxymethylcellulose (Na-CMC), etc.;

mono-, di-, oligo-, polysaccharides including dextrose, fructose, glucose, isomaltose, lactose, maltose, sucrose, tagatose, trehalose, inulin, and maltodextrin;

polyols include sugar alcohols such as lactitol, maltitol, mannitol, sorbitol, xylitol and inositol;

the polyvinylpyrrolidone includes Kollidon K30, Kollidon 90F or Kollidon VA64, and

proteins, including casein.

Glidants and lubricants that may be included are, for example, stearic acid, metallic stearates, talc, waxes and glycerides with high melting temperatures, colloidal silica, sodium stearyl fumarate, polyethylene glycol and alkyl sulfates.

Surfactants that may be used are, for example, nonionic (e.g., polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, glyceryl monooleate and polyvinyl alcohol), anionic (e.g., sodium docusate and sodium lauryl sulfate), and cationic (e.g., benzalkonium chloride, benzethonium chloride and cetyltrimethylammonium bromide) or mixtures thereof.

Other suitable pharmaceutically acceptable excipients may include coloring agents, flavoring agents, and buffering agents.

The invention also provides a method comprising the step of processing pre-compacted material obtained by roller compaction into a solid dosage form, as appears from the claims. Such dosage forms may also be provided with a coating, so long as the coating does not substantially hinder the release of the active drug substance from the composition. Typically, a film coating may be used.

Suitable lubricants include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, and the like. Magnesium stearate is preferably used.

Suitable fillers include xylitol, mannitol, compressible sugar, lactose, calcium phosphate and microcrystalline cellulose.

Suitable artificial sweeteners include dextrose, fructose, glycerol, glucose, isomalt, lactitol, lactose, maltitol, maltose, mannitol, sorbitol, sucrose, tagatose, trehalose, xylitol, alitame, aspartame, acesulfame, cyclamic acid, cyclamate (e.g., calcium cyclamate, sodium cyclamate), neohesperidin dihydrochalcone, thaumatin, saccharin salts (e.g., ammonium saccharin, calcium saccharin, potassium saccharin, sodium saccharin), and mixtures thereof.

If desired, known perfumes and known FD & C colorants can be added to the composition.

Example 1

Comparison of regular-shaped and polycrystalline perforated calcium carbonate Compounds for roller compacted tablet base

The study is based on the following formulation:

TABLE 1 formulation of calcium carbonate based on regular shape

TABLE 2 formulation based on polycrystalline porous calcium carbonate

For all tests from 1 to 14, the sugar alcohol was broken up in a rocking sieve using 250 μm openings and then mixed with calcium carbonate in a high shear mixer (Fielder PM 25, using low stirring speed, without using a chopper) for 2 minutes.

The mixture was granulated on a roller mill (Gerteis 3W-Polygran). And finally manually lubricated with magnesium stearate.

Lamination is based on a device with embossing rollers and a controller. The key setting parameters are: gap Width (GW), force (F), Roll Speed (RS), and mesh size.

TABLE 3 Rolling compaction parameters

GW,mm	3.5
		F,kN/cm	12 15
RS,rpm	5
		Mesh size, mm	1.5

The granules were compressed on a fettep 1090 type tablet press equipped with a complete punch with an oval shape (18.9 x9.4 mm). The weight of the tablet was approximately 1,683 mg. The crush strength data for all processes were obtained using Schleuniger AT 4.

As can be seen from figure 1, for regular shaped calcium carbonate, the type and particle size of the sugar alcohol selected has a significant effect on the crushing strength. Preferred are sorbitol and isomalt having a fine particle size. The effect of different sugar alcohols on the crushing strength of tablets can be explained by the difference in compression properties shown in fig. 2. In this figure, the crushing strength of tablets based on only a single sugar alcohol has been measured. However, from figure 3, it can be seen that for irregularly shaped calcium carbonate, the type and particle size of the sugar alcohol becomes unimportant for practical applications. All tablets containing irregularly shaped calcium carbonate have a crushing strength which lies at or above the maximum obtained by using regularly shaped calcium carbonate together with the preferred sugar alcohol having a fine particle size.

The better compression properties of the polycrystalline porous calcium-containing compound observed when comparing the crushing strength of tablets based on regular-shaped and polycrystalline porous calcium carbonate may also be found when comparing the sieve analysis of matching particles, as shown in fig. 4. In this figure, a significantly higher amount of fines can be seen in batches containing regularly shaped calcium carbonate, which are particles smaller than 125 μm. Higher amounts of fines are due to less suitable compression properties.

Example 2

Comparison of tablets with different sugar alcohol content obtained based on Rolling of polycrystalline porous calcium carbonate Compound

The study is based on the following formulation. Test number

For all tests, the sugar alcohol was broken into pieces in a rocking sieve using 250 μm mesh and then manually mixed with calcium carbonate.

For all tests, the mixture was granulated on a roller mill according to example 1.

For all tests, magnesium stearate (0.3%) lubrication was performed manually.

The granules were tabletted on a fettep 1090 type tablet press equipped with a complete punch with an oval shape (18.9 x9.4 mm). The weight of the tablets was adjusted so that the height of the tablets reached 7.0. + -. 0.1 mm. The crush strength data for all processes were obtained using Schleuniger AT 4.

As can be expected from example 1, the compression properties given by using xylitol at a concentration of about 25% are the same as those seen when using regular-shaped calcium carbonate and sorbitol having the optimum particle size, i.e. a somewhat smaller size than "current sorbitol".

Xylitol concentrations of 5% and 10% resulted in somewhat lower optimum compression properties, as evidenced by the need to use higher impact forces to achieve suitable crush strengths. This means that the use of calcium carbonate with a polycrystalline porous structure enables the addition of xylitol in sufficiently large amounts to be able to have an effect on the sensory properties of the tablet. The addition of xylitol is desirable because the sensory properties of Sturcal L are significantly poorer than those obtained when using Scoralite.

Further discussion of the compression properties will continue in example 6.

Example 3

Comparison of tablets obtained based on Rolling of calcium phosphate-containing Compounds

The addition of xylitol is desirable because the sensory properties of tablets containing calcium phosphate are significantly poorer than those of tablets containing Scoralite. In this case, it would be clearly advantageous if the concentration of xylitol could be varied with only limited or no effect on the crushing strength of the tablets. This means that the full influence of the taste properties can be masked with xylitol. This is a challenge because, as seen in example 1, FIG. 2, xylitol is a sugar alcohol with poor compression properties.

The study is based on the following formulation:

table 1, calcium phosphate based formulation. Test number

Psd average particle size based on D (v;0.5)

DC can be directly compressed

For all experiments, the sugar alcohol was broken up in a rocking sieve using 250 μm mesh and then manually mixed with calcium phosphate.

For trials No. 15 to 29, the mixture was granulated on a roller mill as described in example 1. For trials from 30 to 39, no granulation of the mixture is required in order to obtain easy tabletting granules, since the calcium-containing compound is directly compressible to specification (DC).

For all tests, magnesium stearate (0.3%) lubrication was performed manually.

The granules were tabletted on a fettep 1090 type tablet press equipped with a complete punch with an oval shape (18.9 x9.4 mm). The weight of the tablets was adjusted so that the height of the tablets reached 7.0. + -. 0.1 mm. The crush strength data for all processes were obtained using Schleuniger AT 4.

As can be seen from fig. 5, a lower main compression force is required to obtain the same crushing strength as when using regular shaped calcium carbonate and sorbitol with the optimum particle size (test 2) when using Tri-Cafos P-sized tricalcium phosphate. This is true even when the calcium phosphate is diluted with a sugar alcohol having poor compression properties (see example 1, fig. 2). Furthermore, no significant effect of the concentration of xylitol on crushing strength was observed.

As can be seen from fig. 6, when the calcium-containing compound is Dicafos PA, an approximately doubled amount of sugar alcohol is required in order to obtain a tablet having a crushing strength comparable to that of test 2. This is due to the poor compression properties of xylitol as shown in figure 2 and the fact that xylitol cannot be subdivided during compression as in sorbitol.

Furthermore, Dicafos PA used in fig. 6 is an irregularly shaped calcium-containing compound (see fig. 22). Therefore, in order to be able to crush the calcium-containing compound and the sugar alcohol, irregularities of the calcium-containing compound are insufficient. As described herein, it is important that the calcium-containing compound has polycrystalline and porous properties. As can be seen from fig. 6A, Dicafos PA is itself compacted, i.e. it does not have a porous structure. Furthermore, Dicafos PA is not polycrystalline.

When comparing fig. 6 and 5, it can be seen that Dicafos PA has poorer compression properties than Tricafos P. This is further illustrated in example 6.

As can be seen from fig. 7, the use of Cafos DB sized β -tricalcium phosphate produced particles with poor compression properties. As a result, it was impossible to obtain satisfactory tablets from tests 25 to 27, and the tablets obtained from tests 28 to 29 were burst (capping). This is further discussed in example 6.

As can be seen from fig. 8, a xylitol concentration less than or equal to 25% will result in tablets with good compression properties. Xylitol concentrations of up to 25% have no effect on crushing strength, but a concentration of 40% allows the tablets to be top-cracked under high main compression forces. When a xylitol/sorbitol mixture of a high concentration of sugar alcohol is used, it cannot be compressed at all. This is further discussed in example 6.

As can be seen from figure 9, all tablets produced when xylitol at the concentration used was mixed with Di-Cafos a sized dicalcium phosphate were comparable to tablets produced based on granules when regular shaped calcium carbonate and sorbitol with the optimum particle size were used (the inventors have previously found that sorbitol with an average particle size much smaller than the average particle size of "current sorbitol", is more suitable for use when compressed with regular shaped calcium-containing compounds). The xylitol/sorbitol mixture has better compression properties. This is further discussed in example 6.

Based on this example, the inventors have surprisingly found that not all sizes of calcium phosphate are equally easy to use for roller compaction. The polycrystalline nature and porosity have a major impact on whether crushing of calcium phosphate is possible.

Example 4

Comparison of tablets obtained based on Rolling of calcium phosphate-containing Compounds with and without sugar alcohols

The study is based on the following formulation:

table 1, calcium phosphate based formulation. Test No

Psd average particle size based on D (v;0.5)

Tri-Cafos P in trial 46 was roller compacted using the same parameters as in example 1. Lubrication and tableting were also performed as in example 1. Tests 15 and 19 are described in example 3.

As can be seen in FIG. 11, the addition of an excipient having poor compression properties, such as xylitol seen in FIG. 2 of example 1, produced tablets having poor crushing strength.

The addition of xylitol in admixture with sorbitol, having optimal granulation, to tricalcium phosphate produced crushing strengths similar to those obtained using pure tricalcium phosphate.

Example 5

Sensory evaluation of tablets obtained based on the compaction of calcium phosphate compounds

Sensory evaluation was performed on tablets obtained from the following tests:

run 18 of example 3, containing tricalcium phosphate (Tri-Cafos P) and 40% xylitol

Tests 35, 36 and 37 of example 3, containing dicalcium phosphate (Di-Cafos A) and 5%, 10% and 25% xylitol, respectively

Sensory testing was performed by 7 trained persons. The tests were carried out according to ISO8587 (class test) and ISO5495 (pairing test).

The results of these evaluations are as follows:

for Di-Cafos A:

● 5% xylitol is not optimal for taste masking

● the variation of the xylitol content between 10 and 25% has no significant effect on the taste masking properties of xylitol.

● the large particle size of Di-Cafos A used resulted in a sand-like feel for all tablets tested.

For Tri-Cafos P:

● to obtain a similar taste masking to that observed in Di-Cafos A, a level of 40% xylitol was required.

● no sand-like feel was perceived due to the small particle size.

Example 6

Evaluation of the compression Properties of calcium phosphates with polycrystalline porous calcium carbonate based on SEM-analysis

The following conclusions can be drawn for the specification of the powder:

as can be seen from fig. 12-15, a cohesive tablet is obtained if the calcium-containing compound has an average particle size of about a few microns. Furthermore, each particle must be polycrystalline in nature resulting in a porous structure. As seen in example 2, fig. 10 and example 3, fig. 5, the use of Sturcal L (calcium carbonate) or Tricafos P (tricalcium phosphate) produced tablets with high crushing strength.

In contrast, as can be seen from fig. 18 and 19, the non-porous structured particles (Cafos DB, β -tricalcium phosphate) produced non-sticky tablets, exhibiting capping even at low pressures. Furthermore, the addition of less than 40% sugar alcohol did not produce a satisfactory tablet as described in example 3. Since Dicafos PA (dicalcium phosphate) also has a non-porous structure (see fig. 22 and 23), the same tendency of crushing strength is seen. In the case of high concentrations of xylitol, the crushing strength was slightly improved compared to Cafos DB, since the capping tendency was less pronounced.

For calcium of the directly compressible (dc) specification, the following conclusions can be drawn:

it can be seen from fig. 20 and 21 that even non-porous structured particles like Tricafos S (tricalcium phosphate) can produce tablets with high crushing strength if the calcium-containing compound used is dc-sized, as illustrated in example 3, fig. 8. This is probably because the breaking of the particles creates a new surface available for bonding. However, high concentrations of xylitol counteract this effect.

As can be seen from figures 16 and 17 in combination with figure 9 in example 3, if the dc specification consists of particles such as Dicafos a (dicalcium phosphate) which have polycrystalline nature and result in a porous structure, the tablet will have the same crushing strength as seen with porous particles such as Sturcal L and Tricafos P which have a size of a few microns.

From this example it can be concluded that in order to obtain a satisfactory tablet crushing strength when using a poor binder such as xylitol, the calcium-containing compound needs to have the following characteristics:

for calcium carbonate:

● polycrystalline grains

● the particles should have a porous structure

For calcium phosphates:

particles having an average particle size of a few microns

The particles should have a polycrystalline nature

The granules should have a porous structure

● DC size granules

The porous structure of the omicron particles is advantageous

Claims (4)

1. A pre-compacted material comprising one or more calcium-containing compounds and one or more sugar alcohols, wherein the calcium-containing compounds have a polycrystalline porous structure.

2. Use of a pre-compacted material as defined in claim 1 for the preparation of a solid dosage form.

3. A dosage form comprising a precompacted material as defined in claim 1, optionally together with one or more pharmaceutically acceptable excipients.

4. A method of preparing a pre-compacted material as defined in claim 1, the method comprising the steps of:

i) mixing one or more polycrystalline porous calcium-containing compounds with one or more sugar alcohols,

ii) rolling the mixture thus obtained.