HK1191864B

HK1191864B - Particulate comprising a calcium-containing compound and a sugar alcohol

Info

Publication number: HK1191864B
Application number: HK14105131.3A
Authority: HK
Inventors: Mathiesen Jacob; Martini Nielsen Carsten; Mohr Olsen Peder; Egon Bertelsen Poul
Original assignee: Dong Wha Pharm. Co., Ltd.
Priority date: 2004-05-24
Filing date: 2014-05-30
Publication date: 2017-06-09

Description

Microparticles comprising a calcium-containing compound and a sugar alcohol

This application is a divisional application of international application PCT/DK2005/000338 filed in china on 23.1.2007 under the application number 200580024852.3 entitled "microparticles comprising a calcium-containing compound and a sugar alcohol".

Technical Field

The present invention relates to particulate materials and solid dosage forms, in particular tablets, comprising a calcium-containing compound having a regular shape, such as a calcium salt, as therapeutically and/or prophylactically active substance and a pharmaceutically acceptable sugar alcohol having a microstructure as evidenced by SEM, such as e.g. sorbitol and/or isomalt (isomalt). The invention also relates to a process for preparing the particulate material and solid dosage form. The process involves agglomerating (aggregration) the calcium-containing compound and the pharmaceutically acceptable sugar alcohol by roll compaction (rolecrompction). The granulated material obtained by roller compaction is suitable for further processing the granulated material into, for example, tablets, such as chewable tablets.

The invention is based on the finding that the result of a coalescence process for the coalescence of a calcium-containing compound depends on the specific shape of the calcium-containing compound and the microstructure of the material used as binder in the coalescence process.

Background

Calcium is essential for many key effects in the body, in the form of ionized calcium and calcium complexes (Campelak. CIinSci1987;72: 1-10). Cell behavior and growth are regulated by calcium, which binds to troponin to control muscle contraction and relaxation (Ebashis. ProcRSocLond1980;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 (BurgoyneRD. Biochim Biophys acta1984;779: 201-16). The secretion of hormones and the activity of key enzymes and proteins is dependent on calcium. Finally, calcium, as a calcium phosphate complex, imparts rigidity and strength to bone (Boskey AL. Springer,1988: 171-26). Since bone accounts for more than 99% of the body's total calcium, skeletal calcium also serves as the primary long-term reservoir of calcium.

Calcium salts such as, for example, calcium carbonate are used as a source of calcium, particularly for patients suffering from and at risk of osteoporosis. In addition, calcium carbonate is used as an acid neutralizing agent in antacid tablets.

In addition, calcium also has anticancer effect in colon. Several preliminary studies have shown that a high calcium diet or intake of calcium supplements is associated with a reduction in colorectal cancer. There is increasing evidence that calcium in combination with aspirin (ASA) and other non-steroidal anti-inflammatory drugs (NSAIDS) can reduce the risk of colorectal cancer.

Recent studies have shown that calcium can alleviate premenstrual syndrome (PMS). Some researchers believe that disruption of calcium regulation is a fundamental factor in the development of PMS symptoms. In one study, half of the women followed three menstrual cycles and were given 1200mg of calcium supplement per day throughout the cycle in a 466 panel consisting of pre-menopausal women selected in the united states. The final results showed that 48% of the women receiving placebo had PMS-related symptoms. While only 30% of women receiving calcium tablets had PMS-related symptoms.

Calcium salts such as, for example, calcium carbonate are used in tablets, and due to the high doses of calcium required, such tablets are usually in the form of chewable tablets. It is a challenge to formulate chewable tablets that contain, for example, calcium salts and have a pleasant taste and an acceptable mouthfeel without the characteristic prominent chalky taste or sensation.

In addition, i) high doses of calcium carbonate (typically 300-. Adequate taste masking is another major challenge when formulating chewable tablets.

The inventors have found an easy way of producing e.g. chewable tablets comprising physiologically tolerable calcium-containing compounds by using granules comprising agglomerates (agglomerates) of the calcium-containing compounds. The granulate is obtained without the use of any solvent, such as water, but involves roller compaction of the calcium-containing compound to form agglomerates having suitable properties for further processing into solid dosage forms such as, for example, tablets.

EP0054333(stauffer chemical company) describes a process for compacting fine particles of calcium phosphate by roll compaction to give a powder. The resulting powder has a greater bulk density than the starting material, which makes it suitable as an excipient in the manufacture of pharmaceutical tablets. In contrast to EP0054333, the present invention does not employ roller compaction with the aim of increasing the bulk density of the pharmaceutically acceptable excipients, but rather employs a novel agglomeration process, i.e. the particles are structured into agglomerates to increase the average particle size to a size suitable for further processing of the material into e.g. tablets, such as e.g. chewable tablets with acceptable taste and/or mouthfeel.

The properties of calcium-containing compounds and the methods of preparing pharmaceutical compositions comprising calcium-containing compounds have previously been described to be of great importance for obtaining an acceptable taste and mouthfeel of chewable tablets (WO 00/28973). In contrast to WO00/28973, the method of the present invention does not employ a step of binding the particles together by a wet granulation process, which means that the method of the present invention can be advantageously employed when it is desired to introduce moisture sensitive substances. An example of such a substance is vitamin D, often included with calcium salts in pharmaceutical dosage forms. The present invention provides a simple and cost-effective alternative for obtaining such dosage forms without the need to involve steps such as wet granulation.

Drawings

Figure 1 shows the use of intragranular sorbitol, extragranular sorbitol or no sorbitol as a binder. Tablet hardness was studied as a function of compression force.

Fig. 2 shows the effect of compression force on the particle size distribution.

Fig. 3 shows the effect of changes in the particle size distribution of the granules on tablet hardness.

FIG. 4 shows the change in sorbitol particle size. Tablet hardness was studied as a function of compression force.

FIG. 5 shows the change in the amount of sorbitol and the addition of microcrystalline cellulose. Tablet hardness was studied as a function of compression force.

Figure 6 shows the effect of moisture content in the ambient air on tablet hardness.

FIG. 7 shows the effect of the addition of another sugar alcohol, maltitol, on tablet hardness.

FIG. 8 shows the effect of omitting the breaking of 38 μm sorbitol mass (lumbreaking) on tablet hardness.

Fig. 9 shows changes in the particle size distribution of the particulate matter. The effect of vitamin D3 was determined on samples taken during the tabletting process.

Figure 10 shows the effect of polyvidone K30 on tablet hardness.

FIG. 11 shows the effect of sugar alcohol type and particle size. Scoralite was used as the calcium source.

FIG. 12 shows the effect of sugar alcohol type and particle size. Merck2064 was used as the calcium source.

FIG. 13 shows the effect of extragranular mixtures of sorbitol of different particle sizes. Scoralite was used as the calcium source.

FIG. 14 shows the effect of particle size of intragranular or extragranular mixtures of sorbitol. Scoralite was used as the calcium source.

Fig. 15 shows SEM photographs of calcium carbonate crystals having a regular shape (Merck 2064 and Scoralite, respectively).

Fig. 16 shows SEM photographs of sugar alcohols having a microstructure (isomalt and sorbitol, respectively).

FIG. 17 shows SEM photographs of sugar alcohols (maltitol, xylitol, and mannitol, respectively) without microstructures.

FIG. 18 shows SEM photographs of roll compacted materials consisting of Scoralite and sorbitol, and Merck2064 and xylitol, respectively.

FIG. 19 shows compression properties of sugar alcohols.

Figure 20 shows the stability using Scoralite 1B.

FIG. 21 shows the stability using Merck 2064.

FIG. 22 shows the effect of mixing time on crush strength stability.

FIG. 23 shows a DVSMass plot of water absorption in the presence or absence of a super disintegrant (superdisintegrant).

Figure 24 shows the proper design and size of the tablet of the present invention.

Figure 25 shows how a tablet can be broken into two parts of substantially the same size by providing pressure at both ends. The tablet had the design shown in fig. 24.

Disclosure of Invention

It has surprisingly been found that roller compaction of a calcium-containing compound together with a pharmaceutically acceptable sugar alcohol having cohesive properties improves the pharmaceutical application properties of the compact thus obtained. As mentioned above, within the scope of the present invention, the use of roller compaction of the powder is used as an alternative to known granulation or granulation processes (i.e. wet granulation or direct compression using a dry binder in the preparation of tablets). The inventors have found that the process of roller compaction is a very gentle process which does not destroy the possibility of the resulting product having an acceptable mouthfeel and at the same time does not have an outstanding chalky taste or sensation. Generally, the purpose of roller compaction is to increase the bulk density of a particular substance or composition, for example to convert bulk material into a smaller volume of material that is more readily used to produce pharmaceutical compositions. To the best of the inventors' knowledge, roller compaction has not been used as a gentle granulation process for maintaining or not destroying the important properties of the material (i.e. the calcium-containing compound) in order to obtain acceptable taste, mouthfeel etc.

With the aim of producing small tablets with acceptable taste and mouthfeel, the inventors have found that the use of a pharmaceutically acceptable sugar alcohol as binding material in the agglomeration process is particularly suitable. However, in order to obtain the proper properties of the roll compacted composition comprising the calcium-containing compound, two main factors are important, namely the properties of the calcium-containing compound itself and the choice of sugar alcohol used as binder in the agglomeration process. To this end, the inventors have found that when using calcium-containing compounds with regular shapes (which themselves have very poor compressibility), it is important that the sugar alcohol used (in order to obtain an acceptable end result) has a microstructure, i.e. a structure that is capable of some deformation during the roll compaction process and is well distributed throughout the tablet, such that sufficient binding is established between the individual calcium (and sugar alcohol) particles.

In the context of the present invention, the term "having a regular shape" in relation to the calcium-containing compound is intended to denote a single particle having cubic crystals such as shown in fig. 15 herein with an approximately round or smooth surface as evidenced by SEM. Regular shapes result in a relatively low specific surface area, i.e. below 1.5m²/g。

In the context of the present invention, the term "microstructure" as used in relation to a sugar alcohol is intended to mean that a single crystal of the sugar alcohol is a polycrystal, such as a plurality of crystals or fibrous crystals comprising smaller units, i.e. the crystals have an identifiable substructure that can be detected by SEM (see, e.g., fig. 16 herein). The microstructure can be somewhat distorted during roller compaction and can be well distributed throughout the tablet, thereby establishing adequate bonding between the individual calcium (and sugar alcohol) particles. In addition, sufficient compressibility is required, see the examples herein.

In addition, contrary to the common general knowledge in the field of pharmaceutical preparations, the inventors found that it is not appropriate to use sugar alcohols of the standard nature generally recommended, such as sorbitol. The standard property has an average particle size of about 300 μm, but as shown in the examples herein, such an average particle size is too large to enable adequate distribution of sorbitol particles around the calcium-containing compound particles, resulting in tablets with unacceptable properties in terms of crushing strength. The particle size (e.g. of sorbitol) must be much smaller in order to obtain a good acceptable crushing strength.

Thus, the pharmaceutically acceptable sugar alcohols used in the present invention have an average particle size of at most about 150 μm, such as, for example, at most about 110 μm, at most about 100 μm, at most about 90 μm, at most about 80 μm, at most about 70 μm, at most about 60 μm, at most about 50 μm, at most about 40 μm, at most about 30 μm, at most about 20 μm or about 10 μm.

In a specific embodiment, the pharmaceutically acceptable sugar alcohol used has an average particle size of from about 5 to about 150 μm, such as, for example, from about 5 to about 110 μm, or from about 5 to about 80 μm.

Furthermore, it is expected that the use of e.g. sorbitol having a much smaller particle size will lead to stability problems, since it is well known that sorbitol is hygroscopic and that smaller particle sizes increase the surface area and thereby the risk of absorbing moisture from e.g. the surrounding environment. However, as described herein, tablets prepared using granulates obtained by roller compaction of a composition comprising a calcium-containing compound and sorbitol, e.g. having an average particle size well below 300 μm, have a stable crushing strength, i.e. the crushing strength of the tablets changes by at most 50%, such as e.g. at most about 40%, at most about 30%, at most about 20%, at most about 15%, at most about 10%, during the period starting from 5 days after production up to the rest of the storage period (e.g. 1 month, 3 months, etc.), when the tablets are stored in open petri dishes at 25 ℃ and 60% RH. The crushing strength of the tablets of the invention should be from about 70 to about 140N.

This improved stability indicates that the product obtained as described herein is suitable for so-called zone 3 or zone 4 countries (as defined in ICHQ 1F), i.e. countries with higher average temperature and relative humidity.

In one aspect, the present invention relates to a process for preparing a particulate material or a solid dosage form comprising one or more calcium-containing compounds having a regular shape as active substance and one or more pharmaceutically acceptable sugar alcohols having a microstructure, which process involves roller compaction of a composition comprising the calcium-containing compound and the sugar alcohol. The invention also relates to said granular material and to a solid dosage form based on the granular material. The sugar alcohols used have cohesive properties and preferably have sweetening properties, as is the case with sorbitol and isomalt.

To achieve satisfactory results, the sugar alcohol (binder) must be present in the particulate material at a concentration of at least about 5% w/w, such as, for example, at least about 10% w/w, at least about 15% w/w, or at least about 20%

The use of roller compaction as a means of agglomerating calcium-containing compounds to obtain a particulate material suitable for the preparation of e.g. chewable tablets with acceptable taste and mouthfeel has two key parameters, namely the shape of the calcium carbonate crystals and the structure of the sugar alcohol crystals. Furthermore, the pharmaceutically acceptable sugar alcohol (binder) is typically present at a minimum concentration of about 5% w/w or about 10% w/w.

In addition, it has also been observed that when a calcium-containing compound having a bulk density of at least about 0.7g/ml is employed, such as for example calcium carbonate in the form of Scoralite, then a composition (comprising the calcium-containing compound and sugar) which is subjected to roller compactionAlcohol) is not significantly higher than the bulk density of the calcium-containing compound itself (i.e. the bulk density before compaction by roll compaction). Therefore, when using this calcium carbonate, the bulk density before and after compaction by a roll cannot be changed much, i.e., by [ (d)_{Granular material}-d_{Calcium-containing compounds})/d_{Granular material}]× 100% the bulk density between the obtained granular material and the calcium-containing compound used varies by at most about 40%, such as, for example, at most about 30% or at most about 20%, calculated 100%.

As described above, the present invention relates to a granular material comprising one or more calcium-containing compounds having a regular shape as an active substance and one or more pharmaceutically acceptable sugar alcohols having a microstructure, typically, such granular material is further processed into convenient dosage forms such as tablets, and such tablets may have suitable technical properties for withstanding usual handling and the like, additionally, when chewable tablets are prepared, the tablets cannot be too hard, i.e. cannot have unacceptably high crushing strength, making them difficult for a patient to chew on, it is therefore important to balance the crushing strength to an acceptable extent³Or a slope of the correlation between greater compressive forces (measured in N).

The present inventors have found that the roller compaction process is very advantageous using pharmaceutically acceptable sugar alcohols having cohesive and sweetening properties. Examples of suitable binders or sweeteners include sorbitol, maltitol, xylitol, fructose, lactitol, isomalt, tagatose and mannitol. Sorbitol has a sweetening effect of 0.55 (compared to sucrose); maltitol has a sweetening effect of < 1; xylitol had a sweetening effect of 1, isomalt had a sweetening effect of <0.5, etc.

To ensure adequate distribution of the pharmaceutically acceptable sugar alcohol between the individual calcium-containing compound particles during roller compaction, the inventors have found that the binder should suitably have an average particle size of at most about 110 μm, such as, for example, at most about 100 μm, at most about 90 μm, at most about 80 μm, at most about 70 μm, at most about 60 μm, at most about 50 μm, at most about 40 μm, at most about 30 μm, at most about 20 μm or about 10 μm. Examples of such materials are sorbitol and isomalt.

In the literature (see pharmaceutical technology, volume1(tablettingtechnology), michael h. rubinstein (ed.), ellis horwood ltd,1987), it is stated that sorbitol has good tabletting properties and that mixing with this excipient will increase tablet strength. However, this document also states that in order to achieve this effect, sorbitol should have "transient" properties produced by spray drying. It has been described that 60-90% of the optimum particle size of "transient" sorbitol, as determined by sieve analysis, is between 212 and 500. mu.m. The recommended concentration in the tablet is 30-80%. However. In the context of the present invention, sorbitol can be used as a binder (with sweetening properties) in tablets based on roller compaction, and it is essential that there is a significant departure from the reported use of sorbitol:

sorbitol should be finely dispersed or distributed between the calcium-containing compound particles to ensure optimal or as good a binding as possible; this results in a limitation of the particle size of the sorbitol.

Is equivalent to D_0.5<A particle size of 100 μm sorbitol seems to be suitable. The particle size is measured using a MalvernMastersizer and is given as D (v; 0.5).

The concentration of sorbitol should exceed 5% w/w, and about 20% w/w seems to be good.

Sorbitol, having the "transient" properties described above, is completely ineffective if the above and relatively large particle size distribution is used.

In particular, two sugar alcohols have proven suitable for the roll compaction process, namely sorbitol and isomalt. However, it is expected that other sugar alcohols will also achieve properties that meet the above criteria, and such sugar alcohols are also contemplated as suitable for use in the present invention. The following are other sugar alcohols mentioned which meet the above criteria.

In particular embodiments, the sugar alcohol is sorbitol, particularly sorbitol having an average particle size of about 25 to about 50 μm, such as, for example, about 35 to about 45 μm, or about 30 to about 45 μm.

In another embodiment, the sugar alcohol is isomalt, particularly isomalt having an average particle size of about 20 to about 50 μm, such as, for example, about 25 to about 35 μm, or about 20 to about 35 μm.

As long as sugar alcohols meeting the above criteria are employed, it is possible to use one or more sugar alcohols which do not necessarily meet these criteria but have other effects such as acting as sweeteners. Such sugar alcohols are typically selected from mannitol, xylitol, maltitol, inositol and lactitol, and mixtures thereof. Examples are Sorbitols, Neosorb P100T, SorbideEx P1666B0, and SorbogamEnesCrystanene Sorbitol from RoquetteFreres, Cerestar, and SPIPolyols Inc., respectively; maltosorb p90 (maltitol) from roquettefres; xylitolCM50, FructofinCM (fructose) and LactotolCM 50 from DaniscoSeetecens; IsomaltST-PF, IsomaltDC100, GaioTagatose, and Manitol, available from Palatinit, ArlaFoods, and Roquette, Freres, respectively. Other examples of suitable sugar-based binders/sweeteners include sucrose, dextrose. It is of course also possible to add specific properties of sorbitol and isomalt which do not meet the above criteria.

In particular embodiments, the granular material of the present invention may comprise a mixture of sorbitol and xylitol. In this case, the weight ratio between sorbitol and xylitol is typically from about 1:0.1 to about 1:1.5, such as, for example, about 1:1. Mixtures of isomalt and xylitol are also suitable, and in this case the weight ratio between isomalt and xylitol is typically from about 1:0.1 to about 1:1.5, such as, for example, about 1:1.

The following paragraphs are given for the description of the calcium-containing compound. However, as previously described herein, the calcium-containing compound used in the roll compaction process of the invention has a regular shape, for example a calcium salt such as calcium carbonate with specific properties. In a preferred aspect, the calcium salt is calcium carbonate, particularly having a shape and average particle size corresponding to Scoralite1B or Merck 2064. In a particular embodiment, the calcium carbonate is Scoralite1B or Merck 2064.

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

Typically, the content of the regularly shaped calcium-containing compound in the particulate material is from about 40% to about 100% w/w, such as, for example, 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 granular material obtained by roller compaction may comprise 100% w/w of the calcium-containing compound, or it may constitute about 50% to about 90% w/w, such as e.g. 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 compaction by a roller.

As described above, during the roll compaction process, the calcium carbonate and the sugar alcohol are brought into close contact and the sugar alcohol crystals are squeezed between the calcium carbonate crystals due to the microstructure of the sugar alcohol crystals. Thus, SEM pictures of the particulate material when compressed into tablets show that the surface of the deformed particles of the pharmaceutically acceptable sugar alcohol is in close contact with the surface of the crystals of the one or more calcium-containing compounds.

The particulate material of the present invention may additionally comprise one or more pharmaceutically acceptable excipients or additives, or comprise one or more therapeutically, prophylactically and/or diagnostically active substances. A description of pharmaceutically acceptable excipients suitable for use in the context of the present invention is given herein.

A particular active substance of interest is vitamin D.

Further, roller compaction of the composition comprising the calcium-containing compound and the sugar alcohol to obtain the particulate material of the invention results in a particulate material having a flowability such that, when tablets are prepared from the particulate material optionally mixed with up to 10% w/w (such as, e.g., up to about 7.5% w/w or up to about 5% w/w) of a glidant using a tablet press running at least 300 tablets per minute, the variation in the quality of the tablets obtained meets the requirements in the european pharmacopoeia. The tablet press may operate, for example, at least 1000 tablets/minute, such as, for example, 2000 tablets/minute, 3000 tablets/minute, 4000 tablets/minute, 5000 tablets/minute, 6500 tablets/minute, and the like. The dwell time during the preparation of the tablets is at most about 1 second.

In a specific embodiment, the particulate material of the present 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 the pharmaceutically acceptable sugar alcohol, with the proviso that the sum does not exceed 100% w/w.

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

More specifically, it is preferred that the particulate material of the present invention comprises from about 65% to about 80% w/w of the calcium-containing compound, such as, for example, from about 70% to about 75% w/w; and about 15% to about 25% w/w sorbitol or isomalt or mixtures thereof, such as, for example, about 20 to about 25% w/w.

The granular material of the present invention may be used as such, but is generally formulated into a suitable solid dosage form. To prepare the dosage form, one or more pharmaceutically acceptable excipients may be added. The dosage forms are intended for oral administration, e.g., as single or multiple unit dosage forms, such as, for example, tablets, capsules, sachets, beads, pills, and the like.

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

In a particular embodiment, the tablet has a shape and size substantially as shown in figure 24 herein. The shape is specifically designed so that the tablet can be broken into two halves of substantially the same size, i.e. containing substantially the same amount of calcium. The disruption is provided by placing the tablet on a flat surface such as a table and then pressing each end of the tablet simultaneously using, for example, two fingers. This is possible because the tablet contacts the table at only one point.

The solid dosage form of the invention may comprise one or more calcium-containing compounds corresponding to about 300 to about 1200mg of calcium, such as for example corresponding to about 400 to about 600mg of calcium. Typically, the total concentration of the one or more calcium-containing compounds in the dosage form is from about 40% to about 99% w/w, such as, for example, 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 specific embodiments, the particulate material is included in the dosage form at a total concentration of about 65% to about 100% w/w, such as, for example, about 70% to about 98% w/w, about 75% to about 95% w/w, about 80% to about 95% w/w, or about 85% to about 95% w/w.

In another specific 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 the pharmaceutically acceptable sugar alcohol, with the proviso that the sum does not exceed 100% w/w. Alternatively, the solid dosage form comprises from about 60 to about 94% w/w of the calcium-containing compound, such as for example from about 65% to about 80% w/w of the calcium-containing compound; from about 5 to about 35% w/w of a pharmaceutically acceptable sugar alcohol, such as, for example, 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, with the proviso that the sum of the ingredients is equal to 100% w/w.

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

As mentioned herein before, the solid dosage form of the invention is stable. Thus, when the tablets are stored in open petri dishes at 25 ℃ and 60% RH, the crushing strength of the tablets changes by at most 50%, such as, for example, at most about 40%, at most about 30%, at most about 20%, at most about 15%, at most about 10%, during the time starting from 5 days after production and the rest of the storage period. Acceptable stability is obtained if the tablet has a crushing strength of about 70 to about 140N during the entire storage period (e.g., 1 month, 3 months) in an open petri dish.

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 such tablets of the invention must have acceptable taste in terms of sweetness, flavor and chalkiness as tested by a professional/technician sensory panel consisting of at least 6 testers.

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

The invention also relates to a process for the preparation of a particulate material as defined above, which process comprises roller compaction of a composition comprising a calcium-containing compound having a regular shape and one or more pharmaceutically acceptable sugar alcohols having a microstructure. The details presented in the appended claims and in the above description relating to the granular material relating to this aspect may be applied mutatis mutandis to this and other aspects of the invention.

A further aspect of the invention is to combine the production of granular 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 roll compactor.

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

i) the granular material as defined herein is prepared by,

ii) optionally mixing one or more pharmaceutically acceptable excipients or additives and/or one or more active substances, and

iii) compressing the material into tablets.

Typically, the compression of step iii) is performed under a pressure adjusted with respect to the diameter of the tablet and the desired height such that, when a tablet having a diameter of about 16mm or a capsule shape (9.4 x 18.9mm) is obtained and a height of at most about 10mm (such as, for example, about 9mm, about 8mm, or about 7mm, or about 6mm) is obtained, the pressure applied is at most about 80kN, such as, for example, at most 70kN, at most 60kN, at most 50kN, at most 40kN, at most 30kN, or at most 20 kN.

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

i) calcium carbonate,

ii) sorbitol and/or isomalt,

iii) vitamin D, and

iv) optionally one or more pharmaceutically acceptable excipients.

The tablet may comprise:

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

ii) about 5 to about 30% 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 the ingredients corresponds to about 100% w/w.

Calcium-containing compounds

The calcium-containing compound comprised in the particulate material produced according to the invention is a physiologically tolerated calcium-containing compound having therapeutic and/or prophylactic activity.

As mentioned above, calcium has many important roles in mammals, particularly humans. In addition, long-term low calcium intake leads to osteopenia in many animal models. Osteopenia affects cancellous bone more than cortical bone and cannot be completely reversed by calcium supplementation. Dysplasia results if the calcium uptake is reduced as the animal grows. In a premature human neonate, the higher the calcium uptake, the greater the increase in skeletal calcium, which if high enough may be equated with calcium retention during pregnancy. During growth, long-term calcium deficiency causes rickets. Calcium supplementation in healthy children before and after the puberty all resulted in increased bone mass. In adolescence, the higher the calcium intake, the greater the calcium retention, with the highest calcium retention just after the first menstruation. Taken together, these data suggest that peak bone mass can be optimized by supplementing a calcium-containing diet in children and adolescents who are thought to ingest sufficient calcium. The mechanisms involved in optimizing calcium deposition in bone during growth are unknown. They are probably an inherent property of the mineralization process, which ensures optimal calcification of osteoids (osteopoids) if the calcium supply is high. Factors affecting growth dysplasia in calcium deficiency are not known, but growth factors that regulate bone size are clearly involved.

Calcium supplementation will reduce the rate of age-related bone loss in adults (Dawson-Hughes B. AmJClinNut1991;54: S274-80). Calcium supplementation is important for individuals who cannot and will not achieve optimal calcium intake from food. In addition, calcium supplementation is important in the prevention and treatment of osteoporosis and the like.

The calcium-containing compound used in the present invention may be, for example, calcium bis (glycinate), calcium acetate, calcium carbonate, calcium chloride, calcium citrate malate, calcium cornate, calcium fluoride, calcium glubionate (calciumglubionate), calcium gluconate, calcium glycerophosphate, calcium hydrogen phosphate, calcium hydroxyapatite (calciumhydroxyyapatite), calcium lactate, calcium lactobionate (calciumlactobionate), calcium lactogluconate (calciumlactoglunate), calcium phosphate, calcium oxyprolinate (calciumpidolate), 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 calcium containing organic compounds such as e.g. calcium organophosphates. The use of bone meal, dolomite and other unrefined calcium sources is discouraged because these sources may contain lead and other toxic contaminants. However, such sources may also be used if purified to the desired extent.

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

Of particular interest are calcium bis (glycinate), 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 oxyprolinate, calcium stearate and tricalcium phosphate. It is also possible to use mixtures of different calcium-containing compounds, it being clear from the examples herein that calcium carbonate is particularly suitable as the calcium-containing compound and that calcium carbonate has a high calcium content.

Of particular interest is calcium carbonate.

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

Calcium carbonate

Calcium carbonate can have three different crystal structures: calcite, aragonite and spherulite (vaterite). Mineralogically, these are specific mineral phases that involve different arrangements of calcium, carbon and oxygen atoms in the crystal structure. These different phases affect the shape and symmetry of the crystalline form. For example, calcite is obtained in four different shapes: scalenohedral, prismatic, spherical and rhombohedral, and aragonite crystals are available as, for example, discrete or clustered needle-like shapes. Other shapes may also be obtained, such as for example a cubic shape (Scoralite1A + B from Scora).

As shown in the examples herein, a particularly suitable property of calcium carbonate is calcium carbonate having an average particle size of at most 60 μm, such as, for example, at most 50 μm or at most 40 μm.

In addition, the calcium carbonate of interest is characterized by having a bulk density of less than 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 (from ScoraWatriggantSA, France) has an average particle size of 5 to 20 μm, an apparent bulk density of 0.7 to 1.0g/mL and 0.6m²Specific surface area per gram;

scoralite1B (from ScoraWatriggantSA, France) had a mean particle size of 10-25 μmDegree, apparent bulk density of 0.9 to 1.2g/mL and 0.4 to 0.6m²Specific surface area per gram;

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

pharmacarll (from Chr. HansenMahawah, New Jerseries) L has an average particle size of 12-16 μm, an apparent bulk density of 1.0 to 1.5g/mL and 0.7m²Specific surface area per gram;

sturcal H has an average 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 about 2.5 μm, an apparent bulk density of 0.32 to 0.43 g/mL;

sturcal M has an average particle diameter of 7 μm, an apparent bulk density of 0.7 to 1.0g/mL, and 1.0m²Specific surface area per gram;

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

mikhart10 had an average particle size of 10 μm,

MikhartSPL had an average particle size of 20 μm,

mikhart15 had an average particle size of 17 μm,

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

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

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

socal P2PHV (available 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 per gram;

CalciPure250Heavy、Calthe CiPure250ExtraHeavy and CalciPureGCCHD212 have a mean particle size of 10-30 μm, an apparent bulk density of 0.9-1.2g/ml, and 0.7m²Specific surface area per gram (obtained from particle dynamic inc., st. louis montana).

The content of the calcium-containing compound in the tablets produced according to the invention is from about 40% to about 100% w/w, such as, for example, 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.

Typically, the dose of calcium for therapeutic and prophylactic purposes is from about 350 mg (e.g. neonate) to about 1200mg (lactating woman) per day. The amount of the calcium-containing compound in the tablet may be adjusted such that the tablet is suitable for administration 1-4 times per day, preferably 1 or 2 times per day.

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

The person skilled in the art knows how to adjust the composition and different process parameters to obtain the desired calcium-containing product.

In one embodiment of the invention, the granulate obtained by the process of the invention is intended to be tableted. It is often necessary to add one or more pharmaceutically acceptable excipients (such as lubricants) for avoiding sticking and/or increasing the flowability of the obtained granulate. Thus, the process may also comprise the step of mixing the granulate obtained with one or more pharmaceutically acceptable excipients.

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

These substances include one or more nutrients such as, for example, one or more vitamins or minerals. In a particular embodiment, the additional active substanceIs a D vitamin, such as, for example, D₃Vitamins, D₂A vitamin or a derivative thereof.

Vitamin D group or other active substances

The granular material as well as the tablets obtained according to the invention may comprise further therapeutically and/or prophylactically active substances. Of particular interest are one or more vitamin D group compounds. Non-limiting examples are dry vitamin D3,100CWS from Roche and dry vitamin D3100GFP from BASF.

The granulate or tablet prepared according to the invention may comprise further therapeutically and/or prophylactically active substances or it may contain one or more nutritional substances, such as, for example, 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, for example, zinc, magnesium, selenium and the like.

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

In addition to its calcium and bone effects, vitamin D is involved in regulating several important systems in the body. Vitamin D is produced by 1,25- (OH) mainly in the kidney₂The complex formed between vitamin D and Vitamin D Receptor (VDR) is treated with drugs at the genome. Vitamin D receptors are widely distributed in many cell types. 1,25- (OH)₂The vitamin D/VDR complex has important regulatory roles in cell differentiation and the immune system. Some effects may depend on the ability of certain tissues other than the kidney to produce 1,25- (OH) locally₂Vitamin D, and functions as a paracrine agent (AdamsJSecurity. Endocrinology1996;137: 4514-7).

In humans, vitamin D deficiency causes rickets in children and osteomalacia in adults. The underlying disorder is a mineral of osteoid regulated by osteoblastsDelay in rate of change (Peacock M. London Livingstone,1993: 83-118). It is unclear whether this delay is due to 1,25- (OH) in osteoblasts₂Disruption of vitamin D-dependent mechanisms or malabsorption due to reduced calcium and supplemental phosphate supply or both. With delayed mineralization, there is a decrease in calcium and phosphate supply, severe secondary hyperparathyroidism with hypocalcemia and hypophosphatemia, and an increase in bone turnover.

Vitamin D insufficiency, as a preclinical stage of vitamin D deficiency, also causes a decrease in calcium supply and secondary hyperparathyroidism, albeit to a lesser extent than when vitamin D deficiency is found. If this condition is maintained for a long period of time, osteopenia results. The biochemical process of the calcium deficient state is based on 1,25- (OH)₂Substrate for vitamin D25-reduction of OHD-induced 1,25- (OH)₂Vitamin D levels are inappropriate (Francis RMetal. EurJClinInvest1983;13: 391-6). Vitamin D deficient states are most commonly found in elderly people. With aging, serum 25-OH vitamin D decreases due to reduced sun exposure and possibly reduced skin synthesis. In addition, in the elderly, the condition is exacerbated by reduced calcium intake and plausible reduced calcium absorption. With aging, the decrease in renal function produces kidney 1,25- (OH)₂A reduction in vitamin D production may be a contributing factor. Many studies have focused on the effect of vitamin D supplementation on bone loss in the elderly. Some of the elderly did not supplement calcium, others did. From the studies it appears that although vitamin D supplementation is necessary to reverse deficiency and insufficiency, when bone is considered, it is more important to provide calcium supplementation because the major bone defect is calcium deficiency. In the literature based on clinical trials, recent findings suggest a trend towards older patients requiring higher doses of vitamin D (Compston JE. BMJ1998;317: 1466-67). An open pseudo-random study with annual injections of 150.000-300.000IU vitamin D (equivalent to about 400-.

From the above, it is known that the combination of calcium and vitamin D is of interest. The recommended daily dose (RDA) of calcium and vitamin D3 is as follows (european commission, reportotopobiosis international community. action for prediction. office for the purpose of making a complex public community, Luxembourg 1998):

RDA of calcium varies from country to country and is being re-evaluated in many countries.

Vitamin D is very sensitive to moisture and undergoes degradation. Thus, vitamin D is typically administered in a protective matrix. Therefore, when preparing tablets containing vitamin D, it is very important that the compression force applied during the tabletting step does not reduce the protective effect of the matrix and thus does not impair vitamin D stability. For this purpose, in the case of the addition of vitamin D also in the composition, the combination of the different ingredients in the granulate or tablet prepared according to the invention proves to be very suitable, since it is possible to use relatively low compression forces during the tabletting process and still achieve tablets with suitable machine strength (crushing strength, friability, etc.).

As mentioned above, tablets comprising vitamin D are expected to meet the following requirements regarding stability:

after storage in a closed container at 25 ℃ and 60% Relative Humidity (RH) for at least 6 months, such as, for example, at least 1 year, at least 1.5 years, at least 2 years, or at least 5 years, the content of vitamin D group in the tablet is reduced by at most about 15% w/w, such as, for example, at most about 10% w/w or at most about 5% w/w.

After storage in a closed container at 40 ℃ and 75% Relative Humidity (RH) for at least 1 month, such as e.g. 2 months, at least 4 months or at least 6 months, the content of vitamin D group in the tablet is reduced by at most about 15% w/w, such as e.g. at most about 10% w/w or at most about 5% w/w.

In particular embodiments, the present invention provides a tablettable formulation comprising:

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

ii) vitamin D, and

iii) optionally one or more pharmaceutically acceptable excipients or actives. More specifically, the tablet may comprise:

i) at least 200mg of a calcium-containing compound (normal range 200-1500mg),

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

iii) optionally one or more pharmaceutically acceptable excipients or actives.

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

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

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

iii) optionally one or more pharmaceutically acceptable excipients or actives,

In particular, the tablet may comprise:

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

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

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

iv) optionally one or more pharmaceutically acceptable excipients or actives,

Pharmaceutically acceptable excipients

In the context of the present invention, the term "pharmaceutically acceptable excipient" is intended to mean any inert material which does not in itself have substantially any therapeutic and/or prophylactic effect. Pharmaceutically acceptable excipients may be added to the active drug, thereby making it possible to obtain pharmaceutical compositions with acceptable technical properties as well. Although pharmaceutically acceptable excipients may have some effect on the release of the active drug substance, materials for modifying the release are not included in this definition.

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

Typically, the disintegrant is selected from: croscarmellose sodium (a cross-linked polymer of sodium carboxymethylcellulose), crospovidone, starch NF; sodium or potassium polacrilin and sodium starch glycolate. Those skilled in the art will appreciate that a compressible tablet desirably disintegrates within 30 minutes, more desirably within 10 minutes, and most desirably within 5 minutes; thus, preferably the disintegrant used causes the tablet to disintegrate within 30 minutes, more preferably within 10 minutes, most preferably within 5 minutes.

Examples of the disintegrator that can be used are, for example, cellulose derivatives including microcrystalline cellulose, low-substituted hydroxypropylcellulose (e.g., LH22, LH21, LH20, LH32, LH31, LH 30); starches, including potato starch; croscarmellose sodium (i.e., croscarmellose sodium salt; e.g., sodium) (ii) a Alginic acid or alginate; polyvinylpolypyrrolidone (e.g. polyvinylpyrrolidone)CL、CLM、CL、XL、XL-10); sodium carboxymethyl starch (e.g. sodium carboxymethyl starch)And)。

fillers/diluents/binders may include, for example, polyols, sucrose, sorbitol, mannitol, erythritolTagatoseLactose (e.g., spray-dried lactose, α -lactose, β -lactose, lactose,Of different gradesMicrotose or) Microcrystalline linear cellulose (e.g., of different grades)Such asPH101、PH102 orPH105、P100、MingAnd) Hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substituted) (such as L-HPC-CH31, L-HPC-LM1, LH22, LH21, LH20, LH32, LH31, LH30), dextrin, maltodextrin (such as5 and10) starch or modified starch (including potato starch, corn starch and rice starch), sodium chloride, sodium phosphate, calcium sulfate, calcium carbonate.

In the pharmaceutical compositions prepared according to the invention, in particular microcrystalline cellulose, L-hydroxypropyl cellulose, dextrin, maltodextrin, starch and modified starch have proven to be very suitable.

In a particular embodiment of the invention, the calcium-containing compound may be roll compacted with one or more pharmaceutically acceptable binders, or the binder may be added after the roll compaction. Suitable binders include those commonly used in the pharmaceutical arts, although binders commonly used in wet granulation processes are unlikely to function to the same extent during agglomeration in the substantial absence of liquid. More specifically, examples include:

cellulose derivatives including methylcellulose, hydroxypropyl cellulose (HPC, L-HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), sodium carboxymethylcellulose (Na-CMC), and the like;

mono-, di-, oligo-, poly-saccharides, including dextrose, fructose, glucose, isomalt, lactose, maltose, sucrose, tagatose, trehalose, inulin, and maltodextrin;

polyols including sugar alcohols such as, for example, lactitol, maltitol, mannitol, sorbitol, xylitol, and inositol;

polyvinylpyrrolidones including Kollidon k30, Kollidon90F, or Kollidon va 64; and

proteins, including casein.

Glidants and lubricants may include, for example, stearic acid, metallic stearates, talc, waxes and glycerides with high melting temperatures, colloidal silicon dioxide, sodium stearyl fumarate, polyethylene glycol and alkyl sulfates.

The surfactant may employ, for example, nonionic surfactants (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, glycerol monooleate, and polyvinyl alcohol); anionic (e.g. docusate sodium and sodium lauryl sulphate) 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.

As can be seen from the claims, the invention also provides a process comprising the step of processing the obtained granular material into a solid dosage form by roller compaction. Such dosage forms may be coated provided that the coating does not significantly delay the release of the active drug substance from the composition. Typically, a film coating may be employed.

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

Suitable bulking agents 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, eletriptan, aspartame, acesulfame potassium, cyclamic acid salts (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 flavorants and known FD & C colorants can be added to the composition.

Specific aspects related to designing a tablet design for a dosage-dispensing machine.

In the world today, the world health care area faces significant changes. Medical progress is further demanded in the future with an increasing number of elderly people who need long-term care. In order to improve compliance, for example, with the elderly population, packaging of medicaments in daily unit/multiple dose packages ("dose dispensing") is used in more and more countries, for example, european countries. Typically, the drug dose is administered for two weeks and the daily dose package contains packages/bags for morning, noon, evening and night drugs, for example. On each bag, information about the person and the medication is printed.

When formulating tablets into chewable tablets, it is a particular challenge to develop tablets that are sufficiently robust to be dispensed by a dosage-dispensing machine. Often, chewable tablets do not have sufficient technical properties required by the dosage-dispensing machine (e.g., the tablets are too brittle and they release dust when exposed to filling equipment, making filling difficult or impossible). At present, there is no product on the market which comprises a calcium-containing compound as therapeutically and/or prophylactically active substance and which is chewable (i.e. has an acceptable taste and mouthfeel) and at the same time has sufficient technical properties to be able to be dispensed by a dosage-dispensing machine. Thus, it is not possible for a patient to obtain a daily dose package packaged by a dose dispensing machine, the package comprising one or more calcium containing chewable tablets. The present inventors have solved the above problems by providing a tablet that is sufficiently robust to withstand the packaging of a dosage-dispensing machine, while at the same time providing the patient or user with the freedom to choose whether he wishes to chew, suck and/or swallow the tablet (i.e. the improved technical properties do not impair the acceptable taste and mouthfeel).

From the above, it is seen that the present invention solves the problem of providing chewable tablets having an acceptable taste (which tablets may also be sucked or swallowed) and having mechanical properties and dimensions suitable for use when the tablets are dispensed by a dosage-dispensing machine.

In general, yield improvement and cost reduction are some advantages when using dosage-dispensing machines, which can be achieved, for example, by:

i) reduced distribution time, which increases personnel efficiency and can distribute staff to perform other tasks,

ii) reduce the incidence of prescribing, dispensing and/or administration errors,

iii) improved patient monitoring by clearly marked unit-dose/multi-dose packages, which help patients receive the correct medication at the appropriate time, and/or

iv) reduce waste of medication.

As mentioned above, the regulatory requirements for tablets dispensed by a dosage-dispensing machine are relatively high, they vary from country to country in terms of application, type of drug, stability, etc.

Currently, there are three important types of dosage-dispensing machines on the market, namely the Tosho machine type Main-Topra2441 CE. The machine dispenses doses and up to 244 different compositions in small plastic bags. Another type of Main-Topra4001CE dispenses up to 400 different compositions at the same rate (45 bags/min) as Main-Topra2441 CE.

Automedtech inc in the united states has, for example, a type ATC212 dose dispensing machine on the european market. The machine dispenses doses in small plastic bags and dispenses up to 212 different compositions. The machine packs 25 bags per minute. Other new types have improved in the number of different compositions to be packaged (330 or 520) and increased in speed to 60 bags per minute.

Hystonmcedical co. ltd has a dose dispensing machine, ATDPS, which dispenses doses in small plastic bags and prepares up to 352 different compositions. The speed was 60 bags/minute. In addition, new machines (ATDPSJV-500SL and ATDPSJV-352SL) have been developed that formulate up to 500 different compositions at the same speed (60 bags/min).

Due to the different sizes and shapes of tablets and capsules, the machines are equipped with different types of cassettes and rotating members, which ensure that only one tablet or capsule is formulated at the same time. The body of the cassette is sufficiently opaque to light and dust and moisture, so that the cassette is well suited for storing medications. It is not possible to misplace the cassette because of the safety lock. The tablets and capsules are not stored in the cartridge for more than a set period of time, so that the quality of the composition can be ensured. The machine will issue a warning when the composition is stored in the cartridge for more than the period of time.

With regard to the size of the tablets, the following requirements should be met to ensure that the tablets can be packaged with a dosage-dispensing machine: the requirements are dynamic and may change over time.

Round tablet

Oval tablet

The dimensions of the circular tablets or oval tablets described above may vary and still conform to the specific illustrated dosage-dispensing machine. Experiments performed by the present inventors have shown that it is acceptable within a range of ± 20%, preferably within a range of ± 10%. Regarding size, the main problem facing the present inventors is to reduce the thickness of the tablet. This problem is solved by using an appropriate combination of one or more active ingredients and pharmaceutically acceptable excipients and by careful selection of the appropriate particle size and/or crystal form of the calcium-containing compound, the nature of the excipients and the method of preparation.

It is important that the tablet is not dust-generating and, as mentioned above, the tablet must be strong enough to withstand the machine stresses used due to the use of the dosage-dispensing machine.

The inventors have found that it is possible to apply a film coating on the tablets, for example to increase chewability and to minimise any dust problems or problems associated with crushing strength or friability. For this purpose, it is noted that the application of a film coating does not compensate for the essential problems regarding crushing strength or fragility, but it can give the final advance exactly in the correct direction. In addition, only a film coating must be applied to maintain an acceptable mouthfeel, i.e., the amount of coating that can be applied, based on the weight of the uncoated tablet, corresponds to an increase in tablet weight of up to about 2% w/w, such as, for example, up to about 1.5% w/w, up to about 1% w/w, or in the range of about 0.25% to 0.75% w/w.

The dimensions of the commercially available calcium carbonate-containing tablets are given below.

Size of calcium carbonate-containing tablets

	Length [ mm ]]	Height [ mm ]]	Width [ mm ]]
				Calcipos-D swallow tablet (egg/capsule)	19.3	5.6	8.7
Calcipos-D chewable tablet (circular)	17.2	7.0	--
				Calcichenw chewable tablet (circular)	16.1	7.0	--
Ideos chewable tablet (Square)	19.6	4.8	19.6

Detailed Description

The following non-limiting examples are intended to illustrate the invention.

Bill of materials

Examples

Example 1

Study of the Effect of intragranular Mixed sorbitol on tablet Strength

The study was based on the following formulations:

TABLE 1 formulation composition

Sorbitol was agglomerated in ConeMill (QuadraU20) and then premixed with calcium carbonate in a high shear mixer (DiosnaP250, low impeller speed, no chopper) for 60 seconds.

Granulating the premix on a roller compactor (Gerteis3W-Polygran), and mixing the compressed granules with povidone K30, aspartame, D₃Vitamins and flavors were mixed in a high shear mixer (DiosnaP250, low impeller speed, no chopper) for 60 seconds. Finally lubricated with magnesium stearate in a high shear mixer (DiosnaP250, low impeller speed, no chopper) for 25 seconds.

The rolling was based on the use of a grooved roller and a control device. The key setting parameters are as follows: gap Width (GW), force (F), Roll Speed (RS), and screen mesh size.

The resulting granular material was a granulate which was compressed on a fully instrumented tablet press fettep 1090 having a 16mm circular standard concave tablet design. The tablet weight was about 1,750 mg. All in-process weight and hardness data were obtained using schleuniger at 4.

In this example, the conditions for roll compaction are as follows:

table 1: rolling compaction condition of roller

	H310001sb.10	H314301sb.02	H314301sb.08
				GW，mm	3.5	2.0	3.0
F，kN/cm	12	8	20
				RS，rpm	10	5	5
Mesh size, mm	1.5	1.5	1.5
				Mixed sorbitol	In the granule	Outside the granule	Outside the granule

The effect of sorbitol with mixing (with an average particle size of about 110 μm as determined by a Malvern laser classifier) on tablet hardness compared to no sorbitol was as shown in figure 1.

In fig. 1, it can be shown that the presence of sorbitol causes an increase in the tablet hardness values compared to tablets formed solely from calcium carbonate. In addition, it is shown that mixing sorbitol 110 μm in or out of the granules has the same effect on tablet hardness.

Example 2

Effect of variation in Rolling compaction on tablet Strength

This experiment was performed according to example 1 with the variations as described in table 2.

Table 2: actual measurement values of GW, F, RS and mesh size

	H326501sb.10	H326501sb.07	H326501sb.11
				GW，mm	4.0	4.0	4.0
F，kN/cm	4	8	12
				RS，rpm	15	15	15
Mesh size, mm	1.5	1.5	1.5

In addition, sorbitol has an average particle size of about 38 μm.

The particle size distribution and hardness variation curves obtained are shown in figures 2 and 3. Fig. 2 and 3 illustrate that even though the variation in the rolling compaction force causes the variation in the particle size, the hardness characteristics of the tablet remain unchanged. However, the increase in compressive force improves the flowability of the pellets due to the decrease in the fraction below 125 μm.

Example 3

Effect of sorbitol particle size variation on tablet Strength

This experiment was performed according to example 1 with the following changes:

actual values for GW, F, RS and mesh size are as follows:

GW3.5mm,

F12kN/cm,

RS10rpm,

the mesh size is 1.5mm.

Sorbitol was used in three properties with an average particle size of about 11 μm, or 38 μm or 110 μm. 11 μm and 38 μm material were obtained by milling 110 μm material.

The tablet is designed as a 14mm circular concave with double radii.

The effect of the sorbitol particle size variation is shown in figure 4.

As can be seen from fig. 4, the size of sorbitol causes a significant increase in the hardness of the tablet at a fixed compression force.

Example 4

Effect of variation of intragranular concentration of sorbitol and presence of microcrystalline cellulose on tablet Strength

This experiment was performed according to example 1 with the following variations described in tables 3 and 4. In each case calcium carbonate and sorbitol were roller compacted separately and the other excipients listed were then mixed.

TABLE 3 formulation composition used

	H335528	H404302	H407504
				Calcium carbonate, Scoralite	67.5%	71.4%	80.1%
Sorbitol, 38 μm	21.1%	22.3%	15.5%
				Mixing ratio-calcium sorbitol	3.2:1	3.2:1	5.2:1
Microcrystalline cellulose M101 type	6.6%
				Starch 1500	4.2%		3.4%
Acesulfame potassium	0.1%		0.1%
				Lemon flavour	0.3%		0.5%
Povidone K30		2.1%
				Aspartame		0.1%
Vitamin D3		0.3%
				Orange flavour particle		3.6%
Magnesium stearate	0.3%	0.3%	0.4%

Table 4: actual measurement values of GW, F, RS and mesh size

	H335528	H404302	H407504
				GW，mm	3.5	4.0	3.5
F，kN/cm	12	12	12
				RS，rpm	15	15	3
Mesh size, mm	1.5	1.5	1.5

Figure 5, which includes batch H310001sb10 from example 1, shows the effect on tablet hardness when different amounts of sorbitol and particle sizes are used. This indicates that it is important to have a sorbitol distribution as completely as possible between the calcium particles. Improper distribution may be the result of too large a particle size or too low a concentration. In addition, figure 5 illustrates that microcrystalline cellulose (mcc) has a secondary effect on tablet hardness compared to the effect of sorbitol.

Example 5

Effect of the Water content of the ambient air on tablet Strength when sorbitol is used as a Binder

This experiment was performed according to example 1 with the following variations described in table 5.

TABLE 5 actual measurement values of GW, FRS, and mesh size

In addition, the tablet is designed to have a double radius 14mm circular concave surface.

Production is carried out under winter and summer conditions. In winter conditions, RH in the ambient air is lower than 50%, while RH is higher than 70% during summer.

The effect of changes in the moisture content of the surrounding air on tablet hardness is shown in figure 6.

Figure 6 shows that the granulate is very sensitive to moisture when using sorbitol with an average particle size of 110 μm.

Tablets based on a sorbitol average particle size of about 38 μm showed no sensitivity to the season when tabletting was carried out.

Example 6

Bulk density of roller compacted formulations containing calcium salts

The bulk density change caused by compaction by the rolls is shown in fig. 6.

TABLE 6 bulk Density variation

Density of mixture (g/cm)³)	Density of roller compacted granules (g/cm)³)
		0.99	1.08

From the data in the above table, it is apparent that the increase in density caused by the roll compaction process is minimal.

only pellets were produced. The povidone 30, aspartame, D3 vitamins and flavors are mixed slightly.

Actual values for GW, F, RS and mesh size are as follows:

GW，mm	3.5
		F，kN/cm	12
RS，rpm	10
		mesh size, mm	1.5

Example 7

Effect of variation of the type of binder used on tablet hardness

This experiment was performed according to example 1 with the following variations described in tables 7 and 8. In each case calcium carbonate and sorbitol or maltitol were roller compacted and the other excipients listed were then mixed.

TABLE 7 formulation compositions used

	H335525	H335528
			Calcium carbonate (Scorallite)	75.3%	67.5%
Sorbitol, 38 μm		21.1%
			Mannitol	13.3%
Microcrystalline cellulose M101 type	6.6%	6.6%
			Starch 1500	4.2%	4.2%
Acesulfame potassium	0.1%	0.1%

Lemon flavour	0.3%	0.3%
			Magnesium stearate	0.3%	0.3%

TABLE 8 actual measurement values of GW, F, RS and mesh size

	H335525	H335528
			GW，mm	3.5	3.5
F，kN/cm	12	16
			RS，rpm	3	15
Mesh size, mm	1.5	1.5

In addition, the tablets were designed in a capsule shape, 9.4mm by 18.9 mm.

The hardness change curve obtained is shown in fig. 7.

As seen from fig. 7, the use of maltitol as the binder did not give good cohesiveness as obtained when sorbitol was used.

Example 8

Effect of non-optimal mixing of sorbitol on tablet hardness

This experiment was carried out according to example 1 with the variations described in table 9.

Table 9, GW, F, RS and mesh sizes found are as follows:

	H326501sb.11	G334701-a	G/H404301	G/H404302
					GW，mm	4.0	3.5	4.0	4.0
F，kN/cm	12	12	12	12
					RS，rpm	15	15	15	15
the sieve pore is largeSmall, mm	1.5	1.5	1.5	1.5
					Crushing sorbitol agglomerate	Is that	Whether or not	Is that	Is that

Sorbitol has an average particle size of about 38 μm.

Figure 8 shows the effect of sorbitol on tablet hardness without breaking up the lumps prior to mixing.

As can be seen from fig. 8, the breaking up of the agglomerates is important. In addition, this illustrates the importance of obtaining an optimal distribution of sorbitol particles between calcium particles.

With the optimum distribution, the tablet hardness is highly reproducible, as shown in fig. 8.

Example 9

Study of the D3 vitamin assay on tablets based on intragranular mixing of fine sorbitol

This experiment was performed according to example 1 with the variations described in table 10.

Table 10: actual measurement values of GW, F, RS and mesh size

	H328001sb.01	G328001sb.02
			GW，mm	4.0	3.5
F，kN/cm	8	12
			RS，rpm	15	15
Mesh size, mm	1.25	1.5

Sorbitol has an average particle size of about 38 μm.

In fig. 9, the D3 vitamin assay is the result of the sample after having been compressed for 2 hours. It can be seen that it is possible to mix a small amount of D3 vitamin at the production scale. The slope of the trend line is close to 0 and is nearly the same in the 2 batches tested in this example.

Example 10

Effect of Mixed Binder Povidone K30 (example of a typical Wet Binder) on tablet hardness

This experiment was performed according to example 1 with the variations described in tables 11 and 12.

TABLE 11 actual values of GW, F, RS and mesh sizes

TABLE 12 variation of the compositions and compressed tablets

Figure 10 shows that the blend dried povidone K30 had no beneficial effect on tablet hardness.

Example 11

Effect of calcium carbonate type and sugar alcohol type and particle size variation on tablet hardness

This experiment was performed as follows:

in all experiments 1-24 described below, the amount of calcium salt was 76.22% w/w and the amount of sugar alcohol was 23.78% w/w of the final tablet mass, except that in experiments 4 and 20 23.78% w/w of the sugar alcohol was replaced by 14.63% w/w of sugar alcohol and 9.15% w/w of Precirol. The actual calcium source type and sugar alcohol type are described in table 13.

TABLE 13 types of calcium and sugar alcohol sources

Experiment number	Sources of calcium salts	Sugar alcohol sources and ps	Sugar alcoholsIllustration of the drawings
				1	Scoralite	Sorbitol, 38 μm	Sorb38
2	Scoralite	Sorbitol, 110 μm	Sorb110
				3	Scoralite	Xylitol, 34 μm	Xyli34
4	Scoralite	Xylitol, 34 μm and Precirol	Xyli34P
				5	Scoralite	Isomalt, 28 μm	Isom28
6	Scoralite	Isomalt, 137 μm	Isom137
				7	Scoralite	Mannitol, 48 μm	Mann48
8	Scoralite	Maltitol, 31 μm	Malt31
				17	Merck2064	Sorbitol, 38 μm	Sorb38
18	Merck2064	Sorbitol, 110 μm	Sorb110
				19	Merck2064	Xylitol, 34 μm	Xyli34
20	Merck2064	Xylitol, 34 μm and Precirol	Xyli34P
				21	Merck2064	Isomalt, 28 μm	Isom28
22	Merck2064	Isomalt, 137 μm	Isom137
				23	Merck2064	Mannitol, 48 μm	Mann48
24	Merck2064	Maltitol, 31 μm	Malt31
				25	Scoralite	Sorbitol, about 300 μm	Sorb300
26	Scoralite	Sorbitol, 38 μm	Sorb38

*: ps mean particle size (d (v;0.5) measured using a MalvernMastersizer)

The calcium salt and sugar alcohol were mixed in a Fielder high shear mixer in a total amount of 6 kg. The sugar alcohol was sieved through a mesh size of 300 μm before mixing. Two 6kg mixes were carried out and the total of 12kg obtained was mixed in a planetary mixer. Thereafter, the mixture was roller-compacted (sugar alcohol within particles) using the following GW, F, RS and mesh size values. (for experiments 25-26, sugar alcohols (sugar alcohols outside the particles) were mixed by hand after compaction on a roller).

GW:3.5mm

F:12kN/cm

RS:5rpm

Mesh size 1.5mm

The compact was mixed with 0.34% w/w magnesium stearate.

Compression was performed on a Fette1090 using an 18.9mm x 9.4mm capsule punch design and a theoretical tablet mass of 1683 mg. For each experiment, a correlation between tablet compression force and crushing strength was found. The crush strength was measured using schleuniger autotest4 and n = 20. The hardness change curves obtained are shown in fig. 11-13.

It can be seen from figures 11-12 that the Scoralite and Merck2064 calcium carbonate mixed within the particulate of the particulate sorbitol or isomalt produced a much higher crush strength than can be obtained using xylitol, mannitol, maltitol, or particulate coarse particles of sorbitol and isomalt. In addition, it was observed that the use of mannitol, xylitol or maltitol during the experiment resulted in tablets with a tendency to capping.

Without being bound by theory, the effect of different sugar alcohols on the crushing strength of tablets can be described as being dependent on their cohesiveness and distribution in the tablet. The distribution of the sugar alcohol in the tablet is decisive, since calcium carbonate crystals with regular shape are less likely to establish the required cohesion to obtain a coherent tablet, see fig. 15. Sugar alcohols which enable a homogeneous distribution in the tablet are particularly suitable. Examples of such sugar alcohols are sorbitol and isomalt, as illustrated in fig. 16, where it is shown that the individual sorbitol and isomalt crystals have a microstructure or uncompressed microstructure, i.e. the individual crystals have some deformability for being squeezed between other particle types. This is in contrast to crystals of mannitol, maltitol, and xylitol where there is no microstructure of the same type, as illustrated in fig. 17. This microstructure is assumed to facilitate further distribution in the tablet by breaking during tablet compression. This microstructure makes possible the distribution of the sugar alcohol as shown in figure 18. Therefore, a calcium carbonate-containing tablet comprising a sugar alcohol with said microstructure is likely to be a coherent tablet, having a satisfactory crushing strength, compared to a tablet based on a sugar alcohol without said microstructure.

However, even if a microstructure is present, it is also desirable that the sugar alcohol particles be sufficiently small, as shown in fig. 11 and 12, where it can be seen that tablets produced from specific sorbitol and isomalt fine particles have a much higher crushing strength than tablets obtained from coarse particles.

Based on the above description of the importance of the particle diameter and microstructure of the sugar alcohol, the results shown in fig. 13 can be easily explained. Even if the tablet illustrated by the curve Sorb300 is based on the teaching of pharmaceutical technology voi1(Tablettingtechnology, editor m.h. rubinstein), the crushing strength is very low when 60-90% of transient sorbitol with a particle size distribution of 212-500 μm is mixed as extra-granular sugar alcohol, even at high compression forces. The crushing strength can be increased significantly by using sorbitol with a finer particle size, see fig. 13 (curve Sorb 38). Even though the different punch designs of example 1 make it difficult to directly compare with the use of sorbitol of 110 μm nature, there is no difference between intragranular and extragranular mixing of sorbitol. Therefore, when sorbitol is used as the extra-granular sugar alcohol, the particle size is very critical. This applies to other sugar alcohols.

However, compressing pure calcium carbonate produces a granulate with very low binding capacity, as illustrated by the very large particle size fraction below 125 μm seen in fig. 14. This means that by adding sugar alcohols outside the granulate rather than inside the granulate, the final mixture for tabletting has very poor flow properties, making tabletting difficult on a production scale.

In addition, as can be seen from fig. 11, adding precrol increases the crushing strength without changing the sensitivity of the crushing strength to changes in the main compression force (maincompression force), that is, precrol is not optimal as a binder.

Example 12

Testing of compressibility of different sugar alcohols

Tablets comprising sorbitol 110 μm, sorbitol 38 μm, isomalt 27 μm, maltitol, mannitol or xylitol were compressed on an instrumented fetteexact 1/F single punch press, recording only the maximum compression force on the upper punch. Prior to compression of each tablet, the punch tip and die cavity were lubricated with a 5% suspension of magnesium stearate in acetone. The acetone was evaporated prior to compression of the tablets.

The sugar alcohol was weighed, transferred into the die cavity and then compressed, see table 14. Immediately after demolding, the crushing strength of the tablets was measured.

TABLE 14

This test was carried out using sorbitol having two different average particle sizes (38 μm and 110 μm), assuming that the tablet crushing strength of the obtained sugar alcohol was substantially independent of the particle size. The assumption is correct as seen in fig. 19 (each point is the average of three measurements). Therefore, the test with respect to the particle size was not repeated for other sugar alcohols.

As can be seen from fig. 19, sorbitol has good compressibility, resulting in the steepest slope of the correlation between compressive force and crush strength. Sorbitol is followed by isomalt, whereas maltitol, mannitol and xylitol have very poor compressibility. These results support the results discussed in example 11 and FIGS. 17-18. Therefore, it is presumed that the sugar alcohol having a polycrystalline structure gives a stronger tablet than the sugar alcohol having no polycrystalline structure.

Example 13

Variation of calcium carbonate and influence of type and particle size of sugar alcohol on crushing strength stability of tablet

Tablets were produced according to example 11. The stability was tested on tablets with initial crushing strengths between 70N and 100N. The conditions for the stability test were 14 days in open petri dishes at 25 ℃/60% (25/60) Relative Humidity (RH). The crushing strength was tested immediately before, 2 days, 7 days and 14 days after the start of the stability test. The crushing strength was measured using a Schleuniger-2E hardness tester, n = 10.

Crush strength stability is shown in figures 20-21.

As can be seen from figures 20 and 21, both Scoralite and Merck2064 calcium carbonate within the granules mixed with specific sorbitol or isomalt fines (both fines and coarse respectively) produced tablets with satisfactory crush strength stability. However, tablets produced using coarse sorbitol have reduced crushing strength during storage in open petri dishes at 25 ℃/60% RH.

A possible explanation for the observed differences in stability of tablets comprising coarse sorbitol or fine sorbitol or isomalt (both fine and coarse) is as follows: to obtain tablets containing sorbitol with the desired initial crushing strength, tablets containing coarse sorbitol require significantly higher main compression forces than tablets containing fine sorbitol. Even though tablets based on coarse sorbitol had less porosity, the crushing strength decreased significantly during the first two days of the stability test. This may be due to the much poorer uniform distribution of coarse sorbitol in the tablet.

For isomalt, satisfactory crush strength stability is obtained in both cases using fine or coarse particles. This is probably due to isomalt having a significantly poorer hygroscopicity than sorbitol.

Example 14

Production of tablets comprising calcium carbonate

Tablets were produced according to example 1 with the following exceptions. In all cases, roller compaction was performed on calcium carbonate and sorbitol, after which the other excipients listed were mixed. A film-forming liquid is applied as described below.

Tablet formulation:

watch 15

The granulate was compressed on a FettePT1090 using a capsule punch (9.4mm x 18.9 mm).

The film-forming liquid was applied to the tablets with an AccellaCoater150(manesty inc.) using the following parameters:

inlet air temperature 50 deg.C

Exit air temperature 45 deg.C

Rpm of coating pan 2.2

Batch size of 75kg

The tablets obtained had a crushing strength of 133N and a disintegration time of less than 12 minutes.

Example 15

Production of tablets comprising calcium carbonate

Pellets were produced according to example 14 with the following exceptions:

TABLE 16

The pellet was compressed on a FettePT2090 using a capsule punch (9.4mm x 18.9 mm). Tablets were coated with O 'HaraFC-660 (O' Hara) using the following parameters.

The tablets obtained had a crushing strength of 135N and a disintegration time of less than 2 minutes.

Example 16

Effect of the use of sugar alcohols and flavors on sensory Properties

According to the ingredients provided by the manufacturer:

-calcium carbonate

-vitamin D₃

-maltodextrin

Croscarmellose sodium

-gelatin

-sucrose

-corn starch

-colloidal silica

-magnesium stearate

Hypromellose (HPMC)

-Macrogol6000

-paraffins

-hydrogenated soybean oil

-hydrogenated cottonseed oil

In the aboveAnd as suchSensory comparisons were made between tablets produced as described in example 15.

The pairwise comparison test was performed according to ISO-5495 using 8 trained persons. This may represent a referenceAnd whether there was a significant difference at the 5% level between the tablets of example 15.

The following properties were compared for the products:

sweet taste

Lemon flavor

Chalk-like nature

The results prove thatIn comparison, the tablet of example 15 differed significantly in all three properties, with more sweetness, more lemon flavor, and less chalky.

Example 17

Production of tablets comprising calcium carbonate

Tablets were produced according to example 14 using the following formulation:

TABLE 17

The respective amounts are adjusted so that each composition contains 1250mg of calcium carbonate and the total amount does not exceed 100%. The tablets were compressed on fettep 2090 using the following punch design:

circular shallow concave surface 16mm

Circular composite cup 14mm

Saccular 9.4X 18.9mm

Saccular 8.6X 18.9mm

Tablets having a crushing strength of greater than 70N and a disintegration time of less than 15 minutes for tablets containing a minimum of about 0.5% croscarmellose sodium (such tablets intended for oral administration by swallowing) are obtained. Optionally, a standard water-soluble coating (e.g., conventional coatings known to those skilled in the art) may be applied to the tablet, in any case, the disintegration time should be less than 30 minutes.

If the tablets are used only for chewing, they are independent of the disintegration time.

Example 18

Study of the Effect of different modes of production on the size of calcium carbonate tablets

This experiment was carried out in a mass production of about 40.000 pieces. Experiments were carried out to investigate whether the technique used for producing the granulate for the product had any influence on the tablet size, in particular on the height of the tablets.

The considered techniques are:

i) fluid bed granulation, and

ii) roller compaction.

	Raw material	Fluidized bed	Compaction with roller
						1g per 1000 pieces of batch]	Batch 2g per 1000 tablets]
I	Calcium carbonate Scoralite	1250.0	1250.0
				II	Sorbitol 38 μm	-	385.5
III	Sorbitol 110 μm	390.0	-
				IV	Povidone K90	36.4	-
V	Microcrystalline cellulose type 101	-	75.0
				VI	Acesulfame potassium	-	1.0
VII	Aspartame	1.0

VIII	Lemon flavour	-	7.5
				IX	Lemon flavor spice granules	50.68	-
X	Magnesium stearate	6.0	6.0
				XI	Purified water	73.0	-
	Tablet weight	1734.08	1725.0

Production of batch 1:

the pellet fluid was produced by dissolving IV in Xl. III was passed through appropriate mesh and mixed with I in a Glatt fluid bed granulator. The powder mixture is granulated by spraying a fluid of granules on the powder layer while performing a fluidization process. The remainder of excipients VII, IX and X were mixed into the granulate and the tablet compressed using fettep 1090 and a capsule punch design (9.4X 18.9 mm).

Production of batch 2

II was passed through appropriate mesh and mixed together with I in a 220I high shear mixer, mixing for 1 minute at an impeller speed of 110rpm and a chopper speed of 1500 rpm. The powder mixture was granulated according to example 1 using a roller compactor. The remaining excipients V, VI, VIII, and X were mixed using a high shear mixer (DiosnaP250) at low impeller speed for 60 seconds without a chopper and finally compressed into tablets using fettep 1090 and a capsule punch design (9.4X 18.9 mm).

	Compressive force [ kN ]]	Tablet height [ mm ]]	Tablet length [ mm ]]
				Batch 1	19.9	7.40	19.04
Batch 2	20.9	7.16	19.07

Comparison of batches 1 and 2 shows that the minimum tablet height is achieved by roller compaction.

Example 19

Stability of calcium carbonate tablets

This experiment was performed in a mass production of about 693,000 pieces, producing 3 batches.

Experiments were performed to study the stability of the coated tablets in open petri dishes and the reproducibility of the crushing strength of the three mixing intervals.

Composition (A): amount of each tablet

Watch 18

The batch was produced according to the following description:

premixing and roller compaction

Calcium carbonate was added to the tumble mixer. Sorbitol was sieved through a 2.0mm mesh size and transferred to a tumbling mixer. The calcium carbonate and sorbitol were pre-mixed in a tumble mixer. Stirring time 15 minutes, speed 6 rpm. And (3) rolling and compacting the premix by using a textured roller, wherein the size of a sieve pore is 1.5mm. Setting: gap 3.5mm, force 12kN/cm, roll speed 15 rpm.

Mixing

The remaining excipients, except magnesium stearate, were mixed into the pellets in a tumble mixer using a speed of 6rpm, with 3 batches of agitation time as shown in table 19.

Table 19: mixing time interval

	Batch 1	Batch 2	Batch 3
				Mixing time	20 minutes	30 minutes	40 minutes

Magnesium stearate was mixed for 5 minutes at a speed of 6 rpm.

Tabletting

The pellets were compressed on a Fette2090 tablet press using a capsule punch design (18.9 x 9.4mm) to obtain a crush strength of 110N.

Coating film

The coating parameters were as described in example 15.

The amount of coating film applied corresponds to a theoretical weight gain of 0.75%.

Stability studies were performed in open petri dishes at 25 ℃/60% RH. The results are shown in FIG. 22. Even with sorbitol having an average particle size of 38 μm, a reduction was observed. This reduction is similar to that of the sorbitol 110 μm based tablet of example 13. The reduction is due to the addition of additional excipients. However, the crushing strength is still high enough to allow handling and is therefore acceptable.

Example 20

Effect of super-disintegrant on Water absorption

A mixture of 72.26% calcium carbonate (Scoralite) and 22.26% sorbitol (38 μm) was roll compacted as described in example 18.

The roll compacted granulate was mixed with the following ingredients:

TABLE 20 compositions of tests 1 and 2 based on monolithic content

The tablets were compressed using a capsule punch design (9.4X 18.9 mm).

Tablets were coated using the following composition

	Excipient	%(w/w)
			I	Hydroxypropyl methylcellulose	2.5
II	Talc	1.5
			III	Propylene glycol	0.5
IV	Purified water	95.5

Coating was carried out using a laboratory-scale coater (CombiCota, Niro, Denmark) with the following parameters:

the temperature of inlet air is 48-50 DEG C

Liquid flow rate of 3-4 g/min

Spraying pressure: 2 bar

The tablets were tested in a dvs (dynamic vapor perspective) apparatus (surface measurement system, UK) at 25 ℃ and 60% RH. Each test is based on 5 tablets. The results are shown in FIG. 23. As can be seen from fig. 23, the addition of the super-disintegrant resulted in only a small increase in water absorption, meaning that it can be expected that the addition of the super-disintegrant had only a small effect on the stability of the technical characteristics of the tablet.

Claims

1. A particulate material comprising a compact obtained by rolling a composition comprising calcium carbonate having a regular shape as an active substance, one or more pharmaceutically acceptable sugar alcohols having a microstructure selected from sorbitol, isomalt and mixtures thereof, wherein the one or more pharmaceutically acceptable sugar alcohols having a microstructure have an average particle diameter of 5 to 150 μm, and one or more pharmaceutically acceptable excipients, wherein the calcium carbonate having a regular shape represents a single particle having a round or smooth surface as evidenced by SEM, and the composition has nodulesBy structurally pharmaceutically acceptable sugar alcohol is meant that the single crystal of the pharmaceutically acceptable sugar alcohol is a crystal having a recognizable substructure as detectable by SEM, wherein the calcium carbonate having a regular shape is a crystal having a 0.3m structure²G to 1.5m²A crystalline form of specific surface area per g, and wherein the particulate material comprises 60 to 94% w/w calcium carbonate, 5 to 35% w/w of one or more pharmaceutically acceptable sugar alcohols; and from 1 to 15% w/w of one or more pharmaceutically acceptable excipients, with the proviso that the sum of the ingredients equals 100% w/w.

2. A particulate material according to claim 1, wherein the slope of the correlation between the crushing strength in N and the compression force in N of the pharmaceutically acceptable sugar alcohol when the pharmaceutically acceptable sugar alcohol is compressed into a tablet comprising 100% w/w sugar alcohol is at least 7 × 10^-3。

3. A particulate material according to claim 1 or 2, wherein the pharmaceutically acceptable sugar alcohol has cohesive properties.

4. A particulate material according to claim 1, wherein the pharmaceutically acceptable sugar alcohol used has an average particle size of 5 to 150 μm.

5. A particulate material according to claim 1 wherein the pharmaceutically acceptable sugar alcohol is sorbitol.

6. A particulate material according to claim 1 wherein the pharmaceutically acceptable sugar alcohol is isomalt.

7. A particulate material according to claim 1 wherein the content of the calcium-containing compound in the particulate material is between 65% and 80% w/w.

8. A particulate material according to claim 1, wherein SEM pictures of the particulate material show that the surface of the deformed particles of the pharmaceutically acceptable sugar alcohol is in close contact with the surface of the crystals of the one or more calcium-containing compounds when the particulate material is compressed into a tablet.

9. A granular material according to claim 1 additionally comprising vitamins or minerals.

10. The particulate material of claim 1, comprising one or more second calcium-containing compounds selected from the group consisting of: calcium citrate, calcium lactate, calcium phosphate including tricalcium phosphate, calcium gluconate, calcium bis (glycinate), calcium citrate maleate, hydroxyapatite, including solvates and mixtures thereof.

11. A granular material according to claim 1 having a flowability such that when tablets are prepared from the granular material optionally mixed with up to 10% w/w of a glidant using a tablet press running at least 300 tablets per minute, the resulting tablets have a change in mass which meets the requirements in the european pharmacopoeia.

12. A particulate material according to claim 11, wherein the dwell time during the preparation of the tablet is at most 1 second.

13. The particulate material of claim 1, comprising 65% to 80% w/w calcium carbonate; and 15% to 25% w/w sorbitol or isomalt or mixtures thereof.

14. A solid dosage form comprising the particulate material of any one of claims 1-13 and optionally one or more pharmaceutically acceptable excipients or additives.

15. The solid dosage form of claim 14 which is a single unit dosage form or a multiple unit dosage form.

16. The solid dosage form of claim 15, which is in the form of a tablet, capsule, sachet, bead or pill.

17. The solid dosage form of claim 16, which is in the form of a tablet.

18. The solid dosage form of claim 14, comprising one or more calcium-containing compounds in an amount equivalent to 250 to 1000mg calcium.

19. The solid dosage form of claim 14, wherein the amount of the one or more calcium-containing compounds corresponds to 400 to 600mg of calcium.

20. The solid dosage form of claim 14, wherein the total concentration of the one or more calcium-containing compounds in the dosage form is from 50% to 95% w/w.

21. The solid dosage form according to claim 14, wherein the total concentration of particulate material contained in the dosage form is from 65% to 100% w/w.

22. The solid dosage form of claim 14, comprising 60 to 94% w/w calcium carbonate; 5 to 35% w/w of a pharmaceutically acceptable sugar alcohol; and 1 to 15% w/w of one or more pharmaceutically acceptable excipients, provided that the sum of the ingredients equals 100% w/w.

23. The solid dosage form according to claim 14, wherein an SEM photograph of a fractured surface of the solid dosage form reveals that the surfaces of the deformed particles of the pharmaceutically acceptable sugar alcohol are in intimate contact with the crystalline surfaces of the one or more calcium-containing compounds.

24. The solid dosage form of claim 14, which is in the form of a chewable, suckable and/or swallowable tablet.

25. A process for the preparation of a particulate material as claimed in any one of claims 1 to 13 which comprises roller compaction of a composition comprising calcium carbonate having a regular shape as active material,One or more pharmaceutically acceptable sugar alcohols having a microstructure selected from sorbitol, isomalt and mixtures thereof, wherein the one or more pharmaceutically acceptable sugar alcohols having a microstructure have an average particle size of from 5 to 150 μm, wherein the calcium carbonate having a regular shape is a calcium carbonate having a 0.3m diameter, and one or more pharmaceutically acceptable excipients²G to 1.5m²A crystalline form of specific surface area per g, and wherein the composition compacted by roller milling comprises 60 to 94% w/w calcium carbonate, 5 to 35% w/w of one or more pharmaceutically acceptable sugar alcohols; and from 1 to 15% w/w of one or more pharmaceutically acceptable excipients, with the proviso that the sum of the ingredients equals 100% w/w.

26. The process according to claim 25, wherein the slope of the correlation between the crushing strength in N and the compression force in N of the pharmaceutically acceptable sugar alcohol when compressed into a tablet comprising 100% w/w sugar alcohol is at least 7 × 10 when the pharmaceutically acceptable sugar alcohol is compressed into a tablet comprising N^-3。

27. The method of claim 25 or 26, wherein the pharmaceutically acceptable sugar alcohol has cohesive properties.

28. The method of claim 25, wherein the pharmaceutically acceptable sugar alcohol is sorbitol.

29. The method according to claim 25, wherein the pharmaceutically acceptable sugar alcohol is isomalt.

30. The method of claim 25, wherein the composition comprises 65% to 80% w/w calcium carbonate; and 15% to 25% w/w sorbitol or isomalt or mixtures thereof.

31. The process according to claim 25, wherein the pharmaceutically acceptable sugar alcohol used is subjected to lump breaking before it is mixed with calcium carbonate.

32. The method of claim 25, further comprising admixing one or more pharmaceutically acceptable excipients or additives to the composition that has been roll compacted.

33. The method of claim 25, further comprising the step of shaping the resulting granular material into a solid dosage form.

34. The method of claim 33, wherein the solid dosage form is as defined in any one of claims 14 to 24.

35. A method of preparing a tablet comprising a calcium-containing compound, the method comprising:

i) preparing a granular material according to any one of claims 1 to 13,

ii) optionally mixing one or more pharmaceutically acceptable excipients or additives, and

iii) compressing the material into tablets.

36. The process of claim 35, wherein the compression of step iii) is performed under a compression force adjusted with respect to the diameter of the tablet and the desired height such that the applied pressure is at most 80kN when a tablet with a diameter of 16mm and a resulting height of at most 10mm is obtained.

37. The process of claim 35 or 36 for preparing a tablet comprising:

i) calcium carbonate,

ii) sorbitol and/or isomalt,

iii) vitamin D, and

iv) optionally one or more pharmaceutically acceptable excipients.

38. The method of claim 37, wherein the tablet comprises:

i) 50% to 90% w/w calcium carbonate,

ii) from 5 to 30% w/w sorbitol and/or isomalt,

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

iv) optionally one or more pharmaceutically acceptable excipients,

provided that the total amount of the ingredients corresponds to 100% w/w.