COMPOSITION FOR CALCIUM SUPPLEMENTATION

Abstract

The present invention relates to a formulation in the form of an aqueous suspension comprising calcium citrate. Said formulation exhibits excellent stability and compliance and finds use in calcium supplementation in subjects in need of such supplementation.

Claims

1. A drinkable formulation in the form of an aqueous stable suspension comprising calcium citrate and isomalt, wherein said aqueous stable suspension is not subject to sedimentation.

2. The drinkable formulation in the form of the aqueous suspension according to claim 1, wherein calcium citrate is calcium citrate tetrahydrate.

3. The drinkable formulation in the form of the aqueous suspension according to claim 1, further comprising sorbitol.

4. The drinkable formulation in the form of the aqueous suspension according to claim 1, wherein calcium citrate is in a concentration, expressed with reference to calcium, in the range from 20 to 100 mg per 1 ml of suspension.

5. The drinkable formulation in the form of the aqueous suspension according to claim 1, wherein isomalt is in a percentage concentration (w/w) in the range from 0.5 to 10%(w/w) with respect to the weight of the final formulation.

6. The drinkable formulation in the form of the aqueous suspension according to claim 1, wherein sorbitol is in a percentage concentration (w/w) in the range from 10 to 30% (w/w) with respect to the weight of the final formulation.

7. The drinkable formulation in the form of the aqueous suspension according to claim 1, wherein the aqueous suspension is in the form of a unitary dose.

8. The drinkable formulation in the form of the aqueous suspension according to claim 7, wherein the aqueous suspension in the form of a unitary dose comprises calcium citrate in an amount corresponding to a unitary dose of calcium in the range from 200 to 1500 mg.

9. The drinkable formulation in the form of the aqueous suspension according to claim 7, wherein isomalt is in an amount from 0.1 to 1 g.

10. The drinkable formulation in the form of the aqueous suspension according to claim 7, wherein sorbitol is in an amount in the range from 1 to 5 g.

11. The drinkable formulation in the form of the aqueous suspension according to claim 7, wherein the total volume of said aqueous suspension is in the range from 5 to 30 ml.

12. The drinkable formulation in the form of the aqueous suspension according to claim 11 comprising calcium citrate in an amount corresponding to a unitary dose of calcium of 1000 mg in a total volume of 10 ml.

13. The drinkable formulation in the form of the aqueous suspension according to claim 11 wherein the total weight of said aqueous suspension is in the range from 5 to 20 g for the unitary dose delivering an equivalent amount of calcium of 500 mg, and in the range from 16 to 20 g for the unitary dose delivering an equivalent amount of calcium of 1000 mg.

14. The drinkable formulation in the form of the aqueous suspension according to claim 4, wherein calcium citrate is in a concentration, expressed with reference to calcium, in the range from 40 to 70 mg per 1 ml of suspension.

15. The drinkable formulation in the form of the aqueous suspension according to claim 4, wherein calcium citrate is in a concentration, expressed with reference to calcium, of 50 mg per 1 ml of suspension.

16. The drinkable formulation in the form of the aqueous suspension according to claim 5, wherein isomalt is in a percentage concentration (w/w) in the range from 2 to 6% (w/w) with respect to the weight of the final formulation.

17. The drinkable formulation in the form of the aqueous suspension according to claim 3, wherein sorbitol is in a percentage concentration (w/w) in the range from 17 to 28% (w/w) with respect to the weight of the final formulation.

18. The drinkable formulation in the form of the aqueous suspension according to claim 8 from 400 to 1200 mg.

19. The drinkable formulation in the form of the aqueous suspension according to claim 24 of 500 mg or 1000 mg.

20. The drinkable formulation in the form of the aqueous suspension according to claim 9, wherein isomalt is in an amount from 0.4 to 1 g.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0029] The invention therefore concerns a formulation in the form of an aqueous suspension comprising calcium citrate and isomalt.

[0030] For the purposes of the present invention, the term “calcium citrate” is intended to mean any salt form obtainable between calcium ions and citrate ions, even in hydrated form, as well as any amorphous or polymorphous form thereof.

[0031] Preferably said calcium citrate is calcium citrate tetrahydrate.

[0032] The formulation in the form of an aqueous suspension of the invention comprises calcium citrate in a concentration, expressed as calcium, in the range from 20 to 100 mg per 1 ml of suspension, more preferably in the range from 40 to 70 mg per 1 ml of suspension, still more preferably of about 50 mg per 1 ml of suspension.

[0033] Said formulation in the form of an aqueous suspension of the invention comprises isomalt in a percentage concentration (w/w) in the range from 0.5 to 10%(w/w), more preferably from 2 to 6%(w/w) with respect to the weight of the final formulation. In a particularly preferred embodiment of the invention, the formulation in the form of an aqueous suspension of the invention further comprises sorbitol. Preferably said sorbitol is present in a percentage concentration (w/w) in the range from 10 to 30% (w/w), preferably from 17 to 28%(w/w) with respect to the weight of the final formulation.

[0034] As it will be apparent from the experimental part that follows, the inventors surprisingly discovered that by suspending calcium citrate salt in an aqueous solution in the presence of isomalt, a ready-to-use suspension, stable over time, was obtained.

[0035] The invention is surprising since many types of solubilizing agents, complexing agents, viscosizing agents, and cosolvents were tested, individually and as mixture thereof, in order to obtain stable calcium citrate suspensions, but in most cases, even where an initial suspension was obtained, the same quickly tended to settle, already within a few hours, or at most a few days, giving rise to insoluble “cakes”.

[0036] The specific use of isomalt, commonly known and used as a sweetening agent, once added to aqueous suspensions of calcium citrate, made surprisingly and unexpectedly possible the preparation of stable suspensions, not subject to sedimentation, with pleasant organoleptic characteristics.

[0037] The performance of these suspensions was even higher when they also included sorbitol.

[0038] The stability of these suspensions was so high also to allow the preparation of formulations containing very high doses of calcium citrate in small suspension volumes.

[0039] In fact, the aqueous suspension formulation of the invention allows to dose a concentration of calcium citrate, expressed with reference to calcium, up to 100 mg per 1 ml of suspension.

[0040] The aqueous suspension formulation of the invention can also be advantageously prepared as a unitary dose.

[0041] Said aqueous suspension of the invention in unitary dosage form comprises calcium citrate in an amount corresponding to a unitary dose of calcium in the range from 200 to 1500 mg, preferably from 400 to 1200 mg, still more preferably of 500 or 1000 mg.

[0042] Said aqueous suspension of the invention in unitary dosage form comprises isomalt in an amount in the range from 0.1 to 1 g, preferably from 0.4 to 1 g. Said aqueous suspension of the invention in unitary dosage form may further comprise sorbitol in an amount in the range from 1 to 5 g, preferably from 2.5 to 5 g. Said aqueous suspension of the invention in unitary dosage form has a total weight in the range from 5 to 20 g, preferably in the range from 6 to 10 g for the unitary dose delivering an equivalent amount of calcium of about 500 mg, and in the range from 16 to 20 g for the unitary dose delivering an equivalent amount of calcium of about 1000 mg.

[0043] Said aqueous suspension of the invention in unitary dosage form has a total volume in the range from 5 to 30 ml, preferably from 8 to 25 ml, more preferably from 9 to 15 ml, still more preferably of about 10 ml.

[0044] In particular, the aqueous suspension of the invention allows the administration of a unitary dose of 1000 mg of calcium, by the intake of a reduced volume of preparation generally comprised between 9 and 15 ml, preferably of about 10 ml, in the form of readily assimilable calcium citrate.

[0045] The possibility offered by the aqueous suspension of the present invention to provide a unitary dose of 1000 mg of calcium also allows, and by a single intake, to administer the entire daily calcium dosage recommended by the scientific and medical community.

[0046] In addition, the possibility offered by the aqueous suspension to provide the unitary dose of 1000 mg of calcium in such a small volume, makes it easy and pleasant its intake even by subjects with swallowing difficulties.

[0047] The formulation in the form of an aqueous suspension of the invention can therefore be readily taken from elderly patients and from pediatric patients.

[0048] Of course, such a formulation may also be prepared in different sizes, comprising lower dosages of calcium, such as typically the unitary dose sizes of 500 mg of calcium, 250 mg of calcium, 200 mg of calcium, or any other dosage considered useful.

[0049] The aqueous suspension formulation of the invention, also in unitary dosage form, comprising calcium citrate and isomalt, and preferably also sorbitol, may further comprise any pharmaceutical excipients useful for the preparation thereof, such as for example pH modifiers, cosolvents, solubilizers, stabilizers, preservatives, sweeteners, flavoring agents.

[0050] Among pH modifiers, for example, organic acids, preferably citric acid or malic acid, are used.

[0051] Among cosolvents, preferably glycerin can be cited.

[0052] Among solubilizers, preferably sodium citrate, sodium gluconate, sodium glucono-delta-lactone, or mixtures thereof, can be cited.

[0053] Among sweeteners, preferably sodium saccharinate or sucralose can be cited.

[0054] Among preservatives, preferably methyl paraben, propyl paraben, or mixtures thereof, can be cited.

[0055] The aqueous suspension of the invention can also be easily flavored, in order to hide the typical “chalky” flavor of these preparations, so as to obtain a suspension that is more palatable and easier to take by patients, especially by pediatric patients.

[0056] Typical flavors that can be used are, for example, creme caramel flavor, orange flavor, cherry flavor, strawberry flavor, lemon flavor.

[0057] Preferably the aqueous suspension of the invention therefore also comprises a flavor, more preferably said flavor is cherry flavor.

[0058] In a preferred embodiment of the invention, the invention concerns an aqueous suspension formulation comprising calcium citrate tetrahydrate, isomalt, sorbitol, citric acid, and sodium citrate.

[0059] In a still more preferred embodiment, said aqueous suspension comprises calcium citrate tetrahydrate, isomalt, sorbitol, citric acid, sodium citrate, methyl paraben, propyl paraben, and cherry flavor.

[0060] The formulation in the form of an aqueous suspension of the invention may therefore be effectively used in the calcium supplementation of any subject in need of supplementation, therefore, for example, in the prevention and treatment of diseases characterized by bone mass loss, such as osteoporosis, fractures, chronic diarrhea syndromes, hypertension, colon cancer.

[0061] Furthermore, the aqueous suspension of the invention, filled into flexible containers, such as for example cheer pack or stick pack, preferably stick pack, makes it possible for the patient the intake in any place or time of the day, since these containers are not bulky and are easily transportable, they can also be worn inside clothes, for example simply inside pockets.

[0062] The invention, therefore, also concerns a single-dose container, preferably flexible, still more preferably a stick pack, containing a pharmaceutical preparation or nutritional supplement in the form of an aqueous suspension comprising calcium citrate and isomalt, preferably sorbitol as well.

[0063] Preferably said calcium citrate is calcium citrate tetrahydrate.

[0064] More preferably said calcium citrate tetrahydrate is contained in such an amount as to provide an equivalent unitary dose of calcium of 200, 250, 500 or 1000 mg, still more preferably of 500 or 1000 mg.

[0065] Furthermore, said pharmaceutical preparation or nutritional supplement may further comprise any pharmaceutical excipients useful for the preparation thereof, such as for example pH modifiers, cosolvents, solubilizers, stabilizers, preservatives, sweeteners, flavoring agents.

[0066] Among usable excipients there are citric acid, malic acid, glicerin, sodium citrate, sodium gluconate, sodium glucono-delta-lactone, sodium saccharinate, sucralose, methyl paraben, propyl paraben, or mixtures thereof.

[0067] In a further embodiment of the invention, the invention therefore concerns a single-dose stick pack containing an aqueous suspension comprising calcium citrate, preferably calcium citrate tetrahydrate, isomalt, sorbitol, citric acid, sodium citrate, methyl paraben, propyl paraben, and cherry flavor.

[0068] Preferably said single-dose stick pack contains about 10 ml of an aqueous suspension comprising calcium citrate tetrahydrate in an amount equivalent to a unitary dose of about 1000 mg of calcium, isomalt, and sorbitol.

[0069] Still more preferably, said single-dose stick pack containing about 10 ml of the aqueous suspension of the invention, contains calcium citrate tetrahydrate in an amount equivalent to a unitary dose of about 1000 mg of calcium, about 0.5 g of isomalt, about 4 g of sorbitol, about 30 mg of citric acid, about 15 mg of sodium citrate, about 15 mg of methyl paraben, about 3 mg of propyl paraben, and about 10 mg of cherry flavor.

[0070] Therefore, in such embodiments of the invention, it is possible to obtain suspensions comprising calcium citrate wherein calcium is in a concentration of up to about 100 mg in 1 ml of suspension.

[0071] In a further embodiment of the invention, said single-dose stick pack contains about 10 ml of an aqueous suspension comprising calcium citrate tetrahydrate in an amount equivalent to a unitary dose of about 500 mg of calcium, about 500 mg of isomalt, about 2.5 g of sorbitol, about 15 mg of citric acid, about 8 mg of sodium citrate, about 8 mg of methyl paraben, about 2 mg of propyl paraben, and about 5 mg of cherry flavor.

[0072] As it will also be apparent from the experimental part that follows, the formulations in the form of an aqueous suspension of the invention, comprising isomalt in combination with calcium citrate, proved to be particularly stable even when using high doses of calcium citrate and small suspension volumes.

[0073] The formulations of the invention resulted therefore advantageous to be easily taken by any type of patient in need of calcium supplementation, in particular elderly patients and pediatric patients.

[0074] The compositions of the invention further comprising sorbitol exhibit marked performances both under the rheological and organoleptic profile.

[0075] It is to be understood that all the aspects identified as preferred and advantageous for the aqueous suspension formulations comprising calcium citrate described above are to be considered likewise preferred and advantageous also for the single-dose containers containing said formulations, and respective uses thereof in the treatment of patients in need of calcium supplementation.

[0076] Examples of embodiments of the present invention are provided below as non-limiting examples.

[0077] Experimental Part

EXAMPLE 1

[0078] With the aim of obtaining stable suspensions, various solutions were prepared by dispersing calcium citrate tetrahydrate in deionized water in the presence of various excipients having solubilizing, complexing, cosolving, stabilizing, and viscosizing properties.

[0079] In the following Tables 1a and 1b, some exemplary formulations among the dozens of tested formulations are reported, in particular A-N formulations obtained by mixing in deionized water the various ingredients in the weight proportions shown in the table are reported.

TABLE-US-00001 TABLE 1a A B C D E F Ingredients grams grams grams grams grams grams deionized water 25.000 10.000 10.000 10.000 7.000 4.000 calcium citrate tetrahydrate 4.745 4.745 4.745 4.745 4.745 4.745 tartaric acid 4.745 malic acid 1.000 1.000 maleic acid 0.050 citric acid 2.000 80% lactic acid 0.200 sodium carboxymethylcellulose 0.500 PEG200 4.000 PG alginate 0.200 sodium citrate 1.000 1.000 1.000 1.500 sodium gluconate 0.500 2.000 mannitol 0.200 0.200 0.200 sorbitol 0.250 sodium cyclamate 0.200 total 34.990 15.945 16.445 16.995 18.695 13.145 Suspension appearance At time point t = 0 fluid fluid fluid fluid fluid fluid At time point t = 24 hours fluid cake very viscous almost-cake cake very viscous At time point t = 48 hours very viscous / cake cake / cake

TABLE-US-00002 TABLE 1b G H I L M N Ingredients grams grams grams grams grams grams deionized water 10.000 8.000 10.000 9.000 4.000 4.000 calcium citrate tetrahydrate 4.745 4.745 4.745 4.745 4.745 4.745 malic acid 1.000 4.000 1.000 1.000 1.000 maleic acid 0.050 0.050 citric acid 1.000 sodium carboxymethylcellulose 0.400 polyvinylpyrrolidone 0.400 glicerin 4.000 4.000 sodium citrate 1.000 1.000 sodium gluconate 2.000 2.000 1.000 1.000 1.000 glucono-delta-lactone 1.000 2.000 1.000 1.000 1.000 mannitol 0.150 sorbitol 0.200 isomalt 0.100 0.100 0.400 sodium saccharinate 0.500 0.500 0.500 total 19.195 16.195 22.895 17.545 16.345 16.645 Suspension appearance At time point t = 0 fluid fluid fluid fluid fluid fluid At time point t = 24 hours very viscous very viscous very viscous fluid with fluid with fluid with partial partial partial sedimentation sedimentation sedimentation (easily re- (easily re- (easily re- dispersible dispersible dispersible sediment) sediment) sediment) At time point t = 48 hours very viscous cake cake fluid with fluid with fluid with partial partial partial sedimentation sedimentation sedimentation (easily re- (easily re- (easily re- dispersible dispersible dispersible sediment) sediment) sediment)

[0080] Once the various aqueous suspensions were prepared, their observation over time was carried out to verify their stability, and therefore the potential occurrence of sedimentation phenomena.

[0081] As reported in the same Tables 1 a and 1 b, in correspondence of each formulation, the appearance and the behavior of the suspension was recorded at the time of preparation (time point t=0), after 24 hours from preparation (time point t=24 hours), and finally after 48 hours from preparation (time point t=48 hours).

[0082] A-I suspensions proved to be completely unsatisfactory, due to more or less rapid sediment formation phenomena (cake) no longer redispersible, or excessive viscosity.

[0083] Only L-N formulations, comprising isomalt allowed to obtain suspensions that remained fluid even after 48 hours from preparation thereof.

[0084] Over an observation period of about 20 days in total, it was observed that these suspensions showed a tendency to form sediments which, however, were easily redispersible, thus making their use as formulations for oral administration completely reasonable.

EXAMPLE 2

[0085] In light of the excellent results obtained in the case of L-N formulations of Example 1, a series of optimization tests were carried out to obtain increasingly stable suspensions, while at the same time trying to define the best sweeteners to be added in order to obtain good palatability, as well as the most suitable flavoring agents to mask the acidity.

[0086] The additional O-X formulations described in Table 2 were then prepared.

TABLE-US-00003 TABLE 2 L M N O P Q R S T Ingredients grams grams grams grams grams grams grams grams grams deionized water 9.000 4.000 4.000 8.000 8.000 4.000 4.000 4.000 4.000 calcium citrate 4.745 4.745 4.745 4.745 4.745 4.745 4.745 4.745 4.745 tetrahydrate malic acid 1.000 1.000 1.000 1.000 1.000 1.000 1.000 0.500 0.300 citric acid propylene glycol 4.000 glicerin 4.000 4.000 4.000 4.000 4.000 methyl paraben 0.015 0.015 0.015 propyl paraben 0.003 0.003 0.003 sodium citrate sodium gluconate 1.000 1.000 1.000 1.000 1.000 1.000 1.000 0.500 1.000 glucono-delta-lactone 1.000 1.000 1.000 1.000 1.000 1.000 1.000 0.500 1.000 sorbitol 0.200 2.700 2.700 2.700 isomalt 0.100 0.100 0.400 0.100 0.400 0.400 0.400 0.400 0.400 sodium saccharinate 0.500 0.500 0.500 0.500 sucralose 0.005 0.005 0.005 flavor 0.010(*) 0.010(**) 0.010(**) total 17.545 16.345 16.645 18.545 18.845 19.345 16.178 14.678 15.478 U V Z X Ingredients grams grams grams grams deionized water 7.000 4.000 8.500 8.000 calcium citrate 4.745 4.745 4.745 4.745 tetrahydrate malic acid 1.000 1.000 citric acid 0.030 0.030 propylene glycol glicerin 1.000 4.000 methyl paraben 0.015 0.015 0.015 0.015 propyl paraben 0.003 0.003 0.003 0.003 sodium citrate 0.015 0.015 sodium gluconate 1.000 1.000 glucono-delta-lactone 1.000 1.000 sorbitol 5.000 5.000 isomalt 0.400 0.600 1.000 0.800 sodium saccharinate sucralose 0.050 flavor 0.010(°) 0.010(°) 0.010(°) 0.010(°°) total 16.173 16.423 19.318 18.618 (*)lemon flavor; (**)orange flavor; (°)cherry flavor; (°°)strawberry flavor

[0087] As it is apparent from the data shown in Table 2, many different excipients were varied and tested, in particular organic acids, solubilizers, sweeteners, cosolvents, always maintaining the presence of isomalt, which, based on the results of the tests carried out in the test described in Example 1, was surprisingly found to be an essential ingredient to ensure obtainment of stable suspensions.

[0088] The evidence that the presence of isomalt in suspensions comprising calcium citrate was a fundamental element to ensure their stability was also confirmed by the present test.

[0089] All the additional O-X suspensions prepared, characterized by very different qualitative compositions, proved to be in any case stable, with an index of redispersibility of the sediment possibly formed from good to excellent, thanks to the presence of isomalt.

[0090] In addition, the performance of the suspensions containing sorbitol in combination with isomalt appeared in general superior, both in terms of stability and organoleptic characteristics.

[0091] Among these, in particular, the formulation Z proved to be the best in every respect.

EXAMPLE 3

[0092] Considering that the presence in the calcium citrate suspension of the isomalt and sorbitol ingredients conferred the best physical and organoleptic characteristics to the preparation, further formulations were prepared, in particular by modifying the amounts of the ingredients in formulation Z, i.e. the best formulation that had been obtained in the previous tests, described in Example 2.

[0093] In particular, the influence of isomalt and sorbitol concentration on stability and viscosity was thus checked, since this parameter is one of the most important to consider in the production of marketable formulations in stick pack format, as well as palatability and pleasantness.

[0094] Z1-Z4 formulations described in the following Table 3 were thus prepared (amounts expressed in grams).

TABLE-US-00004 TABLE 3 Z Z1 Z2 Z3 Z4 water 8.500 8.500 8.500 8.500 8.500 calcium citrate 4.745 4.745 4.745 4.745 4.745 isomalt 1.000 0.500 0.100 1.000 0.500 sorbitol 5.000 5.000 5.000 3.000 3.000 citric acid 0.030 0.030 0.030 0.030 0.030 sodium citrate 0.015 0.015 0.015 0.050 0.050 methyl paraben 0.015 0.015 0.015 0.015 0.015 propyl paraben 0.003 0.003 0.003 0.003 0.003 flavor 0.010 0.010 0.010 0.010 0.010 total 19.318 18.818 18.418 17.353 16.853 viscosity (Pa .Math. s) 4.307 4.911 5.801 6.857 1.500

[0095] All formulations proved to be stable, with completely acceptable viscosity values, adequate rheology, pleasing in terms of organoleptic properties, and adequate to be packaged in the stick pack format.

[0096] In particular, the test results also showed that it was possible to reduce the amounts of both isomalt and sorbitol, while continuing to obtain suspensions with characteristics suitable for use.

[0097] Specifically, it was possible to obtain stable and pleasant suspensions even with isomalt amounts lower than 1000 mg per unitary dose, i.e. in the range from 100 to 1000 mg, and with sorbitol amounts lower than 5 g per unitary dose, i.e.in the range from 3 to 5 g.

[0098] The possibility of reducing the amounts of excipients is obviously an aspect of interest, both from an industrial point of view, considering that this would entail lower costs of production, and from a pharmaceutical compliance point of view, considering that this would allow the preparation of pharmaceutical preparations or nutritional supplements in stick pack formats characterized by lower suspension volumes, and thus easier to take by any type of patient, especially children and the elderly.

EXAMPLE 4

[0099] In order to further reduce the preparation volume, tests to reduce the amount of water were also carried out.

[0100] In particular, the Z5 formulation was prepared, as a further variant of the Z formulation, whose qualitative and quantitative composition is reported in the following Table 4 (amounts expressed in grams).

TABLE-US-00005 TABLE 4 Z Z5 water 8.500 4.682 calcium citrate 4.745 4.745 isomalt 1.000 0.500 sorbitol 5.000 4.000 citric acid 0.030 0.030 sodium citrate 0.015 0.015 methyl paraben 0.015 0.015 propyl paraben 0.003 0.003 flavor 0.010 0.010 Total amount in grams 19.318 14.000 density (g/cm.sup.3) 1.424 1.371 Volume (ml) 13.566 10.211

[0101] The experiment showed that, despite the considerable reduction in the amount of water, with the achievement of a total volume for unitary dose preparation of just over 10 ml, it was still possible to obtain a completely stable suspension with good organoleptic characteristics.

[0102] The solubilizing/stabilizing synergistic effect of the combination of calcium citrate with isomalt and sorbitol made it possible to prepare stable suspensions with a very high content of calcium citrate, capable of providing an equivalent amount of calcium equal to about 100 mg/ml of suspension.

[0103] Given the small total volume of the preparation, the Z5 formulation, which can be realized in the stick pack format, clearly proved to be of considerable interest from a commercial point of view, thanks to its superior pharmaceutical compliance.

EXAMPLE 5

[0104] A further Z6 formulation, described in the following Table 5, was prepared with the aim of obtaining a stick pack formulation in the unitary dosage of 500 mg of calcium.

TABLE-US-00006 TABLE 5 Ingredients g deionized water 3.300 calcium citrate tetrahydrate 2.372 isomalt 0.500 sorbitol (70% solution) 3.570 citric acid 0.015 sodium citrate 0.008 methyl paraben 0.008 propyl paraben 0.002 cherry flavor 0.005 total 9.780 viscosity (Pa .Math. s) 4.771

[0105] Also this formulation proved to be stable and pleasing to taste, thus confirming the possibility of making pharmaceutical preparations and nutritional supplements based on calcium citrate in any unitary dosage, in particular also the 500 mg calcium dosage.

[0106] In conclusion, the formulations in the form of an aqueous suspension of the invention, comprising isomalt in combination with calcium citrate, proved to be surprisingly stable, even after long observation times, also when using high doses of calcium citrate in small suspension volumes.

[0107] In particular, the calcium citrate suspensions comprising also sorbitol proved to be particularly performing, with high stability and excellent organoleptic characteristics. The formulations of the invention are also particularly advantageous as they allow the administration in a single dose of the entire recommended daily dose of calcium, that is 1000 mg of calcium, inter alia readily bioavailable, being in the form of calcium citrate.

[0108] The formulations of the invention nevertheless allow the preparation of each type of unitary dose, such as for example the unitary dose of 500 mg of calcium.

[0109] The aqueous suspension formulations of calcium citrate comprising hence isomalt and, preferably, also sorbitol, therefore represent an ideal solution for the administration of calcium in a readily bioavailable form, such as calcium citrate, to patients who are in need of supplementation thereof to prevent or counteract all the diseases related to bone mass loss, such as osteoporosis and fractures.