Pharmaceutical compositions for the treatment or prevention of osteoporosis

ES 2 192 136 B1

DESCRIPTION

Pharmaceutical compositions for the treatment or prevention of osteoporosis.

The present invention relates to new pharmaceutical compositions for the treatment or prevention of osteoporosis or other bone diseases characterized by loss of bone mass. More particularly, this invention relates to oral pharmaceutical compositions, in the form of chewable tablets, effervescent granules or effervescent tablets containing a salt of fluoride ions, vitamin D and elemental calcium (in salt form) together with suitable amounts of pharmaceutically acceptable excipients, useful for the treatment or prevention of osteoporosis or other bone diseases characterized by loss of bone mass.

Prior state of the art

Osteoporosis is the most common alteration of the skeleton, it is defined as the decrease in bone mass per unit of volume in relation to what is considered normal for a certain age, sex and race, with the organic structure and mineral content of the bone being normal. bone. Osteoporosis can be secondary (due to different known pathologies) and primary or idiopathic, being in this case of two different types: Type I characterized by the loss of trabecular bone and Type II characterized by the loss of cortical bone.

The mechanism by which bone loss occurs in idiopathic osteoporosis encompasses an imbalance between formation and resorption, where osteoclasts are responsible for bone resorption, a process that is followed by the formation of bone mass by osteoblasts. Idiopathic osteoporosis is caused either by an excess of osteoclast activity or by a decrease in osteoblast activity.

Fluorine is a known inducer of osteoblastic proliferation, with sodium fluoride (FNa) and sodium monofluorophosphate (MFP) being the only clinically acceptable salts.

There are various theories regarding the mechanism of action by which fluorine favors the formation of bone mass, the most accepted being the one proposed by Lau KHW (Metabolism, 1989), according to which fluorine, at mitogenic concentrations, selectively inhibits the activity of the phosphotyrosyl phosphatase enzyme in osteoblasts and stimulates their proliferation and bone formation.

Patent application EP0455503 describes a composition for the treatment of diseases related to bone loss, containing sodium monofluorophosphate and an estrogen.

PCT application WO 97/16193 describes a pharmaceutical composition for the treatment of osteoporosis containing the compound 1a-fluoro-25-hydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol.

FNa is absorbed mainly in the stomach, being able to be absorbed, although to a lesser extent, in the beginning of the small intestine; FNa in the acidic environment of the stomach is transformed into hydrofluoric acid, which is the cause of the harmful effects, in the form of gastric irritability, caused by the administration of FNa. On the other hand, the time in which the maximum concentration of sodium fluoride is reached at the plasma level is approximately 0.56 h, which indicates the rapid absorption of this active principle. Furthermore, FNa is incompatible with Ca compounds.²⁺ since the formation of calcium fluoride occurs, which is very poorly soluble, and therefore reduces the bioavailability of fluoride and calcium. As the main disadvantage of the MFP, the bitter saline taste difficult to mask can be mentioned, although the chemical instability in solution at a pH lower than 1.5 is also noteworthy, which translates into its hydrolysis to fluoride and orthophosphate.

The optimal therapeutic range for fluoride ions is 10 to 50 mg / day for an adult human. The MFP dose normally used in bioavailability studies is equivalent to 13.2 mg or 10.5 mg of fluoride per tablet. It is advisable not to administer more than 25 mg of fluoride / day. This dose has been established on the basis that it has been observed that when doses of 60 mg of FNa / day are used, there is an exchange of calcium between the cortical to trabecular bone and the formation of abnormal bone occurs.

The use of calcium and vitamin D as a complement in the therapy used in the treatment of osteoporosis is widely known. Calcium is the predominant mineral in bone and its absorption is facilitated by the presence of vitamin D.

In patent application WO 96/09036 combinations of vitamin D and calcium carbonate are described for the treatment of osteoporosis.

In WO 92/19251 nutritional supplements are described containing a calcium salt and vitamin D, and optionally containing an estrogen.

Osteomalacia is one of the most important problems in long-term administration of fluoride, because the calcification of the newly formed bone is deficient, which increases its crystallinity and decreases its elasticity. Therefore, the use of calcium and vitamin D supplements is considered essential in order to normalize bone mineralization and avoid the appearance of osteomalacia.

ES 2 192 136 B1

The term vitamin D includes vitamin D, cholecalciferol (D3), ergocalciferol (D2), and their biologically active metabolites and precursors. These promote intestinal absorption of calcium, contribute to the regulation of calcium in plasma by acting in the process of formation and resorption and stimulate the reabsorption of calcium in the kidney.

The combination of poor gastrointestinal absorption of calcium and a deficient intake of it increases the risk of a negative calcium balance in older people. As a consequence, PTH secretion is increased, which stimulates bone resorption. The calcium supplement decreases the serum levels of PTH, avoiding an excessive loss of bone mass associated with resorption.

The recommended amount of calcium varies depending on the authors and the salt in which it is found. In patients treated with sodium fluoride, elemental calcium (1000-1500 mg / day), calcium carbonate, lactate or gluconate (1000 mg of Ca²⁺/ day) and calcium citrate (800 mg of Ca²⁺/day). When calcium is associated with MFP, the most commonly used salts are calcium carbonate (1000-1500 mg of Ca²⁺/ day) and citrate and gluconate (500-1000 mg of Ca²⁺/day).

Vitamin D should not be administered in supraphysiological concentrations because it alters renal function, while excessively high doses increase the risk of stress fracture (in cortical bone) due to increased bone resorption, while intermediate doses do not increase resorption in treated patients. with fluoride. Therefore, the optimal amounts of vitamin D in treatment together with fluoride ranges from 200 IU / day to 8000 IU / day.

Although pharmaceutical compositions of calcium salts with cholecalciferol in the form of chewable tablets are known, this is not the case with pharmaceutical compositions of fluorine salts, due to the problems that the active principle entails in this type of formulation, as well as physical compatibility. chemistry with calcium.

There is a need for a vitamin-calcium-fluorine ion combination that comprises, in a single and the same pharmaceutical form, an optimal relative dosage of vitamin D, calcium and fluoride for the treatment of osteoporosis or diseases related to bone loss. , thereby improving patient comfort and compliance, as well as reducing gastrointestinal side effects and those related to abnormal bone mineralization or osteomalacia as a result of long-term fluoride treatment.

Oral pharmaceutical forms such as effervescent granules, chewable tablets and effervescent tablets represent the most appropriate formulas to ensure a higher degree of compliance by the patient, especially in those who present swallowing difficulties or elderly, at the same time obvious advantages over other pharmaceutical forms in terms of patient comfort.

The object of the present invention is oral pharmaceutical compositions, in the form of effervescent granules, chewable tablets and effervescent tablets, which contain fluoride ions, elemental calcium and vitamin D as active ingredients, together with suitable amounts of pharmaceutically acceptable excipients.

When the pharmaceutical composition object of the present invention is presented in the form of effervescent granules, this granulate is usually packed in sachets with suitable technical characteristics for this purpose, thus optimizing its presentation and ensuring correct dosage by the user. patient.

Providing pharmaceutical forms with good palatability represents a great problem when we use effervescent or chewable oral pharmaceutical forms and where an active ingredient has an unpleasant taste (such as sodium monofluorophosphate or sodium fluoride) and another, calcium salt, is incorporated. in a very important amount in the formulation and also has poor palatability characteristics.

In addition, other additional factors inherent to the formulation in the form of chewable tablets should be taken into account, such as good taste without bitter aftertaste, non-cloying taste, good chewiness, absence of guminess to avoid sticking to teeth or dentures, adequate friability values ​​and hardness.

Explanation of the invention

The present invention solves the aforementioned problems of palatability, technical characteristics and stability, by providing a new oral pharmaceutical composition, comprising:

- between 100 IU and 4000 IU of vitamin D;

- between 500 and 600 mg of elemental calcium;

- between 2 and 15 mg of fluoride ions;

- between 0.1 and 1% of a sweetener with an intense flavor selected from the group consisting of aspartame, sodium saccharin, sodium cyclamate, potassium acesulfame and their mixtures;

together with suitable amounts of other pharmaceutically acceptable excipients, for the preparation of a medicament for the prevention or treatment of osteoporosis or other bone diseases characterized by loss of bone mass.

ES 2 192 136 B1

In a preferred embodiment, the fluoride ions come from a fluoride salt selected from sodium fluoride, sodium monofluorophosphate, and mixtures thereof.

When the fluoride salt selected is sodium fluoride, an appropriate technological treatment must be carried out to avoid physical contact between the calcium released by the calcium salt and the fluoride released by the sodium fluoride, since the formation of calcium fluoride would occur, which is very poorly soluble, and therefore would decrease the bioavailability of fluorine and calcium.

Since it is known in the state of the art that fluoride can be absorbed in the intestine, and in order to avoid irritation of the gastric mucosa produced by sodium fluoride, and its rapid absorption, which produces plasma ion peaks fluoride that trigger rheumatic complications such as fluorosis, it is more appropriate to resort to a gastro-resistant coating of sodium fluoride, by using a material that modulates its release, delaying it in time sufficiently to avoid the formation of calcium fluoride. The sustained release of FNa must comply with the premises of sufficiently delaying the release of the active principle in time, in order to avoid the coexistence of fluoride ions and calcium ions, which would cause the formation of the insoluble salt calcium fluoride, decreasing this mode the bioavailability of both, and also should allow a sustained release so as to avoid plasma peaks of fluoride ions that exceed toxic levels for them.

Therefore, the use of any suitable material for the sustained release of active principles is suitable for coating the FNa.

In a preferred embodiment of the present invention, the material used for coating the FNa is selected from the group consisting of cellulose derivatives, methacrylic acrylic polymers, glyceryl behenate and their mixtures.

In a more preferred embodiment, the cellulose derivative is selected from the group consisting of ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and methylcellulose.

In an even more preferred embodiment the material used for coating the FNa is ethylcellulose.

In another preferred embodiment of the present invention, the fluoride ion salt used is sodium monofluorophosphate.

The preferred calcium salt in the present invention is selected from calcium carbonate, calcium pidolate, calcium lactate, calcium citrate, calcium gluconate, calcium chloride, calcium glucoheptonate, calcium glycerophosphate , calcium phosphate and their mixtures.

In a preferred embodiment, the calcium salt used is selected from the group consisting of calcium carbonate, calcium gluconate, calcium lactate, calcium citrate, and mixtures thereof.

In an even more preferred embodiment, the calcium salt used is calcium carbonate.

Optionally, the calcium salt can be previously granulated with maltodextrins or with pregelatinized starch to favor its granulation, so that a raw material with adequate flow and compressibility characteristics is achieved.

The oral pharmaceutical compositions of the present invention are formulated as effervescent granules, effervescent tablets, or chewable tablets.

In a preferred embodiment, said pharmaceutical composition is formulated in the form of a chewable tablet and contains between 10 and 200 mg of citric acid.

Effervescent formulations generally include an agent capable of releasing CO₂, such as alkali metal carbonates or bicarbonates, together with an agent that induces the release of CO₂, as organic acids or their acid salts, which are present in solid form and can be formulated with the active principles and other excipients in the form of granules or tablets, without a premature release of CO2. Organic acids such as tartaric acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid or citric acid are preferred.

In a preferred embodiment, said pharmaceutical composition is formulated in the form of an effervescent granule or tablet and contains between 100 and 400 mg of an alkali metal carbonate or bicarbonate and between 200 and 500 mg of an organic acid or its acidic salt.

In an even more preferred embodiment, said effervescent pharmaceutical composition contains between 100 and 400 mg of sodium bicarbonate and between 200 and 500 mg of citric acid.

The presence of the sweetener, accompanied by the flavoring, allows masking the bitter taste of sodium monofluorophosphate or fluoride, so that it is perfectly suitable for oral formulation, since

ES 2 192 136 B1 either as chewable tablets or as granules or effervescent tablets. Sweeteners provide a sweet taste, pleasant and refreshing mouthfeel due to their negative dissolution heat. Its presence in the formulation, when it comes to tablets, must comply with the premises of not reducing the compressibility of the mixture and allowing a reproducibility of the breaking strength fork, a critical parameter in the case of tablets.

In a preferred embodiment, the composition also contains a suitable amount of a low-flavor sweetener that is selected between 1 and 30% of the weight of the composition, of one or more sweeteners selected from the group consisting of sorbitol, mannitol, xylitol, fructose. , maltose, maltitol, lactitol, and their mixtures; optionally accompanied by a suitable amount of flavoring, where the appropriate amount of flavoring is selected between 0.01 and 1% of the weight of the composition of one or more aromas selected from the group consisting of essence of orange, lemon, strawberry, fruit essences of the forest, mint and anise.

In addition to the sweetener and flavoring, the presence of other pharmaceutically acceptable excipients is necessary, excipients with disintegrating characteristics and binders being preferred, which gives the tablet the appropriate consistency, these being of the crospovidone, croscarmellose and cellulose derivatives type.

In a preferred embodiment, the disintegrating-binder excipient is a cellulose derivative. In an even more preferred embodiment, the cellulose derivative is hydroxypropyl cellulose.

The presence of citric acid contributes to masking the bitter taste of sodium monofluorophosphate or sodium fluoride, while acting as an effervescent disintegrant since saliva activates disintegration by effervescence in contact with calcium salt. In the case of effervescent formulations, the presence of citric acid favors the release of CO₂ by the alkali metal carbonate or bicarbonate present in the formulation, thus achieving the desired effervescence effect.

The compositions of the present invention are surprisingly stable for long periods of time, while promoting their physical-chemical compatibility, since it has been found that the calcium salt in contact with the monofluorophosphate in an acidic environment similar to juice gastric, acts as a buffering medium avoiding the hydrolysis of monofluorophosphate to fluoride and orthophosphate, therefore minimizing gastric irritation by fluoride and the formation of the insoluble salt F2Ca, which would mean a decrease in the bioavailability of the active principles fluorine and calcium.

The results are similar when we use FNa as a source of fluoride ions, since in addition to the buffering effect of the calcium salt, it has been found that the previous granulation of the FNa with the gastro-resistant material, thus obtaining a sustained release of the active principle, allows to achieve that the release of fluoride ions is prolonged in time; in this way, they are prevented from reacting with calcium ions, released immediately in the acidic environment of gastric juice, and which are absorbed mainly in the duodenum, thus minimizing the formation of insoluble salt F2Ca, avoiding a decrease in the bioavailability of the active ingredients fluorine and calcium.

When the pharmaceutical form is a tablet (either to chew or effervescent), it must meet certain technical characteristics of this type of formulation, such as the hardness and friability of the tablet. For which excipients have been selected that guarantee to keep the hardness parameter constant over time. Non-hygroscopic excipients have been used, not only to avoid the tendency of the tablet to decrease its hardness over time, but also because they could drastically affect the stability of one of the active principles, vitamin D. Likewise, they have been avoided the use of excipients that lose moisture over time to avoid an increase in the hardness of the tablets.

The pharmaceutical compositions of the present invention (in the case of being formulated as chewing tablets) have adequate technical characteristics (low friability and hardness values), despite the limitation represented by the amount of excipients that can be added to the composition. , since only the amount of the active principles represents around 50-70% of the totality of it.

The pharmaceutical compositions of the present invention (in the case of being formulated as chewing tablets), present friability values ​​even lower than those generally indicated for this type of pharmaceutical forms (around 34%).

Examples

The invention is illustrated by the following non-limiting examples:

Gastric compatibility test

The following test illustrates the compatibility of the formulation of two of the three active principles in the same pharmaceutical form without any type of incompatibility in the gastrointestinal tract.

Two of the three active principles are taken into account, the calcium salt and the fluoride ion salt, in this case the

ES 2 192 136 B1 sodium monofluorophosphate, since vitamin D is insoluble in aqueous media, using amounts in the same proportion as that used in the formulations described herein (test samples).

The gastric environment has an approximate pH of 1.16, so a solution with that pH is prepared at 37 ° C, the samples are kept with slight agitation for two hours, a time that gastric digestion lasts under normal conditions. Sodium monofluorophosphate samples are used as a control (blank).

By means of a selective fluorine ion electrode, the initial value of free fluoride is quantified and subsequently hydrolysis is forced, in order to release the fluorine ions completely and be able to quantify the total.

The results obtained for the sodium monofluorophosphate test are shown in Table I.

TABLE I

<td>Show</td><td>% Recovery (Before hydrolysis)</td><td>% Recovery (After hydrolysis)</td><td>initial pH</td>

<td>White 1</td><td> 7,51%</td><td> 97,7%</td><td> 0,86</td>

<td>White 2</td><td> 8,40%</td><td> 98,4%</td><td> 0,89</td>

<td>Problem 1</td><td> 2,61%</td><td> 94,14%</td><td> 5,60</td>

<td>Problem 2</td><td> 3,28%</td><td> 97,93%</td><td> 6,27</td>

As the results show, at gastric pH and during 2 hours (estimated time of gastric digestion duration), only 7.96% ± 0.63 is recovered for the blank and 2.95% ± 0.47 for the target. This is the problem, so it can be deduced that sodium monofluorophosphate is hardly hydrolyzed at that pH, so the fluoride ion is not released in a significant amount, which is the one that would react with Ca²⁺ to form the insoluble salt CaF₂. On the other hand, the fact that lower recovery values ​​are obtained with respect to the blank in the test sample is due to the pH of the solution after two hours, which indicates that the calcium salt present in the sample acts as an agent. buffering.

Example 1

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium monofluorophosphate in the form of chewable tablets flavored with berries.

Following the general technique for the preparation of chewable tablets by direct compression, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), with adequate technical characteristics. and that obtained good organoleptic acceptance in tests with healthy volunteers:

Cholecalciferol400

Sorbitol 400.00

Aspartame10.00

L-HPC 200.00

Sodium monofluorophosphate 100.00

CaCOs 90% MD 1666.67

Ac. Citrus50.00

Magnesium stearate24.00

Berry fruit essence 2.50

Tablet breaking strength 10 kp, friability (% according to pharmacopoeia) 0.99%, friction friability 0.19%

Example 2

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium monofluorophosphate in the form of chewable tablets with orange flavor

Following the general technique for the preparation of chewable tablets by direct compression, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), with adequate technical characteristics.

ES 2 192 136 B1 and that obtained good organoleptic acceptance in tests with healthy volunteers:

<td>Cholecalciferol</td><td> 400</td>

<td>Sorbitol</td><td> 100.00</td>

<td>Aspartame</td><td> 10.00</td>

<td>L-HPC</td><td> 200.00</td>

<td>Sodium monofluorophosphate</td><td> 100.00</td>

<td>Thief. 95% MD</td><td> 1580.00</td>

<td>Ac. Citric</td><td> 75.00</td>

<td>Magnesium stearate</td><td> 24.00</td>

<td>Orange essence</td><td> 2.09</td>

Tablet breaking strength 7.3 kp, friability (% according to pharmacopoeia) 2.67%, friction friability 0.79%

Example 3

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium monofluorophosphate in the form of chewable tablets flavored with berries.

Following the general technique for the preparation of chewable tablets by direct compression, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), with adequate technical characteristics. and that obtained good organoleptic acceptance in tests with healthy volunteers:

<td>Cholecalciferol</td><td> 800</td>

<td>Sorbitol</td><td> 400.00</td>

<td>Aspartame</td><td> 10.00</td>

<td>L-HPC</td><td> 200.00</td>

<td>Sodium monofluorophosphate</td><td> 100.00</td>

<td>Thief₃ 90% MD</td><td> 1666.67</td>

<td>Ac. Citric</td><td> 50.00</td>

<td>Magnesium stearate</td><td> 24.00</td>

<td>Forest fruit essence</td><td> 2.50</td>

Example 4

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium monofluorophosphate in the form of chewable tablets with orange flavor

Following the general technique for the preparation of chewable tablets by direct compression, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), with adequate technical characteristics. and that obtained good organoleptic acceptance in tests with healthy volunteers:

<td>Cholecalciferol</td><td> 400</td>

<td>Sorbitol</td><td> 200.00</td>

<td>Aspartame</td><td> 10.00</td>

<td>L-HPC</td><td> 200.00</td>

<td>Sodium monofluorophosphate</td><td> 100.00</td>

<td>Thief₃ 90% MD</td><td> 1666.67</td>

<td>Ac. Citric</td><td> 25.00</td>

<td>Magnesium stearate</td><td> 24.00</td>

<td>Orange essences</td><td> 2.00</td>

Tablet breaking strength 10.02 kp, friability (% according to pharmacopoeia) 0.60%, friction friability 0.20%

ES 2 192 136 B1

Example 5

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium monofluorophosphate in the form of chewable tablets with orange flavor

Following the general technique for the preparation of chewable tablets by direct compression, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), with adequate technical characteristics. and that obtained good organoleptic acceptance in tests with healthy volunteers:

<td>Cholecalciferol</td><td> 400</td>

<td>Sorbitol</td><td> 500.00</td>

<td>Aspartame</td><td> 5.00</td>

<td>Saccharin</td><td> 5.00</td>

<td>Lactose monohydrate</td><td> 67.00</td>

<td>Croscarmellose sodium</td><td> 30.00</td>

<td>Sodium monofluorophosphate</td><td> 100.00</td>

<td>Thief₃ 90% MD</td><td> 1666.67</td>

<td>Magnesium stearate</td><td> 50.00</td>

<td>Orange essence</td><td> 2.30</td>

Tablet breaking strength 11.70 kp, frictional friability 0.84%

Example 6

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium monofluorophosphate in the form of chewable tablets with strawberry flavor

Following the general technique for the preparation of chewable tablets by direct compression, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), with adequate technical characteristics. and that obtained good organoleptic acceptance in tests with healthy volunteers:

<td>Cholecalciferol</td><td> 400</td>

<td>Sorbitol</td><td> 500.00</td>

<td>Aspartame</td><td> 5.00</td>

<td>Saccharin</td><td> 5.00</td>

<td>Lactose monohydrate</td><td> 67.00</td>

<td>Croscarmellose sodium</td><td> 30.00</td>

<td>Sodium monofluorophosphate</td><td> 75.00</td>

<td>Thief₃ 90% MD</td><td> 1666.67</td>

<td>Magnesium stearate</td><td> 50.00</td>

<td>Strawberry essence</td><td> 2.30</td>

Example 7

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium monofluorophosphate in the form of effervescent tablets with orange flavor

Following the general technique for the preparation of effervescent tablets, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), which obtained good organoleptic acceptance in tests. with healthy volunteers:

ES 2 192 136 B1

<td>Calcium citrate</td><td> 2280.00</td>

<td>Calcium carbonate</td><td> 300.00</td>

<td>Sodium monofluorophosphate</td><td> 100.00</td>

<td>Cholecalciferol</td><td> 400</td>

<td>Saccharin</td><td> 15.00</td>

<td>Sodium bicarbonate</td><td> 200.00</td>

<td>Anhydrous citric acid</td><td> 400.00</td>

<td>Defoamer silicone</td><td> 3.20</td>

<td>Polyethylene Glycol 4000</td><td> 30.00</td>

<td>Scent of orange</td><td> 10.00</td>

Example 8

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium monofluorophosphate in the form of effervescent granules with orange flavor

Following the general technique for the preparation of this type of formulation, pharmaceutical compositions in the form of effervescent granules of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components per pharmaceutical form) , which obtained good organoleptic acceptance in tests with healthy volunteers:

<td>Calcium gluconate lactate</td><td> 2948.00</td>

<td>Calcium carbonate</td><td> 300.00</td>

<td>Sodium monofluorophosphate</td><td> 100.00</td>

<td>Cholecalciferol</td><td> 400</td>

<td>Saccharin</td><td> 15.00</td>

<td>Sodium bicarbonate</td><td> 200.00</td>

<td>Citric acid monohydrate</td><td> 435.00</td>

<td>Defoamer silicone</td><td> 3.20</td>

<td>Scent of orange</td><td> 10.00</td>

Example 9

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium fluoride in the form of effervescent tablets with lemon flavor

Following the general technique for the preparation of effervescent tablets, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), which obtained good organoleptic acceptance in tests. with healthy volunteers. Sodium fluoride was previously treated with ethylcellulose in order to incorporate it into the final formula endowed with a gastro-resistant coating.

<td>Calcium citrate</td><td> 2280.00</td>

<td>Calcium carbonate</td><td> 300.00</td>

<td>Sodium fluoride</td><td> 21.05</td>

<td>Cholecalciferol</td><td> 400</td>

<td>Saccharin</td><td> 15.00</td>

<td>Sodium bicarbonate</td><td> 200.00</td>

<td>Anhydrous citric acid</td><td> 400.00</td>

<td>Defoamer silicone</td><td> 3.20</td>

<td>Polyethylene Glycol 4000</td><td> 30.00</td>

<td>Ethylcellulose</td><td> 2.11</td>

<td>Lemon scent</td><td> 10.00</td>

Example 10

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium fluoride in the form of effervescent granules with orange flavor

Following the general technique for the preparation of this type of formulation, pharmaceutical compositions in the form of effervescent granules of the aforementioned active principles were prepared with the compositions

ES 2 192 136 B1 indicated (IU amounts for vitamin D and in milligrams for the rest of the components by pharmaceutical form), which obtained good organoleptic acceptance in tests with healthy volunteers.

Sodium fluoride was previously treated with ethylcellulose in order to incorporate it into the final formula endowed with a gastro-resistant coating.

<td>Calcium gluconate lactate</td><td> 2948.00</td>

<td>Calcium carbonate</td><td> 300.00</td>

<td>Sodium fluoride</td><td> 21.05</td>

<td>Saccharin</td><td> 15.00</td>

<td>Sodium bicarbonate</td><td> 200.00</td>

<td>Citric acid monohydrate</td><td> 435.00</td>

<td>Defoamer silicone</td><td> 3.20</td>

<td>Ethylcellulose</td><td> 2.11</td>

<td>Scent of orange</td><td> 10.00</td>

Example 11

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium fluoride in the form of chewable tablets flavored with berries.

Following the general technique for the preparation of chewable tablets by direct compression, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), with adequate technical characteristics. and that they obtained good organoleptic acceptance in tests with healthy volunteers.

Sodium fluoride was previously treated with ethylcellulose in order to incorporate it into the final formula endowed with a gastro-resistant coating.

<td>Cholecalciferol</td><td> 400</td>

<td>Sorbitol</td><td> 400.00</td>

<td>Aspartame</td><td> 10.00</td>

<td>L-HPC</td><td> 200.00</td>

<td>Anhydrous citric acid</td><td> 50.00</td>

<td>Sodium fluoride</td><td> 21.05</td>

<td>Thief₃ 90% MD</td><td> 1666.67</td>

<td>Ethylcellulose</td><td> 2.11</td>

<td>Magnesium stearate</td><td> 24.00</td>

<td>Forest fruit essence</td><td> 2.50</td>

Example 12

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium fluoride in the form of chewable tablets with lemon flavor

Following the general technique for the preparation of chewable tablets by direct compression, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), with adequate technical characteristics. and that they obtained good organoleptic acceptance in tests with healthy volunteers.

Sodium fluoride was previously treated with ethylcellulose in order to incorporate it into the final formula endowed with a gastro-resistant coating.

ES 2 192 136 B1

<td>Cholecalciferol</td><td> 400</td>

<td>Sorbitol</td><td> 400.00</td>

<td>Aspartame</td><td> 10.00</td>

<td>Croscarmellose sodium</td><td> 30.00</td>

<td>Anhydrous citric acid</td><td> 50.00</td>

<td>Sodium fluoride</td><td> 25.00</td>

<td>Thief₃ 90% MD</td><td> 1666.67</td>

<td>L-HPC</td><td> 125.00</td>

<td>Ethylcellulose</td><td> 2.50</td>

<td>Magnesium stearate</td><td> 24.00</td>

<td>Lemon essence</td><td> 1.23</td>

Tablet breaking strength 13.00 kp, friability (% according to pharmacopoeia) 0.90%, friction friability 0.47%

Example 13

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium fluoride in the form of chewable tablets with orange flavor

Following the general technique for the preparation of chewable tablets by direct compression, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), with adequate technical characteristics. and that they obtained good organoleptic acceptance in tests with healthy volunteers.

Sodium fluoride was previously treated with ethylcellulose in order to incorporate it into the final formula endowed with a gastro-resistant coating.

<td>Cholecalciferol</td><td> 400</td>

<td>Xylitol</td><td> 400.00</td>

<td>Aspartame</td><td> 10.00</td>

<td>Sodium fluoride</td><td> 25.00</td>

<td>Calcium phosphate</td><td> 1547.50</td>

<td>L-HPC</td><td> 200.00</td>

<td>Ethylcellulose</td><td> 3.75</td>

<td>Magnesium stearate</td><td> 24.00</td>

<td>Orange essence</td><td> 2.09</td>

Tablet breaking strength 9.25 kp, friability (% according to pharmacopoeia) 1.02%, friction friability 0.63%

Example 14

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium fluoride in the form of chewable tablets flavored with berries.

Following the general technique for the preparation of chewable tablets by direct compression, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), with adequate technical characteristics. and that they obtained good organoleptic acceptance in tests with healthy volunteers.

Sodium fluoride was previously treated with ethylcellulose in order to incorporate it into the final formula endowed with a gastro-resistant coating.

ES 2 192 136 B1

<td>Calcium carbonate 90% MD</td><td> 1666.67</td>

<td>Sodium fluoride</td><td> 25.00</td>

<td>Cholecalciferol</td><td> 400</td>

<td>Fructose</td><td> 300.00</td>

<td>L-HPC</td><td> 150.00</td>

<td>Sorbitol</td><td> 100.00</td>

<td>Croscarmellose sodium</td><td> 30.00</td>

<td>Aspartame</td><td> 5.00</td>

<td>Saccharin</td><td> 5.00</td>

<td>Ethylcellulose</td><td> 2.50</td>

<td>Stearic acid</td><td> 24.00</td>

<td>Forest fruit essence</td><td> 2.09</td>

Tablet breaking strength 9.75 kp, friability (% according to pharmacopoeia) 0.97%, friction friability 0.56%

Example 15

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium fluoride in the form of chewable tablets with orange flavor

Following the general technique for the preparation of chewable tablets by direct compression, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), with adequate technical characteristics. and that they obtained good organoleptic acceptance in tests with healthy volunteers.

Sodium fluoride was previously treated with Eudragit RS 100® in order to incorporate it into the final formula with a gastro-resistant coating.

<td>Calcium phosphate</td><td> 1547.5</td>

<td>Cholecalciferol</td><td> 400</td>

<td>Xylitol</td><td> 400.00</td>

<td>Aspartame</td><td> 5.00</td>

<td>Saccharin</td><td> 5.00</td>

<td>L-HPC</td><td> 200.00</td>

<td>Sodium fluoride</td><td> 25.00</td>

<td>Eudragit</td><td> 2.50</td>

<td>Magnesium stearate</td><td> 24.00</td>

<td>Orange essence</td><td> 2.09</td>

Tablet breaking strength 13.50 kp, friability (% according to pharmacopoeia) 0.80%, friction friability 0.32%

Example 16

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium fluoride in the form of chewable tablets flavored with berries.

Following the general technique for the preparation of chewable tablets by direct compression, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), with adequate technical characteristics. and that they obtained good organoleptic acceptance in tests with healthy volunteers.

Sodium fluoride was previously treated with ethylcellulose in order to incorporate it into the final formula endowed with a gastro-resistant coating.

ES 2 192 136 B1

<td>Thief. 90 MD</td><td> 1666.67</td>

<td>Sodium fluoride</td><td> 25.00</td>

<td>Cholecalciferol</td><td> 800</td>

<td>Fructose</td><td> 300.00</td>

<td>L-HPC</td><td> 150.00</td>

<td>Sorbitol</td><td> 100.00</td>

<td>Croscarmellose sodium</td><td> 30.00</td>

<td>Aspartame</td><td> 5.00</td>

<td>Saccharin</td><td> 5.00</td>

<td>Ethylcellulose</td><td> 2.50</td>

<td>Magnesium stearate</td><td> 24.00</td>

<td>Forest fruit essence</td><td> 2.09</td>

<td colspan="2">Tablet breaking strength 13.25 kp, friability (% according to pharmacopoeia) 0.78%, friction friability</td>

0.37%

Example 17

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium fluoride in the form of chewable tablets with orange flavor

Following the general technique for the preparation of chewable tablets by direct compression, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), with adequate technical characteristics. and that they obtained good organoleptic acceptance in tests with healthy volunteers.

Sodium fluoride was previously treated with ethylcellulose in order to incorporate it into the final formula endowed with a gastro-resistant coating.

<td>Calcium phosphate</td><td> 1547.50</td>

<td>Cholecalciferol</td><td> 800</td>

<td>Mannitol</td><td> 400.00</td>

<td>Aspartame</td><td> 10.00</td>

<td>L-HPC</td><td> 200.00</td>

<td>Sodium fluoride</td><td> 25.00</td>

<td>Ethylcellulose</td><td> 2.50</td>

<td>Magnesium stearate</td><td> 24.00</td>

<td>Orange essence</td><td> 2.09</td>

Tablet breaking strength 9.50 kp, friability (% according to pharmacopoeia) 1.03%, friction friability 0.71%

Example 18

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium fluoride in the form of effervescent tablets with orange flavor

Following the general technique for the preparation of effervescent tablets, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), which obtained good organoleptic acceptance in tests. with healthy volunteers.

Sodium fluoride was previously treated with Eudragit RS 100® in order to incorporate it into the final formula with a gastro-resistant coating.

ES 2 192 136 B1

<td>Calcium lactate</td><td> 3266.63</td>

<td>Sodium fluoride</td><td> 25.00</td>

<td>Cholecalciferol</td><td> 400</td>

<td>Acesulfame potassium</td><td> 30.00</td>

<td>Sodium bicarbonate</td><td> 200.00</td>

<td>Anhydrous citric acid</td><td> 300.00</td>

<td>Tartaric acid</td><td> 100.00</td>

<td>Defoamer silicone</td><td> 3.20</td>

<td>Polyethylene glycol 6000</td><td> 30.00</td>

<td>Orange scent</td><td> 3.00</td>

<td>Eudragit RS 100®</td><td> 2.50</td>

Example 19

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium fluoride in the form of effervescent tablets with orange flavor

Following the general technique for the preparation of effervescent tablets, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), which obtained good organoleptic acceptance in tests. with healthy volunteers.

Sodium fluoride was previously treated with Eudragit RS 100® in order to incorporate it into the final formula with a gastro-resistant coating.

Calcium lactate

3266.63

Sodium fluoride

25.00

Cholecalciferol

800

<td>Acesulfame potassium</td><td> 30.00</td>

<td>Sodium bicarbonate</td><td> 200.00</td>

<td>Anhydrous citric acid</td><td> 300.00</td>

<td>Ascorbic acid</td><td> 100.00</td>

<td>Defoamer silicone</td><td> 3.20</td>

<td>Polyethylene glycol 6000</td><td> 30.00</td>

<td>Orange scent</td><td> 3.00</td>

<td>Eudragit RS 100®</td><td> 2.50</td>

Example 20

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium fluoride in the form of effervescent tablets with lemon-lime flavor

Following the general technique for the preparation of effervescent tablets, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), which obtained good organoleptic acceptance in tests. with healthy volunteers.

Sodium fluoride was previously treated with ethylcellulose in order to incorporate it into the final formula endowed with a gastro-resistant coating.

<td>Calcium gluconate lactate</td><td> 2948.00</td>

<td>Calcium carbonate</td><td> 300.00</td>

<td>Sodium fluoride</td><td> 21.05</td>

<td>Cholecalciferol</td><td> 400</td>

<td>Saccharin</td><td> 25.00</td>

<td>Sodium bicarbonate</td><td> 200.00</td>

<td>Citric acid monohydrate</td><td> 435.00</td>

<td>Defoamer silicone</td><td> 3.20</td>

<td>Ethylcellulose</td><td> 3.75</td>

<td>Lemon lime scent</td><td> 7.50</td>

ES 2 192 136 B1

Example 21

Pharmaceutical composition containing cholecalciferol, calcium carbonate, sodium fluoride in the form of effervescent tablets with orange flavor

Following the general technique for the preparation of effervescent tablets, tablets of the aforementioned active principles were prepared with the indicated compositions (IU amounts for vitamin D and in milligrams for the rest of the components for each tablet), which obtained good organoleptic acceptance in tests. with healthy volunteers.

Sodium fluoride was previously treated with Eudragit RS 100^® in order to incorporate it into the final formula with a gastro-resistant coating.

<td>Calcium gluconate lactate</td><td> 4645.14</td>

<td>Sodium fluoride</td><td> 25.00</td>

<td>Cholecalciferol</td><td> 400</td>

<td>Saccharin</td><td> 15.00</td>

<td>Aspartame</td><td> 15.00</td>

<td>Sodium bicarbonate</td><td> 200.00</td>

<td>Citric acid monohydrate</td><td> 435.00</td>

<td>Defoamer silicone</td><td> 3.20</td>

<td>Orange scent</td><td> 7.00</td>

<td>Eudragit RS 100®</td><td> 2.50</td>