OA10336A - Vitamin-calcium therapeutic combination in unit dosage form of tablets its production process and its use - Google Patents

Abstract

A therapeutical combination including elemental calcium and at least one vitamin D as the combined active principles, and further containing at least one dry and wet binder combined in a synergistic amount with at least one diluent, at least one binder and at least one lubricant, at least one of said diluent and said binder being a sweetener. The ratio of elemental calcium to vitamin D, expressed in mg of elemental Ca per IU of vitamin D, is advantageously 1-1.5, preferably 1.2-1.3.

Description

1 010336

Vitamin-calcium therapeutic combination in galenical unit form of tablets, its method of obtaining and its use

The present invention relates to a novel combination vitamin-calcium tick, its method of obtaining and its use.

Many vitamin-calcium combinations are known for combating various diseases.

Therapeutic effects associated with the co-administration of calcium and vitamin D are well known, as reported for example in the articles of Marie C. Chapuy et al. - Effect of Calcium and Cholecalciferol Treatment for Three Years on Hip Fracturesin Elderly Women, British Medical Journal, 308, 1081-1082 (April 23, 1994), by Marie C. Chapuy et al. - Vitamin D3 and Calcium toPrevent Hip Fractures in Elderly-Women, New England Journal of Medicine, 327, 1637-1642 (December 3, 1992) and in the article titled Supplementation with Vitamin D3 and Calcium Prevents Hip Fractures in Elderly Women, Nutrition Reviews, No \. 51, 6, pp. 1S3-185.

These articles also show the variability of the therapeutic effects of the combination as a function of the calcium dosage and Vitamin D, with an optimal daily dose being, for an indication in the prevention and treatment of osteoporosis, around 1000 to 1200 mg of calcium element and 800 IU of vitamin D3. 9 010336

Calcium and vitamin D are usually administered to the patient simultaneously, but in different forms, for example, calcium salt tablets and vitamin D drops.

In fact, the pharmaceutically acceptable calcium salts and vitamin D have, as far as they are concerned, very specific characteristics from the point of view of the galenic (see, in particular, EP-A-0 413 828 which relates to a stabilized preparation of vitamin D3 for potentiating the stability of the active ingredient), which leads to packaging in separate forms. However, this makes it difficult to respect the absolute and relative doses of calcium and vitamin D, and therefore the correct observance of the treatment, particularly over a long period. Calcium and vitamin D combinations have already been proposed in the same form, for example by WO-A-94 06435 (gynecological treatment method using a combination of Vitamin D and calcium), WO-A A-92 19251 (Vitamin Davec combination of calcium for fighting osteoporosis, more particularly in oral form), EP-A-0 197 514 (a pharmaceutical composition comprising a parathyroid hormone or a physiologically active fragment thereof). combination with hydroxylated vitamin D or a non-toxic calcium salt to increase osteose mass) or DE-A-42 12 122 (low calorie protein-based element, a calcium salt and vitamin D).

In these known forms, however, the proportions between calcium and vitamin D are generally quite different from the optimum optimal proportions indicated especially in the aforementioned literature.

These known forms moreover often correspond more to vitamins and calcium supplements (dietary supplements or OTC specialties sold without a medical prescription) than to genuine therapeutic pharmaceutical speci fi cs intended to prevent or treat conditions such as than osteoporosis with a precise dosage. Thus, there is at present a need to be able to have a vitamin-calcium combination comprising, in one and the same form, an optimal relative dosage between calcium and vitamin D, especially for the prevention and the treatment of osteoporosis. 3 0 1 0336

But because of the nature of the pharmaceutically acceptable calcium salts available, it is relatively difficult to associate calcium in elemental form with vitamin D in certain specific dosages. This is particularly true if it is desired to obtain tablets per cm by direct compression manufacturing method. The constraints of the active ingredients, namely the elemental calcium and the form of vitamin D, do not allow direct implementation.

The present invention solves the aforementioned problems by proposing a vitamin-calcium therapeutic combination under a unit dosage form of tablets, comprising as active principles calcium calcium in elemental form and at least one Vitamin D, characterized in that it further contains at least one dry and wet binder combined in a synergistic amount with at least one diluent, at least one binder and at least one lubricant, at least one of said diluent and said binder being a sweetener .

The subject of the present invention is also a process for obtaining a vitamin-calcium therapeutic combination comprising elemental calcium and at least vitamin D, which is characterized in that it consists of: (a) granulating calcium in elemental form with a dry binder and in a wet medium; (b) premixing vitamin D with a sweetening binder in a separate step; (c) mixing in another separate step a sweetening diluent, an additional sweetening agent and a flavor with the products of steps (a) and Ce 1 while adding a lubricant; (d) optionally compressing the mixture on a rotary press. The invention also relates to the use of the new vitamin-calcium therapeutic combination for combating osteoporosis. The invention also relates to the following characteristics: the ratio of calcium in elemental form to vitamin D, expressed in mg of Ca element per IU of vitamin D, is between 1 and 1.5, preferably between 1 and 1.5. , 2 and 1.3; Calcium in elemental form comes from a calcium salt selected from calcium carbonate, calcium pidolate, calcium lake, calcium citrate, calcium gluconate, calcium carbonate, Calcium chloride, calcium glucoheptonate, calcium glycerophosphate and calcium phosphate; the vitamin D is chosen from vitamin D2 or ergocalciferol, lavitamine D3 or cholecalciferol or a mixture thereof, the tablet belongs to the group comprising the tablets to be broken, the scored tablets, the tablets to be sucked, the comprim-che cheeks, dispersible tablets and tablets for oral suspension; at least one of said sweetening diluent and said sweetening binder is a flavoring agent capable of improving the taste characteristics of the combination, advantageously a polyol, especially chosen from mannitol, sorbitol, xylitol and maltitol; the dry and wet binder is selected from cellulose, lamaltodextrin and polyvinylpyrrolidone; the lubricant is selected from magnesium stearate, acidestearic acid, hydrogenated castor oil, hydrogenated cottonseed oil and glycerol behenate; the combination also contains a flavoring agent and / or an acidifier and / or an additional sweetener selected from sodium saccharinate, sodium cyclamate and aspartame; the vitamin-calcium combination corresponds to the formula general:

Calcium carbonate 1,250 mg (amount corresponding to calcium element 500 mg)

Cholecalciferol 4 mg *

Xylitol 661 mg

Sorbitol 500 mg

Polyvinylpyrrolidone 45 mg

Aroma (lemon, orange, etc.) 20 mg

Magnesium stearate 20 mg (* Vitamin D3 at 100,000 IUU / g), said formula corresponding to a finished tablet at 2500 mg. Various advantages and features of the present invention reside in the present invention.

Ο I (13 3 G will come out of an example of realization below.

In this example, the combination of the invention is in the form of a chewable tablet of the following formula (for a tablet at 2500 mg):

Calcium carbonate 1 250 mg (Amount corresponding to calcium element 500 mg) Cholecalciferol 4 mg * Xylitol 661 mg Sorbitol 500 mg Polyvinylpyrrolidone 45 mg Flavor (lemon, orange, etc.) 20 mg Magnesium stearate 20 mg (* Vitamin D3 dosed at 100,000 IU / g) 15

The calcium carbonate is of SCORALITE IB® SCORA type; it is a white powder of very fine particle size of about 12 micrometers in diameter, of high density (d = 1.3 g / cm.sup.3) having poor flow and poor compressibility.

Vitamin D is cholecalciferol (type 100 CWS®, ROCHE); it is a granular powder, with a mean diameter of about 200 micrometers, this yellowish color, dosed at 100,000 IU per gram.

The presence of DL-α-tocopherol (about 0.2% w / w vitamin E) gives it high stability and prevents its oxidation.

The diluent-sweetener used in the invention is preferably duylylitol XYLITAB 300® type, FINNSUGAR. This xylitol is a sugar-sweet polyol (equivalent to that of sucrose), providing a pleasant freshness sensation in the mouth, it is acariogenic and very little in the way (2.4 Kcal / g against 4 Kcal / g for sucrose). This pleasant feeling allows a better observance of the treatment by the patient. The xylitol used has compressive properties superior to those of standard xylitol.

This compound is in the form of a granular white crystalline powder having an average diameter of 250 micrometers. 6 0 1 0336

The hant-sweetener used in the present invention is in particular sorbitol (type NEOSORB P 60 W®, ROQUETTE). This polyol is in the form of a white granular powder, having a diameter of 200 micrometers and has excellent binding properties in compression. Sorbitol is sweet (70% of that of saccharose), acariogenic and low in calories (2.4 Kcal / g).

The binder of the present invention is preferably polyvinylpyrrolidone (KOLLIDON K 30®, BASF); it is in the form of a whitish granular powder and has very large binding properties in wet granulation. The value of the constant K characterizes the soluble polyvinylpyrrolidones and depends on their relative solubility. The flavoring is particularly a lemon flavor (SBI); it is in the form of a fine, yellowish powder composed of essential oils atomized on maltodextrin. Numerous tests carried out during the implementation of the present invention which have compared different flavors have shown that the lemon flavor is perfectly well-suited to the masking of the chalky taste of calcium carbonate and that it associates itself agreeably with the sensation of freshness provided by xylitol.

The lubricant is generally magnesium stearate, which is present in the form of a fine, whitish powder, making it possible to avoid the seizing phenomenon at the dies of the presses to be treated when the vitaminic-calcium combination of the present invention 25 is in the form of tablets.

The amount of elemental calcium per dose will preferably be 50 mg which corresponds to 1250 mg of calcium carbonate.

The amount of cholecalciferol is 4 mg per dose, which corresponds to 400 IU of a vitamin D3 dosed at 100,000 IU / g. In practice, the amount of cholecalciferol per tablet depends on the dosage of the raw material used.

These doses correspond in particular to the optimal dosage indicated by the publications mentioned above, both in absolute value (daily doses of calcium and vitamin D3, respectively) and relative (calcium / vitamin ratio of the order of 1). 25 mg of Ca elution with IU vitamin D).

The numerous tests of the formulas of this example made it possible to optimize the amounts of the various excipients.

In order to obtain a chewable tablet with the most pleasing taste, the combination of dry and wet binding combined in a synergistic amount with at least the sweetening diluent, at least the sweetening binder and the lubricant must be important. In the case of a tablet, it will usually have a mass of 2500 mg.

In certain embodiments of the present invention, an amount of xylitol of about 661 mg is used, which corresponds to the amount required to be incorporated in order to obtain the best calcium carbonate flavor masking without reducing the compressibility. of the mixture, the properties of xylitol in compression being average. Sorbitol is used at about 500 mg because it is the amount necessary to incorporate to obtain a perfect reproducibility of the range of resistance to break, a critical parameter in the case of chewable tablets. A higher quantity, at the expense of xylitol, would reduce the taste qualities of the tablet. Polyvinylpyrrolidone is used at about 45 mg, in wet granulation of calcium carbonate, a portion (20 mg) is dry blended with calcium carbonate, the remaining portion (25 mg) is used in solution. 10% in cold demineralized water. A polyvinylpyrrolidone content of less than 40 mg results in an excessively friable calcium carbonate grain. A larger quantity does not bring real benefits.

The amount of lemon flavor is about 20 mg, which is the amount needed to satisfactorily aromatize the tablet. A small variation in this amount (± 3 mg) hardly changes the final cost.

The amount of magnesium stearate is about 20 mg. This is the amount needed to achieve satisfactory lubrication during compression. A smaller amount, about 15 mg, causes a seizure phenomenon, while a greater amount, 25 mg tends to decrease the hardness of the tablet and may change its taste. 8 010336

The physical characteristics of the elements of the vita-calcium-calcium combination of the present invention will be indicated hereinafter.

The calcium carbonate has a zero flow and a similar density (g / cm) of about 1.28 to 1.35 and a residual moisture in percent of 0.1. Vitamin D3 cholecalciferol in the form of a powdery concentrate has a flow rate of 6 seconds per 100 g of powder, an apparent density in g / cm3 of 0.73, a residual moisture in percent of 6.4 and a dosage in IU / g of 100,000.

Xylitol has a zero flow, an apparent density in g / cm3 of about 0.68-0.69, residual moisture in percent of 0.2 to 0.3.

The sorbitol has flows in the range of 4 to 5 seconds per 100 g of powder, an apparent density in g / cm 3 of 0.71 to 0.73 and a residual moisture in percent of 0.5 to 0.8.

The preferred steps of the process for obtaining the vitaminic-calcium combination of the present invention will now be discussed.

Moist granulation of the calcium carbonate is first carried out.

In this embodiment, calcium carbonate and polyvinyl pyrrolidone are screened on a vibratory screen provided with a suitable mesh opening grid; these powders are introduced into a mixer and mixed at a suitable speed for a short time. The polyvinylpyrrolidone solution is added in successive steps. Granulation is carried out until a wet mass is obtained, allowing a next precalibration step.

Precalibration is carried out on a granulator provided with a suitable mesh opening mesh.

The resulting product is dried on a fluidized air bed and allowed to cool. The loss of mass upon drying is determined and a calibration on a suitable mesh gate is carried out.

At the same time, vitamin D3 is premixed and, after a warming, it is mixed with sorbitol in a blender for a suitable time and at a suitable rotational speed. The mixture is then mixed with the other components by xylitol, sorbitol and flavoring on a vibrating screen equipped with a suitable mesh size mesh. These three components are mixed with the vitamin D3-sorbitol premix in a blender at an appropriate rate. The granular calcium carbonate is then introduced and mixed for the required time at the appropriate speed.

The magnesium stearate is sieved on a vibrating screen provided with a grid of appropriate mesh opening and then the whole is mingled in a mixer. The above assembly can then be compressed on a press to be compressed by regularly controlling the uniformity of the mass and the resistance to breakage. Mixing times, rotational speeds and screen sizes are conventional and are well known to those skilled in the art. Thus, the present invention makes it possible to obtain a vitamin-calcium combination containing 500 mg of elemental calcium and 4 mg of vitamin D 3 per dose, which combination is in particular in the form of a chewable tablet which is of pleasant taste. and hardness adapted to patients. More particularly, by way of non-limiting example, the doses which will generally be used will be in the following ranges: calcium in elemental form, about 500 mg to about 1500 mg, vitamin D or vitamin D mixture, about 3.5 mg to about 12mg. Such a vitamin-calcium combination, especially in the form of tablets, contains neither sugar nor sodium.

However, other galenic forms are possible.

It is thus possible to make a scored tablet (to be swallowed) of the following formula, for a tablet of 1.60 g:

Calcium carbonate 1.250 g Vitamin D3 0.004 g Microcrystalline cellulose 0.236 g Polyvinylpyrrolidone 0.040 g Magnesium stearate 0.020 g 35 10 0 1 0336

In general, for the use of tablets of the type to crack or suck calcium carbonate will be used. Other selstels than calcium triphosphate can be used, but their absorption by the body is less, which leads to adapting the quantities accordingly (for the same amount of elemental calcium absorbed, it takes about 1.2 g of calcium triphosphate for 1 g of calcium carbonate). 10 15 20 25 30 35

Claims (17)

1. Vitamin-calcium therapeutic combination in unit dosage form of tablets, comprising, as active ingredients, calcium in the elemental form and at least one vitamin D, characterized in that it contains, in addition, at least one dry binder and in wet medium combined in synergistic amount with at least one diluent, at least one binder and at least one lubricant, at least one of said diluent and said binder being a sweetener. 10 2. Association according to claim 1, wherein the ratio of calcium elemental form to vitamin D, expressed in mg of Ca element per IU of vitamin D, is between 1 and 1.5. 3. Association according to claim 2, wherein the ratio of calcium in elemental form to vitamin D, expressed in mg of Ca element per IU of vitamin D, is between 1.2 and 1.3. 4. The combination according to claim 1, wherein the calcium in elemental form is derived from a calcium salt selected from decalcium carbonate, calcium pidolate, calcium lactate, calcium citrate, calcium gluconate, calcium chloride, calcium glucoheptonate, calcium glycerophosphate and calcium phosphate. 5. The combination of claim 1, wherein the vitamin D is selected from vitamin D2 or ergocalciferol, vitamin D3 or cholecalciferol or a mixture thereof. The combination according to claim 1, wherein the tablet belongs to the group consisting of chewable tablets, securable tablets, sucking tablets, chewable tablets, dispersible tablets and oral suspension tablets. The combination according to claim 1, wherein at least one of said sweetening diluent and said sweetening binder is a flavor agent for improving the taste characteristics of the combination. The combination of claim 7, wherein at least one of said sweetening diluent and said sweetening binder is a polyol. δ 9. The combination according to claim 8, wherein the polyol is selected from mannitol, sorbitol, xylitol and maltitol. 10. The combination of claim 1 wherein the dry and wet binder is selected from cellulose, maltodextrin and polyvinylpyrrolidone. 11. Combination according to claim 1, wherein the lubricant is selected from magnesium stearate, stearic acid, hydrogenated castor oil, hydrogenated cottonseed oil and glycerol behenate. 11 010336 CLAIMS 12. The combination of claim 1, further comprising a flavoring agent. 13. The combination of claim 1, further comprising an acidifier. The combination of claim 1, further comprising an additional sweetener selected from sodium saccharin, sodium cyclamate and aspartame. 15. Combination according to claim 3, of the general formula: Calcium carbonate (amount corresponding to calcium element 1 250 mg500 mg) Cholecalciferol 4 mg Xylitol 661 mg Sorbitol 500 mg Polyvinylpyrrolidone 45 mg Flavor (lemon, orange, etc.) 20 mg Magnesium stearate 20 mg 13 0 1 0336 (* Vitamin D3 assayed at 100,000 XJI / g), said formula corresponding to a finished tablet at 2500 mg. 16. A process for obtaining a vitaminic-calcium therapeutic combination in unit dosage form of tablets comprising as associated active principles of calcium in elemental form and at least one vitamin D, characterized in that it consists of: ) to granulate calcium in elemental form with a dry binder and in a wet medium; (B) premixing vitamin D with a sweetening binder in a separate step; (c) mixing in a further separate step a sweetening diluent, an additional sweetening binder and an aroma with the products of steps (a) and (b) while adding a lubricant; (D) optionally compressing the mixture on a rotary press. 17. The use of the vitamin-calcium therapeutic combination of one of claims 1 to 15 for combating osteoporosis. 20 - 25 30 35