WO2011113965A1

WO2011113965A1 - Pharmaceutical composition in solid form containing isoflavones, a calcium salt and vitamin d3

Info

Publication number: WO2011113965A1
Application number: PCT/ES2010/000109
Authority: WO
Inventors: Ana María JIMÉNEZ REDONDO; Ángel Muñoz Ruiz; Nuria SANZ MENÉNDEZ; Fernando MARTÍNEZ-ALZAMORA GARCÍA; Antonia GÓMEZ CALVO; Gonzalo HERNÁNDEZ HERRERO
Original assignee: Farmalider, S.A.
Priority date: 2010-03-18
Filing date: 2010-03-18
Publication date: 2011-09-22

Abstract

The present invention relates to a new pharmaceutical composition in solid form comprising specific quantities of isoflavones, calcium ions in salt form and vitamin D₃. Moreover it relates to the utilization of said composition for the preparation of powders for oral suspension, granules for oral suspension, effervescent tablets and dispersible tablets. Furthermore it relates to powders for oral suspension, granules for oral suspension, effervescent tablets and dispersible tablets prepared with said composition. The composition of the invention is employed for the prevention and/or treatment of osteoporosis in women in the early stages of the menopause who may suffer slight or moderate symptoms associated with the menopause due to a reduction in oestrogens.

Description

PHARMACEUTICAL COMPOSITION IN SOLID FORM CONTAINING ISOFLAVONES, A CALCIUM SALT AND VITAMIN D ₃

Technical field

The present invention relates to a new pharmaceutical composition in solid form containing isoflavones, calcium ions in the form of salt and vitamin D ₃ for the prevention and / or treatment of osteoporosis.

Prior art

According to the FAO (Food and Agriculture Organization of the United Nations), osteoporosis is a chronic disease, currently very common in the elderly, especially in women, in industrialized countries. The disease is characterized by excessive demineralization of the bones, which translates into a decrease in bone mass and its mechanical resistance, generating weakness and fragility in the bones.

Bones are a dynamic tissue that constantly experiences resorption and formation. Bone formation exceeds resorption in children of growing age, is in balance in healthy adults and is behind resorption after menopause and in elderly people.

In western countries it has been recognized that osteoporosis represents one of the most important health problems that affects women and the elderly in general, significantly affecting expectations and quality of life. In fact, osteoporosis is the leading cause of bone fractures in women of postmenopausal age. There are several alternatives for the prevention and treatment of osteoporosis. The use of hormones was one of the first used, but due to doubts about its safety, and the availability of other drugs, the role of hormonal treatment has been changing.

The use of fluoride to increase bone density has also been described. For example, PCT patent application WO-A-03/055500 describes an oral pharmaceutical composition in the form of chewable tablets, effervescent granules or effervescent tablets containing a salt with fluoride ions, vitamin D and elemental calcium in the form of salt .

Among the drugs used to prevent the loss of bone mass can be mentioned bisphosphonates (for example alendronate or etidronate), calcitonin, which is a hormone produced by the thyroid gland that is involved in calcium and phosphorus metabolism, and modulators selective estrogen receptors (for example raloxifene).

However, one of the best treatments for osteoporosis is considered prevention. Thus, an adequate intake of calcium and the practice of physical exercise during adolescence and youth can increase bone mass, which results in a reduction in bone loss and a lower risk of fracture in later years.

It is also well known that supplementing the diet with a combination of calcium and vitamin D can positively influence the remineralization of bones. Calcium is one of the main minerals in the human body, being more than 99% of it in the bones, and their absorption is favored by the presence of vitamin D.

In the articles Chapuy et al., N. Engl. J. Med., 1992,327 (23): 1637-1642, Chapuy et al., BMJ, 1994; 308: 1081-1082, Dawson-Hughes et al., N. Engl. J. Med. 1997; 337: 670-676, Chapuy ef al. , Osteoporos Int. 2002; 13: 257-264 and Jackson et al., N. Engl. J. Med. 2006; 354; 669-683 describes that supplementing the diet with vitamin D ₃ and calcium reduces the risk of non-vertebral fractures among elderly people, particularly among women.

In the PCT patent application WO-A-92/19251 nutritional supplements are described which include the calcium salt of a mixture of citric acid and malic acid and vitamin D. In a preferred embodiment, the complement also includes an estrogen.

PCT patent application WO-A-96/09036 describes tablets for the treatment of osteoporosis comprising 400 Ul (international units equivalent to 10 pg) of vitamin D ₃ and 500 mg of calcium ions.

In the meta-analyzes carried out by Bischoff-Ferrari HA et al. , with 9,820 subjects from seven clinical trials, published in JAMA, 2005; 293 (18): 2257-64 and by Boonen S. et al., With 54,592 subjects from nine clinical trials, published in J. Clin. Endocrinol Metab., 2007; 92 (4): 1415-23, it is concluded that a dose of Vitamin D between 700 and 800 IU / day, with or without a calcium supplement, results in a 26% reduction in the relative risk of suffering a fracture of hip and 23% of non-vertebral fractures compared to the use of ^" calcium alone or placebo. However, when analyzing the therapeutic value of Vitamin D in combination With calcium, or otherwise without the administration of calcium, it is observed that only the combination of oral Vitamin D with calcium reduces the risk of hip fractures, this reduction of the risk of fractures being equivalent to 25%, with respect to the use of Vitamin D alone.

In a review by Boonen et al., J. Intern. Med., 2006, 259 (6), 539-552, it is indicated that the complement with the combination of calcium and vitamin D is an essential component for the treatment of osteoporosis. Reference is also made to the fact that compliance with the medical prescription is essential to optimize clinical efficacy.

The administration of phytoestrogens, for example isoflavones, for the prevention and / or treatment of osteoporosis is also described in the prior art.

In the article Potter ef a /., Am. J. Clin. Nutr. 1998; 68 (suppl): 1375S-9S, it is described that daily administration of 90 mg of isoflavones for 24 weeks significantly increases the content and density of bone mass in the lumbar spine of postmenopausal women.

In the article by Alekel et al., Am. J. Clin. Nutr., 2000; 72 (3): 844-52, the results of a 24-week trial in perimenopausal women are described and it is concluded that soy protein rich in isoflavones at a daily dose of 80.4 mg of isoflavones combined with Low doses of calcium (160 mg) and Vitamin D attenuates the loss of bone mass in the lumbar vertebrae of these women. In articles published by Chen et al., In J. Clin. Endocrinol

Metab., 2003; 88 (10): 4740-7 and Menopause. 2004; 1 1 (3): 246-254, be describes that daily administration to postmenopausal women of a combination containing 80 mg of soy isoflavones with low doses of calcium (500 mg) and vitamin D3 (125 Ul) increases bone mineralization after 12 months of treatment, preferably in those women with low levels of bone mass or that are in a late stage of postmenopause.

In the meta-analysis carried out by Ma et al. with 608 subjects from ten clinical studies, published in Clin. Nutr., 2008; 27 (1): 57-64, it is concluded that the administration of doses greater than 90 mg / day of isoflavones attenuates the loss of bone mass of the spine in postmenopausal women.

In the article by Morabito et al., J. Bone Miner. Res., 2002; 17 (10):

1904-12, it is described that the daily administration of the genistein phytoestroger at a dose of 54 mg / day or a hormone replacement therapy for 1 year increases in both cases the density of the bone mass in the hip and lumbar spine.

In the article by Marini et al., Ann. Intern. Med., 2007; 146 (12): 839-847, it is described that the treatment of osteopenic postmenopausal women with the combination of genistein phytoestrogen at a dose of 54 mg plus low doses of calcium (500 mg) and Vitamin D (400 Ul) for 2 years has effects positive about their bone density. In the article by Mucci et al., Minerva Ginecol., 2006; 58 (4): 323-

334, a formulation for the treatment of vasomotor menopausal symptoms containing soy isoflavones, lactobacilli, calcium, vitamin D3, magnesium and magnolia bark extract is described. PCT patent application WO-A-2007/021 166 describes compositions containing isoflavones and which are used in the treatment of menopausal physiological disorders and symptoms In the European patent application EP-A-1481676 oral pharmaceutical compositions are described useful for the treatment of women affected by menopausal disorders. Such compositions contain lactic bacteria and soy isoflavones. US Pat. No. 565401 1 describes a dietary supplement for postmenopausal women that contains minerals (calcium, magnesium, boron, copper, manganese, iron, chromium and zinc), vitamins (D, B- | ₂ , B ₆ , E and C) and also contains phytoestrogens. In the article M. Kido, Clin. Calcium., 2005; 15 (6): 1042-1044, it is described that osteoporosis can be prevented with proper diet and physical exercise. Among the dietary supplements that can increase bone density are calcium, vitamin D, vitamin K and isoflavones. He also warns that the combined use of multivitamins and multiminerals with calcium or vitamin D can lead to hypercalcemia and can be toxic.

European patent application EP-A-0931549 describes an instant granulate containing 500 mg of calcium, 400 Ul of vitamin D3 and 7.7 g of soybean meal, which corresponds to a content between 15.4 and 23 mg of isoflavones Said granulate contains a surfactant to improve the wettability of soybean meal and to achieve a better suspension of the granulate in water before administration. Despite everything referred to in the state of the art, there is still a need to have a pharmaceutical formulation containing an appropriate combination of isoflavones, vitamin D ₃ and a calcium compound for the prevention and / or treatment of Osteoporosis in women who are at an early stage of menopause, to avoid having to resort to several products to follow the prescribed medical treatment and to ensure a good degree of compliance as it is a prolonged treatment. Object of the invention

Therefore, the object of the invention is a pharmaceutical composition in solid form comprising isoflavones, calcium ions in the form of salt and vitamin D3. The use of said pharmaceutical composition for the preparation of a powder or granulate for oral suspension, an effervescent tablet and a dispersible tablet is also part of the object of the invention.

Also part of the object of the invention is a powder for oral suspension comprising said pharmaceutical composition.

Also part of the object of the invention is a granulate for oral suspension comprising said pharmaceutical composition. An effervescent tablet comprising said pharmaceutical composition is also part of the object of the invention.

Likewise, a dispersible tablet comprising said pharmaceutical composition is part of the object of the invention.

Detailed description of the invention The object of the present invention is a solid pharmaceutical composition comprising, for every 500 to 2,000 mg of calcium ions in salt form,

a) between 40 and 120 mg of soy isoflavones and

b) between 600 and 1,200 Ul of vitamin D ₃ .

The authors of this invention have developed a pharmaceutical composition in solid form with isoflavones, a compound of calcium and vitamin D ₃ for the prevention and / or treatment of osteoporosis that can be used to prepare powders or granules for oral suspension, effervescent tablets and dispersible tablets, which avoids having to resort to several products to follow the prescribed medical treatment, and that, thereby, ensures a good degree of compliance, particularly in the case of prolonged treatments.

Calcium salt

The calcium ions present in the pharmaceutical composition of the invention come from a salt. The calcium salts that are used as a source of calcium ions can be organic or inorganic. These include, for example: calcium carbonate, calcium bicarbonate, calcium chloride, calcium fluoride, calcium fluorophosphate, dibasic calcium phosphate, monobasic calcium phosphate, tribasic calcium phosphate, calcium pyrophosphate, calcium sulfate , calcium acetate, calcium propionate, calcium glucarate, calcium lactate, tricalcium dicitrate, monocalcic citrate, calcium gluconate, calcium glutamate, calcium lactobionate, calcium levulinate, calcium pantothenate, the hemicálcic salt of pantothenic acid, calcium phenylpyruvate, calcium ascorbate, calcium glucoheptonate, calcium tartrate, calcium malate and calcium glycerophosphate. Preferably, the calcium salt is selected from the group consisting of calcium carbonate, calcium chloride, dibasic calcium phosphate, monobasic calcium phosphate, tribasic calcium phosphate, calcium lactate, tricalcium dicitrate, monocalcic citrate, calcium gluconate and / or mixtures of such salts.

Particularly preferably, the calcium salt is selected from the group consisting of calcium carbonate, calcium lactate, tricalcium dicitrate, calcium gluconate and / or mixtures of such salts.

Particularly preferably, the calcium salt is calcium carbonate.

The above-mentioned calcium salts are commercially available and can be obtained, for example, from the companies Sigma Aldrich, Merck, Solvay Osterreich GmbH, Specialty Minerals, DMV, Particle Dinamics Inc., Societá Genérale per Nndustria della Magnesia SpA, JM Huber Corporation, Omya SAS, Shanghai Dayu Biochemistry CO. Ltd., Magnesia Gmbh. Rhodia Organic Fine Ltd, or JRS Pharma Ltd.

The content of calcium salt present in the composition of the invention is such that it provides between 500 and 2,000 mg of calcium ions, preferably between 800 and 1,500 mg, especially between 900 and 1,400 mg, and in particular between 1,000 and 1,200 mg of calcium ions

Thus, for example in the case of using calcium carbonate, to provide 500 mg of calcium ions it is necessary to use 1,250 mg of calcium carbonate.

Soy Isoflavones Isoflavones are polyphenolic compounds that are widely distributed in the plant kingdom. More than 700 of them have been described. However, isoflavones that have estrogenic effects belong to a small subgroup and are almost exclusively from the legume family, usually referred to as "phytoestrogens."

Soy beans are the most important source of estrogenic isoflavones in people's diet.

In soy, isoflavones are mainly in the form of glycosides, that is, the isoflavone molecule is bound to a sugar molecule, mainly glucose. After ingestion of soybeans, the rest of the sugar in the molecule is hydrolyzed by the action of gastric acids and by the fermentation of intestinal bacteria. In this way isoflavone is released in the form of an aglycone, which is absorbed and passes into the bloodstream.

Among the glycosides of soy isoflavones are: genistin, daidzine and glicitin. Their respective aglycones are called genistein, daidzein and glycytein.,

The soy isoflavones contained in the composition of the invention may be incorporated therein in the form of soy flour, defatted soy flour, soy protein powder or mixtures thereof. However, it is preferred to use an extract of soy isoflavones containing isoflavones in the form of genistin, daidzine and glycidine glycosides. Such extracts can be found on the market, for example under the name SOLGEN 40 (Soybean isoflavone dry extract 40%) marketed by the company Solbar Plant Extracts Ltd. Said extract contains 40% by weight of soy isoflavones.

Soy isoflavones can also be incorporated in the form of nanoparticles, for example such as those described in patent application WO-A-2007/000192.

The pharmaceutical composition of the invention contains between 40 and 120 mg of soy isoflavones per 500 to 2,000 mg of calcium ions in salt form, preferably between 60 and 100 mg, especially preferably between 70 and 90 mg and in particular between 75 and 85 mg.

Especially preferred amounts are: 80 mg of soy isoflavones per 1,000 mg of calcium ions in salt form and 80 mg of soy isoflavones for every 1,200 mg of calcium ions in salt form.

Vitamin Da

Vitamin D is associated with the prevention of rickets and is essential for adequate calcium absorption. Vitamin D is a fat-soluble vitamin that includes different forms with open steral structure. The most important representatives are: vitamin D ₂ (ergocalciferol) and vitamin D ₃ (cholecalciferol), although mention can also be made of vitamin Di (molecular compound of ergocalciferol with lumisterol in a 1: 1 ratio), vitamin D ₄ (22-dihydroergocalciferol ) and vitamin D ₅ (sitocalciferol).

In the pharmaceutical composition of the invention, vitamin D ₃ can be incorporated either as such or as a powder concentrate. For example, the Dry Vitamin D ₃ Type 100 CWS product, marketed by the company DSM, is available on the market. Said product It is a powdered cholecalciferol concentrate that contains, as excipients, dl-a-tocopherol, partially hydrogenated soybean oil, hydrolyzed bovine gelatin, sucrose and corn starch. The vitamin D3 content of this concentrate is 100,000 Ul per gram of concentrate.

Alternatively, vitamin D ₃ can also be incorporated in the form of nanoparticles. Frequently, the content of vitamin D ₃ is expressed in international units (IU), where 1 Ul equals 0.025 pg of vitamin D ₃ .

The pharmaceutical composition of the invention contains between 600 and 1,200 Ul of vitamin D ₃ for every 500 to 2,000 mg of calcium ions in salt form, preferably between 700 and 1,000 Ul and especially between 750 and 900 Ul. Especially preferred are 800 Ul for every 1 000 mg of calcium ions in salt form, 880 Ul for every 1 000 mg of calcium ions in salt form, 800 Ul for every 1,200 mg of calcium ions in salt form and 880 Ul per 1,200 mg of calcium ions in salt form.

Especially preferred pharmaceutical compositions of the invention are those that contain the combinations of calcium ions, soy isoflavones and vitamin D ₃ shown in Tables I to IV: Table I

Component Quantity

Calcium ions in salt form 1,000 mg

Soy Isoflavones 80 mg

Vitamin D ₃ 800 Ul

Table II

Component Quantity

Calcium ions in salt form 1, 000 mg

Soy Isoflavones 80 mg

Vitamin D3 880 U.l.

Table III

Component Quantity

Calcium ions in salt form 1,200 mg

Soy Isoflavones 80 mg

Vitamin D3 800 U.l.

Table IV

Component Quantity

Calcium ions in salt form 1,200 mg

Soy Isoflavones 80 mg

Vitamin D ₃ 880 Ul The use of the composition of the invention for the preparation of a powder or granulate for oral suspension, an effervescent tablet and a dispersible tablet is also part of the object of the invention.

The pharmaceutical composition of the invention is useful for the prevention and / or treatment of osteoporosis in women who are at an early stage of menopause and who may also suffer from mild to moderate vasomotor symptoms, especially hot flashes, due to the lack of estrogen

Also part of the object of the invention is a powder or granulate for oral suspension comprising a therapeutically effective amount of the pharmaceutical composition in solid form of the invention and at least one pharmaceutically acceptable excipient. Powder for oral suspension is a finely divided powdery product intended to be suspended in water before being administered. The granule 'for oral suspension is a powdery product or a set of dry aggregates sufficiently resistant for handling intended to be suspended in water before being administered. Said powder or granules can be prepared using methods well known to those skilled in the art, for example those contained in manuals pharmaceutical technology as "Remington The Science and Practice of Pharmacy", 20 ^th Edition, Lippincott, Williams & Wilkins, Philadelphia, 2000 [ISBN: 0-683-306472]. For example, and in the case of powder for oral suspension, it can be prepared by a procedure that includes weighing the individual components and homogenizing them in a mixer suitable for dry mixing of solid products. It can also be prepared by wet granulation, thus obtaining the granulate for oral suspension. Once a homogeneous product has been obtained, the powder or granulate for Oral suspension is preferably conditioned as a single dose. A single dose may consist, for example, of a tightly sealed envelope containing the amount of powder for oral suspension to prepare an extemporaneous suspension. In this way the correct dosage is facilitated by the patient, since he knows that the entire contents of the envelope should be taken. The envelopes can be formed by an outer layer of paper, an intermediate layer of aluminum and an inner layer of polyethylene or modified polyethylenes. Said envelopes can be prepared by procedures that are available to the person skilled in the art.

Among the pharmaceutically acceptable excipients that can be included in the powder for oral suspension are anti-caking agents such as anhydrous colloidal silica, tribasic calcium phosphate, magnesium trisilicate, talc; lubricating agents such as magnesium stearate, calcium stearate, glyceryl palmostearate, magnesium oxide, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, glycerin behenate; suspending agents such as xanthan gum, guar gum, alginic acid, bentonite, carbomers, sodium or calcium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropyl alginate, microcrystalline or powdered cellulose, colloidal anhydrous silica, catholic magnesium dextrin, aluminasic silica, aluminasic silica, aluminasic silica, aluminas, silica maltitol, povidone, sorbitan esters, tragacanth; binding agents such as magnesium trisilicate, cellulose, starch, talc, polyvinyl pyrrolidone, tribasic calcium phosphate; dispersing agents such as low-grade hydroxypropylcellulose, poloxamers or sorbitan esters; sweetening agents such as aspartame, mannitol, sorbitol, sodium saccharin, sodium cyclamate, sucrose, dextrose, fructose, glucose, inulin, isomalt, lactitol, maltose, maltol, mannitol, sucralose, trehalose, xylitol, thaumatine; flavoring and flavoring agents, and / or mixtures thereof. Among the pharmaceutically acceptable excipients that can be included in the granulate for oral suspension are the same as for the powder for oral suspension, but using a liquid carrier for agglutination of the solid components, for example purified water.

Preferably, the powder or granulate for oral suspension comprises as excipients mannitol, anhydrous colloidal silica, xanthan gum and hydroxypropylcellulose of low degree of substitution. In a particularly preferred embodiment, the powder or the granulate for oral suspension further comprises a sweetener system and flavoring agents. The liquid vehicle for agglutination is the only substantial difference between both pharmaceutical forms. A single dose of powder or granulate for especially preferred oral suspension comprises 1,000 mg of calcium ions in salt form, 800 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 420 and 500 mg of mannitol, between 50 and 70 mg of colloidal anhydrous silica, between 80 and 100 mg of xanthan gum, between 80 and 120 mg of hydroxypropylcellulose of low degree of substitution.

Another single dose of powder or granulate for especially preferred oral suspension comprises 1 000 mg of calcium ions in salt form, 880 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 420 and 500 mg of mannitol, between 50 and 70 mg of anhydrous colloidal silica, between 80 and 100 mg of xanthan gum, between 80 and 120 mg of low-grade hydroxypropylcellulose.

Another single dose of powder or granulate for especially preferred oral suspension comprises 1,200 mg of calcium ions in salt form, 800 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 420 and 500 mg of mannitol, between 50 and 70 mg of colloidal anhydrous silica, between 80 and 100 mg of xanthan gum, between 80 and 120 mg of low-grade hydroxypropylcellulose. Another single dose of powder or granulate for especially preferred oral suspension comprises 1,200 mg of calcium ions in salt form, 880 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 420 and 500 mg of mannitol, between 50 and 70 mg of anhydrous colloidal silica, between 80 and 100 mg of xanthan gum, between 80 and 120 mg of low-grade hydroxypropylcellulose.

In a particularly preferred embodiment, the single-dose powder or granules for suspension further comprises between 10 and 14 mg of sodium saccharin and I enter 20 and 100 mg of flavoring and flavoring agents.

Physico-chemical properties of excipients characteristics as well as the name of the commercial products under which they are sold can be found in the book of RC Rowe et al., Handbook of Pharmaceutical Excipients, 4th edition, Pharmaceutical Press, London, 2003 [ISBN: 0-85369-472-9].

Also part of the object of the invention is an effervescent tablet comprising a therapeutically effective amount of the pharmaceutical composition in solid form of the invention, a carbonic anhydride generating system and at least one pharmaceutically acceptable excipient. In addition to the composition of the invention, effervescent tablets include a solid system for generating carbon dioxide, generally a carbonate and / or an alkali metal bicarbonate, such as sodium or potassium bicarbonate, together with an organic acid or an acid salt. of it, which react quickly in presence of water Among the organic acids can be mentioned: citric acid, tartaric acid, ascorbic acid, malic acid, fumaric acid and maleic acid. Preferably citric acid is used. Other excipients may also be included in the effervescent tablet, for example diluting agents such as lactose, calcium phosphate, calcium sulfate, calcium carboxymethyl cellulose, microcrystalline or powdered cellulose, cellulose acetate, dextrates, dextrins, dextrose, fructose, glycerin palmostearate, kaolin , lactitol, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, polymethacrylates, pregelatinized starch, sodium chloride, starch, sucrose, sucrose; binding agents such as polyvinylpyrrolidone, magnesium trisilicate, cellulose, starch, talcum, tribasic calcium phosphate; sweetening agents such as mannitol, sorbitol, sodium saccharin, sodium cyclamate, aspartame, sucrose, dextrose, fructose, glucose, inulin, isomalt, lactitol, maltose, maltol, mannitol, sucralose, trehalose, xylitol, thaumatine; lubricating agents such as magnesium stearate, calcium stearate, glyceryl palmostearate, magnesium oxide, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, glycerin behenate, polyethylene glycol; antifoaming agents such as simethicone emulsion; agglutination vehicle as purified water; flavoring and flavoring agents, and / or mixtures thereof. The excipients are selected to achieve a degree of friability and hardness that are appropriate both to maintain the shape of the tablet during the entire period of manufacture and validity of the product, and to ensure that they disintegrate completely in water in the period of time established in the current monographs for said pharmaceutical form. This selection is a task that is usually carried out by the person skilled in the art. An especially preferred effervescent tablet comprises as excipients anhydrous citric acid, sodium bicarbonate, lactose monohydrate, polyvinyl pyrrolidone, polyethylene glycol 6000 and an antifoaming agent. In a particularly preferred embodiment, the effervescent tablet further comprises a sweetener system and flavoring and flavoring agents.

In a preferred embodiment, the effervescent tablet comprises, as a carbonic anhydride generating system, between 3,000 and 5,000 mg of anhydrous citric acid and between 200 and 300 mg of sodium bicarbonate and between 2,500 and 3,000 mg of calcium carbonate, especially between 3,500 and 4,500 mg of anhydrous citric acid, and between 220 and 280 mg of sodium bicarbonate and between 2,500 and 3,000 mg of calcium carbonate, and in particular between 3,900 and 4,100 mg of anhydrous citric acid and between 240 and 260 mg of bicarbonate of sodium and between 2,500 and 3,000 mg of calcium carbonate.

An especially preferred effervescent tablet comprises 1,000 mg of calcium ions in the form of carbonate, 800 U.l. of vitamin D3, 80 mg of soy isoflavones, between 3,900 and 4,100 mg of anhydrous citric acid, between 240 and 260 mg of sodium bicarbonate, between 320 and 420 mg of lactose monohydrate, between 10 and 20 mg of polyvinylpyrrolidone K25, between 150 and 180 mg of polyethylene glycol 6000 and between 0.5 and 5 mg of simethicone emulsion as antifoam agent. »

Another especially preferred effervescent tablet comprises 1,000 mg of calcium ions in the form of carbonate, 880 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 3,900 and 4,100 mg of anhydrous citric acid, between 240 and 260 mg of sodium bicarbonate, between 320 and 420 mg of lactose monohydrate, between 10 and 20 mg of polyvinylpyrrolidone K25, between 150 and 180 mg of polyethylene glycol 6000 and between 0.5 and 5 mg of simethicone emulsion as antifoam agent.

Another especially preferred effervescent tablet comprises 1,200 mg of calcium ions in the form of carbonate, 800 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 3,900 and 4,100 mg of anhydrous citric acid, between 240 and 260 mg of sodium bicarbonate, between 320 and 420 mg of lactose monohydrate, between 10 and 20 mg of polyvinylpyrrolidone K25, between 150 and 180 mg of polyethylene glycol 6000 and between 0.5 and 5 mg of simethicone emulsion as an antifoam agent.

Another especially preferred effervescent tablet comprises 1,200 mg of calcium ions in the form of carbonate, 880 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 3,900 and 4,100 mg of anhydrous citric acid, between 240 and 260 mg of sodium bicarbonate, between 320 and 420 mg of lactose monohydrate, between 10 and 20 mg of polyvinylpyrrolidone K25, between 150 and 180 mg of polyethylene glycol 6000 and between 0.5 and 5 mg of simethicone emulsion as an antifoam agent. In a particularly preferred embodiment, the effervescent tablet further comprises between 10 and 20 mg of sodium saccharin, between 50 and 75 mg of sodium cyclamate and between 5 and 25 mg of flavoring and flavoring agents. The physical-chemical characteristics of the excipients, as well as the name of the commercial products under which they are marketed, can be found in the book "Handbook of Pharmaceutical Excipient" already mentioned. Effervescent tablets can be manufactured according to procedures that are well known in the state of the art, such as described in the aforementioned Remington book. For example, they can be prepared by a procedure that includes the weighing of the components, the granulation of part thereof together or separately in one or more granules and their subsequent homogenization with the rest of the components of the formulation in a mixer suitable for subsequent compression. It can also be prepared by dry mixing the components of the formulation and compression. Once homogeneous tablets have been obtained, they are preferably conditioned in a material that protects them from light and moisture. For example, in a tube with a cap fitted with a desiccant and closure system, or in an aluminum-aluminum blister or a PVC / Aclar-aluminum blister. The tubes can be formed by polypropylene and the caps by polyethylene with white desiccant gel. All the components of the indicated conditioning materials can be prepared by procedures that are available to the person skilled in the art.

Also part of the object of the invention is a dispersible tablet, possibly coated, intended to be dispersed in water before administration, resulting in a homogeneous dispersion comprising a therapeutically effective amount of the pharmaceutical composition in solid form of the invention, and a disintegrating system Said dispersible tablet can be prepared using methods well known to the person skilled in the art, for example those contained in pharmaceutical technology manuals such as the Remington book already mentioned. For example, it can be prepared by a procedure that includes weighing individual components and homogenizing them in a mixer suitable for dry mixing of solid products. It can also be prepared by wet granulation. Once a homogeneous product has been obtained, the powder or granulate is compressed giving rise to dispersible tablets, which can be conditioned, by example, in PVC blisters - aluminum, PVC / PVDC - Aluminum or Aluminum - Aluminum. In addition to a therapeutically effective amount of the composition of the invention, dispersible tablets include a solid disintegrating system that, in contact with water, causes rapid disintegration of the tablet, generally a disintegrating agent such as alginic acid, carboxymethyl cellulose, low hydroxypropyl cellulose. degree of substitution, microcrystalline or powdered cellulose, anhydrous colloidal silica, croscarmellose sodium, crospovidone, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium starch glycollate, pregelatinized starch or starch and / or mixtures thereof. In addition, other excipients may be included in the dispersible tablet, for example diluting agents such as lactose, calcium phosphate, calcium sulfate, calcium carboxymethyl cellulose, microcrystalline or powdered cellulose, cellulose acetate, dextrates, dextrins, dextrose, fructose, glyceryl palmostearate, kaolin , lactitol, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, polymethacrylates, pregelatinized starch, sodium chloride, starch, sucrose, sucrose; disintegrating agents, binding agents ran polyvinylpyrrolidone, magnesium trisilicate, cellulose, starch, talcum, tribasic calcium phosphate; sweetening agents such as mannitol, sorbitol, sodium saccharin, sodium cyclamate, aspartate, sucrose, dextrose, fructose, glucose, inulin, isomalt, lactitol, maltose, maltol, mannitol, sucralose, trehalose, xylitol, thaumatine; lubricating agents such as magnesium stearate, calcium stearate, glyceryl palmitosterate, magnesium oxide, sodium benzoate, lauryl sulfate, sodium, sodium stearyl fumarate, stearic acid, talc, glycerin behenate, polyethylene glycol, flavoring and flavoring agents, and / or mixtures thereof.

In the case of coated dispersible tablets, in addition to the aforementioned excipients for dispersible tablets, those related to the formation of the coating, which comprise film-forming polymers such as hydroxypropylmethylcellulose, Eudragit®, cellulose acetophthalate, hydroxypropylmethylcellulose phthalates, polyvinyl acetophthalate, alginic acid and its derivatives, cellulose hydrogen phosphate, ethyl cellulose, plasticizers such as glycylene glycol glycol glycol monoglyceryl, ethylene glycol glycinate , phthalate esters, castor oil, sebacic acid esters, silicones, solvents such as methanol, methylene chloride, isopropanol, acetone, purified water, ethyl acetate, isopropanol, ethanol and coloring agents and / or mixtures thereof.

The excipients are selected to achieve a degree of friability and hardness that are appropriate to maintain the shape of the tablet throughout the period of manufacture and validity of the product, as well as adequate disintegration characteristics. This selection is a task that is usually carried out by the person skilled in the art.

An especially preferred dispersible tablet comprises, as excipients, microcrystalline cellulose, starch, pregelatinized starch, crospovidone and sodium stearyl fumarate. In a particularly preferred embodiment, the dispersible tablet further comprises a sweetener system and flavoring and flavoring agents. An especially preferred dispersible tablet comprises

1,000 mg of calcium ions in salt form, 800 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 860 and 1,050 mg of microcrystalline cellulose, between 840 and 1,030 mg of starch, between 330 and 410 mg of pregelatinized starch, between 360 and 400 mg of crospovidone and between 41 and 51 mg of sodium stearyl fumarate. Another especially preferred dispersible tablet comprises 1,200 mg of calcium ions in salt form, 800 Ul of vitamin D3, 80 mg of soy isoflavones, between 860 and 1,050 mg of microcrystalline cellulose, between 840 and 1,030 mg of starch, between 330 and 410 mg of pregelatinized starch, between 360 and 400 mg of crospovidone and between 41 and 51 mg of sodium stearyl fumarate.

Another especially preferred dispersible tablet comprises 1,000 mg of calcium ions in salt form, 880 U.l. of vitamin D3, 80 mg of soy isoflavones, between 860 and 1,050 mg of microcrystalline cellulose, between 840 and 1,030 mg of starch, between 330 and 410 mg of pregelatinized starch, between 360 and 400 mg of crospovidone and between 41 and 51 mg of sodium stearyl fumarate. Another dispersible tablet especially comprises 1,200 mg of calcium ions in salt form, 880 U.l. of vitamin D3, 80 mg of soy isoflavones, between 860 and 1,050 mg of microcrystalline cellulose, between 840 and 1,030 mg of starch, between 330 and 410 mg of pregelatinized starch, between 360 and 400 mg of crospovidone and between 41 and 51 mg of sodium stearyl fumarate.

In a particularly preferred embodiment, the dispersible tablet further comprises between 10 and 20 mg of sodium saccharin, between 50 and 75 mg of sodium cyclamate and between 5 and 25 mg of flavoring and flavoring agents.

The physical-chemical characteristics of the excipients, as well as the name of the commercial products under which they are marketed, can be found in the book "Handbook of Pharmaceutical Excipients" already mentioned. Regardless of the pharmaceutical form used, to compensate for possible losses of vitamin D3, either during manufacturing and / or during the period of validity of the composition of the invention, it can be overdosed between 10% and 20% during the fabrication process.

The compositions of the invention in the form of powder or granulate for oral suspension or effervescent tablet or dispersible tablet contain proportions of calcium ions in the form of salt, soy isoflavones and vitamin D3 that are suitable for prevention and / or treatment of osteoporosis in women who are in an early stage of menopause.

Soy isoflavones (genistein and daidzein), known as phytoestrogens, act as selective natural modulators of estrogen receptors by selective binding to beta-estrogenic receptors. These compounds, administered with a complement of calcium and vitamin D3, behave as adjuvants in the prevention and treatment of postmenopausal osteoporosis, preventing bone loss resulting from estrogenic deficiency and thus reducing the risk of fractures in postmenopausal women. Additionally, due to their estrogen modulating actions, soy isoflavones decrease vasomotor symptoms of the climacteric, especially hot flashes and night sweats.

The presentation in the form of a single dose powder or granulate for oral suspension, effervescent tablet and dispersible tablet ensures the degree of compliance by the patient in a treatment that is carried out for long periods of time. The composition of the invention has a high safety profile, since for the components thereof no serious or unexpected adverse reactions have been described when used for the prevention and / or treatment of menopause. For example, in relation to calcium ions in salt form, according to the article by Dawson-Hughes et al. already mentioned, the side effects observed in clinical trials with calcium carbonate are mainly gastrointestinal and include diarrhea, nausea, epigastric pain and constipation, and occur with a frequency of less than 1%. With regard to vitamin D ₃ , it should be noted that the main source of it is exposure to sunlight and that in one day you can get up to 250 pg (10,000 Ul) of vitamin D3, suggesting that this would be the limit physiological. Therefore, daily administration of 800 to 880 Ul does not cause toxic effects. In the article by R. Vieth, Am. J. Clin. Nut., 1999, 69, 842-856, it is described that the toxicity due to vitamin D ₃ in which hypercalcemia is observed appears from 1,000 pg (40,000 IU). With respect to soy isoflavones, in the article by Munro et al., Nutr. Rev., 2003, 61 (1), 1-33, it is described that it is known that they have been consumed for years as part of soy-rich diets without reports of adverse effects.

The following examples serve to illustrate the invention, but do not limit it in any way. Examples

In all the examples the following sources have been used for each of the active ingredients, without being equally limiting, just to illustrate the invention. The calcium carbonate salt in which 3,000 mg thereof equals 1,200 mg of calcium ion is used to incorporate the calcium ion. For the incorporation of the vitamin D3 uses a powdered cholecalciferol concentrate, at a rate of 100,000 Ul per gram of concentrate, containing as excipients dl-a-tocopherol, partially hydrogenated soybean oil, hydrolyzed bovine gelatin, sucrose and corn starch. This product is available on the market under the trade name Dry Vitamin D ₃ Type 100 CWS marketed by the company DSM. Soy isoflavones extract contains 40% isoflavones. In the market it can be found under the trade name SÓLGEN 40 (Soybean isoflavone dry extract 40%) marketed by the company Solbar Plant Extracts LTD.

Example 1.

Preparation of a powder formulation for oral suspension with 1.0 g of calcium ions in salt form, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones

The process for preparing the powder formulation for oral suspension with a dose of 1.0 g of calcium ions in salt form, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones, included the weighing of the individual components , the homogenization in several phases of the ingredients in a mixer suitable for mixing solid products and filling the single-dose sachets with 3.5 g of the formulation. Table V shows the ingredients used

Table V

* Cholecalciferol concentrate is overdosed by 20%, that is, it is added at a rate of 9.6 mg instead of the declared 8.0 mg, to compensate for losses during the period of validity of the product, adjusting the final weight with the mannitol

The daily dose is in a single dose of 3.5 g powder, which is contained in an envelope consisting of an outer layer of paper, an intermediate layer of aluminum and an inner layer of polyethylene. Said envelope can be prepared according to the usual technical knowledge without the need for a particular technology. Example 2

Preparation of a powder formulation for oral suspension with 1.2 g of calcium ions in salt form, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones

Following a procedure analogous to that described in Example 1, a powder formulation was prepared for oral suspension with 1.2 g of calcium ions in salt form, 800 Ul of vitamin D3 and 80 mg of soy isoflavones. 3,000 mg of calcium carbonate (corresponding to 1.2 g of calcium ions), 9.6 mg of cholecalciferol concentrate in powder form (corresponding to 960 Ul of vitamin D ₃ ) and 200 mg of extract of soy isoflavones (corresponding to 80 mg of isoflavones). The amounts of the other excipients were the same as in Example 1. A single dose contains 4.0 g of the powder for oral suspension obtained.

Example 3

Preparation of a powder formulation for oral suspension with 1.0 g of calcium ions in salt form, 880 Ul of vitamin D ₃ and 80 mg of soy isoflavones

Following a procedure analogous to that described in Example 1, a powder formulation for oral suspension was prepared with 1.0 g of calcium ions in the form of salt, 880 Ul of vitamin D ₃ and 80 mg of soy isoflavones. 2,500 mg of calcium carbonate (corresponding to 1.2 g of calcium), 10.56 mg of cholecalciferol concentrate in powder form (corresponding to 1,056 Ul of vitamin D3) and 200 mg of isoflavone extract were used. soybeans (corresponding to 80 mg of isoflavones). The amounts of the other excipients were the same as in Example 1, with the exception of mannitol, the amount of which was reduced to 457.44 mg. A single dose contains 3.5 g of the powder for oral suspension obtained.

Example 4

Preparation of a powder formulation for oral suspension with 1.2 g of calcium ions in salt form, 880 Ul of vitamin D ₃ and 80 mg of soy isoflavones

Following a procedure analogous to that described in Example 1, a powder formulation for oral suspension was prepared with 1.2 g of calcium ions in the form of salt, 880 Ul of vitamin D3 and 80 mg of soy isoflavones. For this purpose, 3,000 mg of calcium carbonate (corresponding to 1.2 g of calcium ions), 10.56 mg of cholecalciferol concentrate in powder form (corresponding to 1,056 Ul of vitamin D ₃ ) and 200 mg of extract were used. soy isoflavones (corresponding to 80 mg of isoflavones). The amounts of the other excipients were the same as in Example 1, with the exception of mannitol, the amount of which was reduced to 457.44 mg. A single dose contains 4.0 g of the powder for oral suspension obtained.

Example 5

Preparation of a formulation in the form of granules for oral suspension with 1.0 g of calcium ions in salt form, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones

The process for preparing the formulation in the form of granules for oral suspension with a dose of 1.0 g of calcium ions in salt form, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones, included the weighing of the individual components , wet granulation of calcium salt and isoflavone extract with a dispersion of cholecalciferol concentrate in water, subsequent homogenization in several phases of said granulate with the other ingredients in a mixer suitable for mixing solid products and filling single dose envelopes with 3.5 g of formulation. Table VI shows the ingredients used.

Table VI

* Cholecalciferol concentrate is overdosed by 20%, that is, it is added at a rate of 9.6 mg instead of the declared 8.0 mg, to compensate for losses during the period of validity of the product, adjusting the final weight with the mannitol It disappears during the manufacturing process The daily dose is in a single dose of 3.5 g granules, which is contained in an envelope consisting of an outer layer of paper, an intermediate layer of aluminum and an inner layer of polyethylene. These about can be prepared according to the usual technical knowledge without the need for a particular technology.

Example 6

Preparation of a formulation in the form of granules for oral suspension with 1.2 g of calcium ions in salt form, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones

Following a procedure analogous to that described in Example 5, a granulated formulation for oral suspension was prepared with 1.2 g of calcium ions in salt form, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones. 3: 000 mg of calcium carbonate (corresponding to 1.2 g of calcium ions), 9.6 mg of cholecalciferol concentrate in powder form (corresponding to 960 Ul of vitamin D3) and 200 mg of extract were used of soy isoflavones (corresponding to 80 mg of isoflavones). The amounts of the other excipients were the same as in Example 5. A single dose contains 4.0 g of the granulate for oral suspension obtained.

Example 7

Preparation of a formulation in the form of granules for oral suspension with 1.0 g of calcium ions in salt form, 880 Ul of vitamin D ₃ and 80 mg of soy isoflavones

Following a procedure analogous to that described in Example 5, a granulated formulation for oral suspension was prepared with 1.0 g of calcium ions in salt form, 880 Ul of vitamin D ₃ and 80 mg of soy isoflavones. 2,500 mg of carbonate of calcium (corresponding to 1.2 g of calcium), 10.56 mg of cholecalciferol concentrate in powder form (corresponding to 1,056 Ul of vitamin D3) and 200 mg of soy isoflavones extract (corresponding to 80 mg of isoflavones) . The amounts of the other excipients were the same as in Example 5, with the exception of mannitol, the amount of which was reduced to 457.44 mg. A single dose contains 3.5 g of the granulate for oral suspension obtained.

Example 8

Preparation of a formulation in the form of granules for oral suspension with 1.2 g of calcium ions in salt form, 880 Ul of vitamin D ₃ and 80 mg of soy isoflavones

Following a procedure analogous to that described in Example 5, a granulated formulation for oral suspension was prepared with 1.2 g of calcium ions in salt form, 880 U.l. of vitamin D3 and 80 mg of soy isoflavones. For this, 3,000 mg of calcium carbonate (corresponding to 1.2 g of calcium ions), 10.56 mg of cholecalciferol concentrate in powder form (corresponding to 1,056 Ul of vitamin D3) and 200 mg of isoflavone extract were used of soybean (corresponding to 80 mg of isoflavones). The amounts of the other excipients were the same as in Example 5, with the exception of mannitol, the amount of which was reduced to 457.44 mg. A single dose contains 4.0 g of the granulate for oral suspension obtained.

Example 9

Preparation of effervescent tablets with 1.0 g of calcium ions in salt form, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones The process for preparing the formulation in the form of an effervescent tablet with a dose of 1.0 g of calcium ions in the form of salt, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones included the weighing of the individual components, the alcoholic granulation by one part of the calcium salt and the isoflavone extract with part of excipients and the emulsion of simethicone, and on the other of the cholecalciferol concentrate with an alcoholic solution of povidone and another part of excipients, the subsequent homogenization in several phases of said granules with the remaining ingredients in a mixer suitable for mixing solid products and compression at a rate of 7.6 g per tablet. Table VII shows the ingredients used.

Table VII

Ingredient mg / comp. Commentary

Calcium carbonate ^$ 2,600 ^$ 1,000 mg of calcium ions remaining at the end of manufacturing

Concentrate of 9.2 * Equivalent to 920 Ul of cholecalciferol * vitamin D ₃

Isoflavone extract 200.0 Equivalent to 80 mg of soy isoflavones

Anhydrous citric acid ^8. 4,040 Effervescent / acidifying agent

Baking soda 250.0 Effervescent agent

Lactose monohydrate ^{* 8.} 377.9 ^* Diluent

Povidone K25 15.0 Binder

Sodium saccharin 15.0 Sweetener Ingredient mg / comp. Commentary

Sodium Cyclamate 60.0 Sweetener

Macrogol 6000 165.0 Lubricant

Aroma 10.0 Flavoring

Simethicone Emulsion 2.0 Antifoam

seca®

Ethanol 96% ^# is. Vehicle

Isopropyl alcohol * is. Vehicle

* Calcium carbonate is overdosed by 4% to compensate for manufacturing losses.

* Cholecalciferol concentrate is overdosed by 15%, that is, it is added at a rate of 9.2 mg instead of the declared 8.0 mg, to compensate for 5% losses during manufacturing and 10% to compensate during the period of validity of the product. The latter 10% is adjusted to the final weight with lactose monohydrate.

^& Anhydrous citric acid and lactose monohydrate are overdosed by 1% to compensate for manufacturing losses.

# Disappear during the manufacturing process.

® The dry simethicone emulsion is composed of: simethicone, methylcellulose (25 mPa.s) and methylcellulose (400 mPa.s) and contains 67% water before drying. The daily dose is in a single dose of 7.6 g effervescent tablet that is contained in a polypropylene tube with a polyethylene cap equipped with a white desiccant gel. Said tube and cap can be prepared in accordance with usual technical knowledge without the need for particular technology. Example 10

Preparation of effervescent tablets with 1.2 g of calcium ions in salt form, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones

Following an analogous procedure to that described in Example 9, effervescent tablets with 1.2 g of calcium ions in salt form, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones were prepared. For this, 3,120 mg of calcium carbonate (1.2 g of calcium ions remaining at the end of manufacture), 9.2 mg of cholecalciferol concentrate in powder form (corresponding to 920 Ul of vitamin D ₃ ) and 200 were used mg of soy isoflavones extract (corresponding to 80 mg of isoflavones). The amounts of the other excipients were the same as in Example 9. Each tablet weighs 8.1 g.

Example 11

Preparation of effervescent tablets with 1.0 g of calcium ions in salt form, 880 Ul of vitamin D ₃ and 80 mg of soy isoflavones

Following an analogous procedure to that described in Example 9, effervescent tablets with 1.0 g of calcium ions in salt form, 880 Ul of vitamin D3 and 80 mg of soy isoflavones were prepared. 2,600 mg of calcium carbonate (1.0 g of calcium ions remaining at the end of manufacturing), 10.12 mg of cholecalciferol concentrate in powder form (corresponding to 1,012 Ul of vitamin D ₃ ) and 200 were used. mg of soy isoflavones extract (corresponding to 80 mg of isoflavones). The amounts of the other excipients were the same as in Example 9, with the exception of lactose monohydrate, the amount of which was reduced to 377.1 mg. Each tablet weighs 7.6 g. Example 12

Preparation of effervescent tablets with 1.2 g of calcium ions in salt form, 880 Ul of vitamin D ₃ and 80 mg of soy isoflavones

Following an analogous procedure to that described in Example 9, effervescent tablets with 1.2 g of calcium ions in salt form, 880 Ul of vitamin D ₃ and 80 mg of soy isoflavones were prepared. For this, 3,120 mg of calcium carbonate were used (with 1.2 g of calcium ions remaining at the end of manufacturing), 10.12 mg of cholecalciferol concentrate in powder form (corresponding to 1,012 Ul of vitamin D ₃ ) and 200 mg of soy isoflavones extract (corresponding to 80 mg of isoflavones). The amounts of the other excipients were the same as in Example 9, with the exception of lactose monohydrate, the amount of which was reduced to 377.1 mg. Each tablet weighs 8.1 g.

Example 13

Preparation of dispersible tablets with 1.0 g of calcium ions in salt form, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones

The process for preparing the formulation in the form of a dispersible tablet with a dose of 1.0 g of calcium ions in the form of salt, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones, included the weighing of the individual components, the wet granulation of the calcium salt and the isoflavone extract with a dispersion of the cholecalciferol concentrate and a portion of the starch in water, the subsequent multi-stage homogenization of said granulate with the other ingredients in a mixer suitable for mixing solid products , and its compression at a rate of 5.5 g per tablet. Table VIII shows the ingredients used. Ingredient mg / comp Comment

Calcium carbonate 2,500 Equivalent to 1,000 mg of calcium ions

Concentrate of 9.6 ^* Equivalent to 960 Ul of cholecalciferol * vitamin D3

Isoflavone extract 200.0 Equivalent to 80 mg of soy isoflavones

Microcrystalline cellulose * 954.4 * Disintegrant / Diluent

Starch 935.0 Binder / Disintegrant

Pregelatinized starch 370.0 Disintegrant

Crospovidone 400.0 Disintegrant

Sodium stearyl fumarate 46.0 Lubricant

Sodium saccharin 15.0 Sweetener

Aroma 10.0 Flavoring

Sodium Cyclamate 60.0 Sweetener

Purified water * is. Vehicle

* Cholecalciferol concentrate is overdosed by 20%, that is, it is added at a rate of 9.6 mg instead of the declared 8.0 mg, to compensate for losses during the period of validity of the product, adjusting

I final weight with microcrystalline cellulose.

It disappears during the manufacturing process

The daily dose is in a 5.5 dispersible tablet, which is contained in a PVC / Aclar - Aluminum blister. Sayings Blister components can be prepared according to the usual technical knowledge without the need for a particular technology.

Example 14

Preparation of dispersible tablets with 1.2 g of calcium ions in salt form, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones

Following a procedure analogous to that described in Example 13, a dispersible tablet formulation with 1.2 g of calcium ions in salt form, 800 Ul of vitamin D ₃ and 80 mg of soy isoflavones was prepared. 3,000 mg of calcium carbonate (corresponding to 1.2 g of calcium ions), 9.6 mg of cholecalciferol concentrate in powder form (corresponding to 960 Ul of vitamin D ₃ ) and 200 mg of extract of soy isoflavones (corresponding to 80 mg of isoflavones). The amounts of the other excipients were the same as in Example 13. Each tablet weighs 6.0 g. Example 15

Preparation of dispersible tablets with 1.0 g of calcium ions in salt form, 880 Ul of vitamin D ₃ and 80 mg of soy isoflavones Following a procedure analogous to that described in Example 13, a dispersible tablet formulation was prepared with 1.0 g of calcium ions in the form of salt, 880 Ul of vitamin D ₃ and 80 mg of soy isoflavones. 2,500 mg of calcium carbonate (corresponding to 1.2 g of calcium), 10.56 mg of cholecalciferol concentrate in powder form (corresponding to 1,056 Ul of vitamin D ₃ ) and 200 mg of isoflavone extract were used. soy (corresponding to 80 mg of isoflavones). The amounts of the other excipients were the same as in Example 13, with the exception of microcrystalline cellulose, the amount of which was reduced to 953.44 mg. Each tablet weighs 5.5 g.

Example 16

Preparation of dispersible tablets with 1.2 g of calcium ions in salt form, 880 Ul of vitamin D ₃ and 80 mg of soy isoflavones

Following a procedure analogous to that described in Example 13, a dispersible tablet formulation with 1.2 g of calcium ions in salt form, 880 Ul of vitamin D ₃ and 80 mg of soy isoflavones was prepared. For this purpose, 3,000 mg of calcium carbonate (corresponding to 1.2 g of calcium ions), 10.56 mg of cholecalciferol concentrate in powder form (corresponding to 1,056 Ul of vitamin D ₃ ) and 200 mg of extract were used. soy isoflavones (corresponding to 80 mg of isoflavones). The amounts of the other excipients were the same as in Example 13, with the exception of microcrystalline cellulose, the amount of which was reduced to 953.44 mg. Each tablet weighs 6.0 g.

Claims

Pharmaceutical composition in solid form containing isoflavones, calcium ions in the form of salt and vitamin D3 characterized in that it comprises, for every 500 to 2,000 mg of calcium ions in the form of salt,

a) between 40 and 120 mg of soy isoflavones, and

b) between 600 and 1,200 Ul of vitamin D ₃ .

Composition according to claim 1, characterized in that the calcium salt is selected from the group consisting of calcium carbonate, calcium chloride, dibasic calcium phosphate, monobasic calcium phosphate, tribasic calcium phosphate, calcium lactate, tricalcium dicitrate, Monocalcic citrate, calcium gluconate and / or mixtures of such salts.

Composition according to claim 2, characterized in that the calcium salt is selected from the group consisting of calcium carbonate, calcium lactate, tricalcium dicitrate, calcium gluconate and / or mixtures thereof.

Composition according to claim 3, characterized in that the calcium salt is calcium carbonate.

Composition according to any one of claims 1 to 4, characterized in that the calcium salt content in the composition is such that it provides between 800 and 1,500 mg of calcium ions. Composition according to claim 5, characterized in that the calcium salt content in the composition is such that it provides between 900 and 1,400 mg of calcium ions.

Composition according to claim 6, characterized in that the calcium salt content in the composition is such that it provides between 1,000 and 1,200 mg of calcium ions.

Composition according to claim 1, characterized in that the content of soy isoflavones is comprised between 60 and 100 mg.

Composition according to claim 8, characterized in that the content of soy isoflavones is between 70 and 90 mg.

Composition according to claim 9, characterized in that the content of soy isoflavones is between 75 and 85 mg.

Composition according to claim 1, characterized in that the content of vitamin D ₃ is between 700 and 1,000 Ul

Composition according to claim 11, characterized in that the content of vitamin D ₃ is between 750 and 900 Ul

13. Composition according to claim 1, characterized in that for every 1,000 mg of calcium ions in salt form contains 80 mg of soy isoflavones and 800 Ul of vitamin D3.

14. Composition according to claim 1, characterized in that for every 1,000 mg of calcium ions in salt form contains 80 mg of soy isoflavones and 880 U.l. of vitamin D3. 15. Composition according to claim 1, characterized in that for every 1,200 mg of calcium ions in salt form contains 80 mg of soy isoflavones and 800 U.l. of vitamin D3.

16. Composition according to claim 1, characterized in that for every 1,200 mg of calcium ions in salt form contains 80 mg of soy isoflavones and 880 Ul of vitamin D ₃ .

17. Use of the pharmaceutical composition according to any of claims 1 to 16 for the preparation of a powder or granulate for oral suspension.

18. Use of the pharmaceutical composition according to any of claims 1 to 16 for the preparation of an effervescent tablet.

19. Use of the pharmaceutical composition according to any one of claims 1 to 16 for the preparation of a dispersible tablet. 20. Powder or granulate for oral suspension characterized in that it comprises a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 16 and at least one pharmaceutically acceptable excipient.

21. Powder or granulate for oral suspension according to claim 20, characterized in that it further comprises mannitol, colloidal silica anhydrous, xanthan gum and hydroxypropylcellulose of low grade substitution, as excipients.

Powder or granulate for oral suspension according to claim 21, characterized in that it further comprises a sweetener system and flavoring agents.

Powder or granulate for oral suspension according to any of claims 20 to 22, characterized in that it is conditioned in the form of a single dose.

Powder or granulate for oral suspension according to claim 23, characterized in that the single dose comprises 1,000 mg of calcium ions in salt form, 800 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 420 and 500 mg of mannitol, between 50 and 70 mg of anhydrous colloidal silica, between 80 and 100 mg of xanthan gum, between 80 and 120 mg of low-grade hydroxypropylcellulose. 25. Powder or granulate for oral suspension according to claim 23, characterized in that the unit dose comprises 1,000 mg of calcium ions in salt form, 880 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 420 and 500 mg of mannitol, between 50 and 70 mg of anhydrous colloidal silica, between 80 and 100 mg of xanthan gum, between 80 and 120 mg of low-grade hydroxypropylcellulose.

Powder or granulate for oral suspension according to claim 23, characterized in that the single dose comprises 1,200 mg of calcium ions in salt form, 800 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 420 and 500 mg of mannitol, between 50 and 70 mg of anhydrous colloidal silica, between 80 and 100 mg of xanthan gum, between 80 and 120 mg of low-grade hydroxypropylcellulose. 27. Powder or granulate for oral suspension according to claim 23, characterized in that the single dose comprises 1,200 mg of calcium ions in salt form, 880 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 420 and 500 mg of mannitol, between 50 and 70 mg of anhydrous colloidal silica, between 80 and 100 mg of xanthan gum, between 80 and 120 mg of low-grade hydroxypropylcellulose.

Powder or granulate for oral suspension according to any of claims 23 to 26, characterized in that the single dose further comprises between 10 and 14 mg of sodium saccharin and between 20 and 100 mg of flavoring agents.

Effervescent tablet characterized in that it comprises a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 16, a carbonic anhydride generating system and at least one pharmaceutically acceptable excipient.

Effervescent tablet according to claim 29, characterized in that it comprises anhydrous citric acid, sodium bicarbonate, lactose monohydrate, polyvinyl pyrrolidone, polyethylene glycol 6000 and an antifoaming agent, as excipients.

Effervescent tablet according to claim 30, characterized in that it further comprises a sweetener system and flavoring and flavoring agents. Effervescent tablet according to claim 29, characterized in that it comprises 1,000 mg of calcium ions in the form of carbonate, 800 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 3,900 and 4,100 mg of anhydrous citric acid, between 240 and 260 mg of sodium bicarbonate, between 320 and 420 mg of lactose monohydrate, between 10 and 20 mg of polyvinyl pyrrolidone K25, between 150 and 180 mg of polyethylene glycol 6000 and between 0.5 and 5 mg of simethicone emulsion.

Effervescent tablet according to claim 29, characterized in that it comprises 1,000 mg of calcium ions in the form of carbonate, 880 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 3,900 and 4,100 mg of anhydrous citric acid, between 240 and 260 mg of sodium bicarbonate, between 320 and 420 mg of lactose monohydrate, between 10 and 20 mg of polyvinyl pyrrolidone K25, between 150 and 180 mg of polyethylene glycol 6000 and between 0.5 and 5 mg of simethicone emulsion.

Effervescent tablet according to claim 29, characterized in that it comprises 1,200 mg of calcium ions in the form of carbonate, 800 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 3,900 and 4,100 mg of anhydrous citric acid, between 240 and 260 mg of sodium bicarbonate, between 320 and 420 mg of lactose monohydrate, between 10 and 20 mg of polyvinyl pyrrolidone K25, between 150 and 180 mg of polyethylene glycol 6000 and between 0.5 and 5 mg of simethicone emulsion.

Effervescent tablet according to claim 29, characterized in that it comprises 1,200 mg of calcium ions in the form of carbonate, 880 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 3,900 and 4,100 mg of anhydrous citric acid, between 240 and 260 mg of sodium bicarbonate, between 320 and 420 mg of lactose monohydrate, between 10 and 20 mg of polyvinyl pyrrolidone K25, between 150 and 180 mg of polyethylene glycol 6000 and between 0.5 and 5 mg of simethicone emulsion.

36. Effervescent tablet according to any of claims 32 to 35, characterized in that it also comprises between 10 and 20 mg of sodium saccharin, between 50 and 75 mg of sodium cyclamate and between 5 and 25 mg of flavoring and flavoring agents.

37. Dispersible tablet characterized in that it comprises a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 16 and a disintegrating system.

38. Dispersible tablet according to claim 37, characterized in that it comprises microcrystalline cellulose, starch, pregelatinized starch, crospovidone and sodium stearyl fumarate, as a disintegrating system.

39. Dispersible tablet according to claim 38, characterized in that it further comprises a sweetener system and flavoring and flavoring agents. 40. Dispersible tablet according to claim 37, characterized in that it comprises 1,000 mg of calcium ions in salt form, 800 Ul of vitamin D3, 80 mg of soy isoflavones, between 860 and 1,050 mg of microcrystalline cellulose, between 840 and 1,030 mg of starch, between 330 and 410 mg of pregelatinized starch, between 360 and 400 mg of crospovidone and between 41 and 51 mg of sodium stearyl fumarate. Dispersible tablet according to claim 37, characterized in that it comprises 1,200 mg of calcium ions in salt form, 800 Ul of vitamin D3, 80 mg of soy isoflavones, between 860 and 1,050 mg of microcrystalline cellulose, between 840 and 1,030 mg of starch, between 330 and 410 mg of pregelatinized starch, between 360 and 400 mg of crospovidone and between 41 and 51 mg of sodium stearyl fumarate.

Dispersible tablet according to claim 37, characterized in that it comprises 1,000 mg of calcium ions in salt form, 880 U.l. of vitamin D3, 80 mg of soy isoflavones, between 860 and 1,050 mg of microcrystalline cellulose, between 840 and 1,030 mg of starch, between 330 and 410 mg of pregelatinized starch, between 360 and 400 mg of crospovidone and between 41 and 51 mg of sodium stearyl fumarate.

Dispersible tablet according to claim 37, characterized in that it comprises 1,200 mg of calcium ions in salt form, 880 Ul of vitamin D ₃ , 80 mg of soy isoflavones, between 860 and 1,050 mg of microcrystalline cellulose, between 840 and 1,030 mg of starch , between 330 and 410 mg of pregelatinized starch, between 360 and 400 mg of crospovidone and between 41 and 51 mg of sodium stearyl fumarate.

Dispersible tablet according to any of claims 40 to 43, characterized in that it also comprises between 10 and 20 mg of sodium saccharin, between 50 and 75 mg of sodium cyclamate and between 5 and 25 mg of flavoring and flavoring agents.