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WO2011113965A1 - Composition pharmaceutique sous forme solide contenant des isoflavones, un sel de calcium et de la vitamine d3 - Google Patents

Composition pharmaceutique sous forme solide contenant des isoflavones, un sel de calcium et de la vitamine d3 Download PDF

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Publication number
WO2011113965A1
WO2011113965A1 PCT/ES2010/000109 ES2010000109W WO2011113965A1 WO 2011113965 A1 WO2011113965 A1 WO 2011113965A1 ES 2010000109 W ES2010000109 W ES 2010000109W WO 2011113965 A1 WO2011113965 A1 WO 2011113965A1
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WO
WIPO (PCT)
Prior art keywords
vitamin
calcium
calcium ions
soy isoflavones
composition according
Prior art date
Application number
PCT/ES2010/000109
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English (en)
Spanish (es)
Inventor
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 (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Farmalider, S.A. filed Critical Farmalider, S.A.
Priority to PCT/ES2010/000109 priority Critical patent/WO2011113965A1/fr
Publication of WO2011113965A1 publication Critical patent/WO2011113965A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • 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.
  • 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.
  • 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.
  • 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 .
  • bisphosphonates for example alendronate or etidronate
  • calcitonin which is a hormone produced by the thyroid gland that is involved in calcium and phosphorus metabolism
  • modulators selective estrogen receptors for example raloxifene
  • osteoporosis is considered prevention.
  • 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.
  • nutritional supplements which include the calcium salt of a mixture of citric acid and malic acid and vitamin D.
  • 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.
  • 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.
  • phytoestrogens for example isoflavones
  • osteoporosis The administration of phytoestrogens, for example isoflavones, for the prevention and / or treatment of osteoporosis is also described in the prior art.
  • 565401 1 describes a dietary supplement for postmenopausal women that contains minerals (calcium, magnesium, boron, copper, manganese, iron, chromium and zinc), vitamins (D, B-
  • minerals calcium, magnesium, boron, copper, manganese, iron, chromium and zinc
  • vitamins D, B-
  • 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.
  • 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.
  • 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.
  • 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.
  • a dispersible tablet comprising said pharmaceutical composition is part of the object 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,
  • 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.
  • 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.
  • 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.
  • the calcium salt is selected from the group consisting of calcium carbonate, calcium lactate, tricalcium dicitrate, calcium gluconate and / or mixtures of such salts.
  • 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 O Kunststoff 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
  • Soy 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.
  • 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.
  • glycosides of soy isoflavones are: genistin, daidzine and glicitin. Their respective aglycones are called genistein, daidzein and glycytein.,
  • 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.
  • 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.
  • 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 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).
  • vitamin D 3 can be incorporated either as such or as a powder concentrate.
  • 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.
  • 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 .
  • IU international units
  • 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.
  • 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
  • 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
  • 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].
  • 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.
  • 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.
  • 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, aluminasic silica,
  • the powder or granulate for oral suspension comprises as excipients mannitol, anhydrous colloidal silica, xanthan gum and hydroxypropylcellulose of low degree of substitution.
  • 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.
  • 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.
  • 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.
  • 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
  • organic acids can be mentioned: citric acid, tartaric acid, ascorbic acid, malic acid, fumaric acid and maleic acid.
  • citric acid is used.
  • 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,
  • 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.
  • the effervescent tablet further comprises a sweetener system and flavoring and flavoring agents.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, isomal
  • 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.
  • film-forming polymers such as hydroxypropylmethylcellulose, Eudragit®, cellulose acetophthalate, hydroxypropyl
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%.
  • vitamin D 3 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.
  • the toxicity due to vitamin D 3 in which hypercalcemia is observed appears from 1,000 pg (40,000 IU).
  • 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 calcium carbonate salt in which 3,000 mg thereof equals 1,200 mg of calcium ion is used to incorporate the calcium ion.
  • the calcium carbonate salt in which 3,000 mg thereof equals 1,200 mg of calcium ion is used to incorporate the calcium ion.
  • the calcium carbonate salt in which 3,000 mg thereof equals 1,200 mg of calcium ion is used to incorporate the calcium ion.
  • 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 S ⁇ LGEN 40 (Soybean isoflavone dry extract 40%) marketed by the
  • 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
  • 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.
  • 9.6 mg of cholecalciferol concentrate in powder form corresponding to 960 Ul of vitamin D 3
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • Table VI shows the ingredients used.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 10.56 mg of cholecalciferol concentrate in powder form corresponding to 1,056 Ul of vitamin D3
  • 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.
  • Isoflavone extract 200.0 Equivalent to 80 mg of soy isoflavones
  • 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.
  • 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.
  • Isoflavone extract 200.0 Equivalent to 80 mg of soy isoflavones
  • the daily dose is in a 5.5 dispersible tablet, which is contained in a PVC / Aclar - Aluminum blister.
  • Blister components can be prepared according to the usual technical knowledge without the need for a particular technology.
  • Example 15 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 Example 15

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Abstract

La présente invention concerne une nouvelle composition pharmaceutique sous forme solide comprenant des quantités spécifiques d'isoflavones, d'ions de calcium sous forme de sel et de la vitamine D3. La présente invention concerne également l'utilisation de cette composition pour préparer des poudres pour suspension orale, des granules pour suspension orale, des comprimés effervescents et des comprimés dispersibles. En outre, l'invention concerne les poudres pour suspension orale, les granules pour suspension orale, les comprimés effervescents et les comprimés dispersibles préparés au moyen de cette composition. La composition selon l'invention est utilisée pour prévenir et/ou traiter l'ostéoporose chez les femmes en phase précoce de ménopause et qui peuvent souffrir de symptômes légers à modérés associés à la ménopause en raison de la réduction des oestrogènes.
PCT/ES2010/000109 2010-03-18 2010-03-18 Composition pharmaceutique sous forme solide contenant des isoflavones, un sel de calcium et de la vitamine d3 WO2011113965A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9649274B2 (en) 2012-06-12 2017-05-16 The Procter & Gamble Company Effervescent dosage form
US10617714B2 (en) 2012-06-12 2020-04-14 The Procter & Gamble Company Effervescent dosage form
US20210378948A1 (en) * 2020-06-08 2021-12-09 Nicoventures Trading Limited Effervescent oral composition

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1481676A1 (fr) * 2003-05-30 2004-12-01 Rotta Research Laboratorium S.P.A. Phytoestrogènes et probiotique pour la santé des femmes
EP1669080A1 (fr) * 2003-09-19 2006-06-14 Sunstar Inc. Procede d'inhibition de resorption alveolaire et de perte de la membrane parodontale et composition a usage interne de mise en oeuvre
US20070224268A1 (en) * 1998-11-13 2007-09-27 Nycomed Pharma As Process for preparing oral calcium compositions
ES2283038T3 (es) * 1997-10-27 2007-10-16 DR. GERGELY & CO. Granulado instantaneo de calcio y soja.

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2283038T3 (es) * 1997-10-27 2007-10-16 DR. GERGELY & CO. Granulado instantaneo de calcio y soja.
US20070224268A1 (en) * 1998-11-13 2007-09-27 Nycomed Pharma As Process for preparing oral calcium compositions
EP1481676A1 (fr) * 2003-05-30 2004-12-01 Rotta Research Laboratorium S.P.A. Phytoestrogènes et probiotique pour la santé des femmes
EP1669080A1 (fr) * 2003-09-19 2006-06-14 Sunstar Inc. Procede d'inhibition de resorption alveolaire et de perte de la membrane parodontale et composition a usage interne de mise en oeuvre

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9649274B2 (en) 2012-06-12 2017-05-16 The Procter & Gamble Company Effervescent dosage form
US10028977B2 (en) 2012-06-12 2018-07-24 The Procter & Gamble Company Effervescent dosage form
US10322144B2 (en) 2012-06-12 2019-06-18 The Procter & Gamble Company Effervescent dosage form
US10617714B2 (en) 2012-06-12 2020-04-14 The Procter & Gamble Company Effervescent dosage form
US20210378948A1 (en) * 2020-06-08 2021-12-09 Nicoventures Trading Limited Effervescent oral composition
US12274779B2 (en) * 2020-06-08 2025-04-15 Nicoventures Trading Limited Effervescent oral composition

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