EP0971719A1 - Therapeutic combination of mineral and vitamin in units of liquid preparation for oral administration - Google Patents

Therapeutic combination of mineral and vitamin in units of liquid preparation for oral administration

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Publication number
EP0971719A1
EP0971719A1 EP98913826A EP98913826A EP0971719A1 EP 0971719 A1 EP0971719 A1 EP 0971719A1 EP 98913826 A EP98913826 A EP 98913826A EP 98913826 A EP98913826 A EP 98913826A EP 0971719 A1 EP0971719 A1 EP 0971719A1
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EP
European Patent Office
Prior art keywords
vitamin
calcium
combination
chosen
sodium
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP98913826A
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German (de)
French (fr)
Inventor
Catherine Meignant
Corinne Vieillard-Baron
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Laboratoires Innothera SAS
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Laboratoires Innothera SAS
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Publication date
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Publication of EP0971719A1 publication Critical patent/EP0971719A1/en
Withdrawn legal-status Critical Current

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    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • 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 mineralo-vitamin therapeutic combinations comprising as active principles associated with calcium in elementary form and at least one vitamin D.
  • WO-A-96/09036 (Innothéra Laboratory) describes such an association in unit dosage form of tablets, in particular chewable tablets, respecting the absolute and relative doses of calcium and vitamin D indicated by the abovementioned literature.
  • the chewable tablet described is dosed so as to allow the desired daily intake of calcium and vitamin D by taking two tablets per day.
  • liquid forms have also been proposed, for example packaged in the form of ampoules containing an oral solution of a soluble calcium salt (such as gluconate or lactate).
  • a soluble calcium salt such as gluconate or lactate.
  • a such a solution due to the solubilization of the calcium salt, however has a certain acidity, which can affect the absorption of the active ingredients and, moreover, not be very well tolerated by the patient.
  • Vitamin-calcium food supplements have also been proposed comprising, inter alia, calcium and a vitamin D, for example by WO-A-96/31130 (Abbott Laboratories), which describes a concentrate in solid form to be diluted with water or fruit juices. But, here again, the calcium salt is always in soluble or solubilized form, with the consequence of a low pH leading to the drawbacks mentioned above.
  • One of the aims of the invention is to provide a mineral-vitamin combination combining calcium and vitamin D, which is presented in the form of a unitary drinkable liquid preparation devoid of high acidity so as to provide good tolerance and good absorption. - the active ingredients.
  • unitary drinkable liquid preparation is meant a ready-to-drink liquid preparation, for example in the form of a drinkable liquid preparation in sachet, in bottle or in ampoule without the patient having to carry out any manipulation, like this. would for example be the case with effervescent granules or soluble powders.
  • Another object of the invention is to provide such a preparation in which the unit dose corresponds to a daily dose lying within the values indicated above (i.e. approximately 1000 to 1200 mg of calcium element and 800 IU of vitamin D per day ), which further facilitates adherence to treatment since a single daily intake becomes sufficient.
  • Another object of the invention is to provide such a calcium / vitamin D association in the form of an oral liquid having a dosage optimal relationship between calcium and vitamin D, especially for the prevention and treatment of osteoporosis, as explained at the beginning of the description.
  • the invention provides a mineralo-vitamin therapeutic association in the form of a unitary drinkable liquid preparation, in particular for the prevention and treatment of osteoporosis in the elderly, this association comprising as active principles associated with calcium- element and at least one vitamin D, characterized in that it comprises: a calcium salt dispersed in an aqueous liquid medium, this salt being essentially insoluble in the aqueous liquid medium; at least one vitamin D; a vitamin D solubilizer in the aqueous medium; and a gelling agent capable of increasing the viscosity of the aqueous medium and thus maintaining the non-soluble calcium salt in homogeneous suspension in this medium.
  • the ratio of calcium in elementary form to vitamin D, expressed in mg of elemental Ca per IU of vitamin D, is between 1 and 1.5, preferably between 1.2 and 1.3;
  • the association is conditioned in the form of unit daily doses, each dose comprising 800 to 1200 mg of calcium element for 600 to 1000 IU of vitamin D;
  • the non-soluble calcium salt is calcium carbonate;
  • Vitamin D is chosen from vitamin D2 or ergocalciferol, vitamin D3 or cholecalciferol or a mixture of these;
  • the vitamin D solubilizer is chosen from polyoxyethylene glycols and their esters, propylene glycols, ethyl alcohol, diethylene glycol ethers, glycerol and saturated and unsaturated polyglycolysed glycerides, type saccharides liquid fructose, liquid maltitol, polyhydroxyethylated sorbitan esters, hydrogenated and non-hydrogenated polyoxyethylene castor oil and maltodextrins, preferably from a polyhydroxyethylated sorbitan ester;
  • the gelling agent is chosen from gums such as guar gum, xanthan gum, tragacanth and gum arabic, agar-agar, carboxymethyl sodium starch, anhydrous colloidal silica, cellulose derivatives such as hydroxypropyl cellulose, hydroxyethylcelluloseulose and sodium carboxymethylcellulose , polymers of acrylic acid and aluminum and magnesium silicates, preferably xanthan gum;
  • the association also comprises a preservative, chosen from parahydroxybenzoic acid, its methyl and propyl esters and the sodium derivatives of these esters, benzoic acid and its salts, sorbic acid and its salts, bisulfites and metabisulfites;
  • the association also comprises a sweetener, chosen from aspartame, sucrose, potassium acesulfame, sodium saccharinate, sodium cyclamate and fructose; - the association presents the following percentage formula: calcium carbonate 16.67 g (amount corresponding to calcium element: 6.67 g); cholecalciferol, amount corresponding to 5333.33 IU; polyhydroxyethylated sorbitan ester (Polysorbate 80) 0.05 g; xanthan gum 0.75 g; fructose 8.67 g; curator q.s. ; aroma q.s. ; purified water q.s. 100 ml, the final pH being between 7 and 9.
  • a sweetener chosen from aspartame, sucrose, potassium acesulfame, sodium saccharinate, sodium cyclamate and fructose
  • a sweetener chosen from aspartame, sucrose, potassium acesulfame, sodium saccharinate, sodium cyclamate and
  • Vitamin D This vitamin is cholecalciferol (vitamin D3 Roche), either in the form of an oily solution (vegetable oil) titrated to 1 million IU / g, or in granulated form, for example of the 100 CWS® type. Rock titrated to 100,000 IU / g. In both cases, the presence of dl- ⁇ -tocopherol gives them great stability and prevents their oxidation.
  • this salt must be a salt that is essentially insoluble (nor soluble) in this formulation, so as to always be present in the liquid medium in the dispersed state, and without there is a shift in the balance of the salt: so the salt does not change in nature (hence good absorption) and the solution does not acidify.
  • the final pH is between 7 and 9.
  • Solubilizer This involves making a lipophilic vitamin (vitamin D3) compatible with a hydrophilic aqueous environment, that is to say, in other words, finding a solvent or a co-solvent vitamin D3 which is compatible with the latter (that is to say that the vitamin must remain soluble and stable in the solvent) and which is compatible with water.
  • the solubilizer must also have an acceptable taste and must not destabilize the chosen gelling agent (see below), nor attack the components of the packaging of the liquid preparation.
  • PEG polyoxyethylene glycols
  • - propylene glycols and ethers of diethylene glycol such as diethylene glycol monoethyl ether (Transcuto ⁇ ), - ethyl alcohol, - glycerol and saturated polyglycolysed glycerides (type PEG-8 glyceryl caprylate / caprate (Labrasol ® )) and unsaturated (type PEG-6 glyceryl monooleate (Labrafil ® M 1944 CS),
  • polysorbate 80 can be used with a content of 0.03% to 0.5% by weight of the final preparation, preferably approximately 0, 05%, - hydrogenated polyoxyethylenated castor oil (type Croduret ® 50 special), Crumophor ® RH 40) and non-hydrogenated (type Etocas ® 35 HV),
  • Gelling agent The role of this gelling agent is to maintain the calcium salt in homogeneous suspension in the aqueous medium without dissolving it or displacing the salt. To do this, the aqueous medium is viscosed by the addition of a polymer, this polymer having to have a good texture in order to disperse the calcium carbonate and keep it in dispersion and, also, to present in the mouth a pleasant taste and texture.
  • a polymer this polymer having to have a good texture in order to disperse the calcium carbonate and keep it in dispersion and, also, to present in the mouth a pleasant taste and texture.
  • suitable gelling agents there may be mentioned:
  • guar type gums xanthan type, tragacanth type and arabic type - the currently preferred choice of gelling agent being xanthan gum in a proportion of 0.1 to 1% by weight, preferably approximately 0.75%, - agar- agar,
  • Sweetener Various types of sweeteners can be chosen, this choice not being critical for the implementation of the invention. These include: aspartame, sucrose, acesulfame potassium (Sunet), sodium saccharinate, sodium cyclamate or fructose (Fructofin C type Al 21). Advantageously, one chooses fructose, which is a natural sweetener having the advantage of not providing sucrose and of not being contraindicated in non-insulin-dependent diabetic subjects.
  • Preservative Various preservatives can be chosen, which here again are not critical for the implementation of the invention, such as parahydroxybenzoic acid, its methyl and propyl esters and the sodium derivatives of these esters, benzoic acid and its salts, sorbic acid and its salts (especially potassium sorbate), bisulfites and metabisulfites.
  • Aroma It is chosen from conventional additives according to the taste (lemon, orange, etc.) that one wishes to give to the preparation.
  • the operating protocol is as follows:
  • the 0.05 g of polysorbate 80 can be replaced by: PEG 400 (1 g), propylene glycol (1 g), Transcutol ® (0.5 g), ethyl alcohol (10 g), glycerol (3 g ), liquid maltitol (1 g) or hydrogenated polyoxyethylene castor oil (1 g).
  • xanthan gum can be replaced by: guar gum (1 g), hydroxypropylcellulose (1 g), hydroxyethylcellulose (1 g), Veegum ® HV (5 g), sodium carboxymethylcellulose (1 g ), Carbopol ® 974 P (0.3 g) or agar-agar (0.5 g).

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Inorganic Chemistry (AREA)
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  • Orthopedic Medicine & Surgery (AREA)
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Abstract

The invention concerns a combination for preventing or treating osteoporosis in an aged subject, comprising as combined active principles metallic calcium and at least one vitamin D. The invention is characterised in that it comprises: a calcium salt dispersed in an liquid aqueous medium, said salt being substantially non-soluble in the liquid aqueous medium; at least one vitamin D; an agent for dissolving the vitamin D in the aqueous medium; and a gelling agent, for increasing the viscosity of the aqueous medium and maintaining the non-soluble calcium salt in homogeneous suspension in this aqueous medium.

Description

Association thérapeutique minéralo-vitaminique sous forme de préparation unitaire liquide buvable Mineral-vitamin therapeutic association in the form of a unitary drinkable liquid preparation
La présente invention concerne les associations thérapeutiques minéralo-vitaminiques comprenant comme principes actifs associés du calcium sous forme élémentaire et au moins une vitamine D.The present invention relates to mineralo-vitamin therapeutic combinations comprising as active principles associated with calcium in elementary form and at least one vitamin D.
Chez les sujets âgés, les effets thérapeutiques liés à l'administration conjointe de calcium et de vitamine D sont bien connus, comme cela est relaté par exemple dans les articles de Marie C. Chapuy et coll. — Effect of Calcium and Cholecalciferol Treatment for Three Years on Hip Fractures in Elderly Women, British Médical Journal, 308. 1081- 1082 (23 avril 1994), de Marie C. Chapuy et coll. — Vitamin D3 and Calcium to Prevent Hip Fractures in Elderly Women, New England Journal of Medicine, 327. 1637-1642 (3 décembre 1992) et dans l'arti- cle intitulé Supplementation with Vitamin D3 and Calcium Prevents Hip Fractures in Elderly Women, Nutrition Reυiews, Vol. 51, f>, pp. 183-185. Ces articles montrent également la variabilité des effets thérapeutiques de l'association en fonction du dosage de calcium et de la vitamine D, avec une dose journalière optimale se situant, pour une in- dication dans la prévention et le traitement de l'ostéoporose, aux alentours de 1000 à 1200 mg de calcium élément et 800 UI de vitamine D3. On connaît de très nombreuses formes galéniques associant calcium et vitamine D.In the elderly, the therapeutic effects linked to the joint administration of calcium and vitamin D are well known, as reported for example in the articles by Marie C. Chapuy et al. - Effect of Calcium and Cholecalciferol Treatment for Three Years on Hip Fractures in Elderly Women, British Médical Journal, 308. 1081-1082 (23 April 1994), by Marie C. Chapuy et al. - Vitamin D3 and Calcium to Prevent Hip Fractures in Elderly Women, New England Journal of Medicine, 327. 1637-1642 (December 3, 1992) and in the article entitled Supplementation with Vitamin D3 and Calcium Prevents Hip Fractures in Elderly Women, Nutrition Reυiews, Vol. 51, f>, pp. 183-185. These articles also show the variability of the therapeutic effects of the association depending on the dosage of calcium and vitamin D, with an optimal daily dose being, for an indication in the prevention and treatment of osteoporosis, around 1000 to 1200 mg of elemental calcium and 800 IU of vitamin D3. We know many galenic forms associating calcium and vitamin D.
Ainsi, le WO-A-96/09036 (Laboratoire Innothéra) décrit une telle association sous forme galénique unitaire de comprimés, notamment de comprimés à croquer, respectant les doses absolues et relatives de calcium et de vitamine D indiquées par la littérature précitée. Le comprimé à croquer décrit est dosé de manière à permettre l'apport journalier voulu de calcium et de vitamine D par la prise de deux comprimés par jour.Thus, WO-A-96/09036 (Innothéra Laboratory) describes such an association in unit dosage form of tablets, in particular chewable tablets, respecting the absolute and relative doses of calcium and vitamin D indicated by the abovementioned literature. The chewable tablet described is dosed so as to allow the desired daily intake of calcium and vitamin D by taking two tablets per day.
Outre les formes sèches d'associations calcium/vitamine D (comprimés pellicules, dragéifiés, à sucer ou à croquer, granulés effervescents, sachets poudre, etc.), on a proposé également des formes liquides, par exemple conditionnées sous forme d'ampoules enfermant une solution buvable d'un sel soluble de calcium (tel que gluconate ou lactate). Une telle solution, du fait de la solubilisation du sel de calcium, présente cependant une certaine acidité, qui peut nuire à l'absorption des principes actifs et, en outre, ne pas être très bien tolérée par le patient.In addition to the dry forms of calcium / vitamin D combinations (film-coated, sugar-coated, chewable or chewable tablets, effervescent granules, powder sachets, etc.), liquid forms have also been proposed, for example packaged in the form of ampoules containing an oral solution of a soluble calcium salt (such as gluconate or lactate). A such a solution, due to the solubilization of the calcium salt, however has a certain acidity, which can affect the absorption of the active ingredients and, moreover, not be very well tolerated by the patient.
Il a été également proposé des suppléments alimentaires vitamino- calciques comprenant, entre autres, du calcium et une vitamine D, par exemple par le WO-A-96/31130 (Abbott Laboratories), qui décrit un concentré sous forme solide à diluer avec de l'eau ou des jus de fruits. Mais, ici encore, le sel de calcium est toujours sous forme soluble ou solubilisée, avec pour conséquence un pH faible conduisant aux incon- vénients cités plus haut.Vitamin-calcium food supplements have also been proposed comprising, inter alia, calcium and a vitamin D, for example by WO-A-96/31130 (Abbott Laboratories), which describes a concentrate in solid form to be diluted with water or fruit juices. But, here again, the calcium salt is always in soluble or solubilized form, with the consequence of a low pH leading to the drawbacks mentioned above.
L'un des buts de l'invention est de proposer une association miné- ralo-vitaminique combinant calcium et vitamine D, qui soit présentée sous forme de préparation unitaire liquide buvable dépourvue de forte acidité de façon à procurer une bonne tolérance et une bonne absorp- tion des principes actifs.One of the aims of the invention is to provide a mineral-vitamin combination combining calcium and vitamin D, which is presented in the form of a unitary drinkable liquid preparation devoid of high acidity so as to provide good tolerance and good absorption. - the active ingredients.
On notera que par "préparation unitaire liquide buvable", on entend une préparation liquide prête à boire, par exemple sous forme de préparation liquide buvable en sachet, en flacon ou en ampoule sans que le patient n'ait à effectuer de manipulation, comme cela serait par exemple le cas avec des granulés effervescents ou des poudres solubles. Un autre but de l'invention est de proposer une telle préparation dans laquelle la dose unitaire correspond à une dose journalière se situant dans les valeurs indiquées plus haut (soit environ 1000 à 1200 mg de calcium-élément et 800 UI de vitamine D par jour), ce qui facilite encore plus l'observance du traitement car une prise unique quotidienne devient suffisante. On a en effet constaté qu'avec les formes sèches telles que celles décrites dans le WO-A-96/09036 précité il est difficile de descendre au-dessous d'une posologie de deux comprimés par jour, un comprimé homothétique pour prise unique présenterait en bouche une consistance trop pâteuse, peu rafraîchissante, etc. susceptible de rebuter les patients ; tel n'est pas le cas d'une préparation liquide buvable, où une plus grande quantité de chacun des constituants peut être administrée sans difficulté.It will be noted that by "unitary drinkable liquid preparation" is meant a ready-to-drink liquid preparation, for example in the form of a drinkable liquid preparation in sachet, in bottle or in ampoule without the patient having to carry out any manipulation, like this. would for example be the case with effervescent granules or soluble powders. Another object of the invention is to provide such a preparation in which the unit dose corresponds to a daily dose lying within the values indicated above (i.e. approximately 1000 to 1200 mg of calcium element and 800 IU of vitamin D per day ), which further facilitates adherence to treatment since a single daily intake becomes sufficient. It has in fact been found that with the dry forms such as those described in the aforementioned WO-A-96/09036 it is difficult to descend below a dosage of two tablets per day, a homothetic tablet for a single intake would have a too pasty, not very refreshing consistency in the mouth, etc. likely to put patients off; this is not the case with a drinkable liquid preparation, where a larger amount of each of the constituents can be administered without difficulty.
Un autre but de l'invention est de proposer une telle association calcium/vitamine D sous forme liquide buvable présentant un dosage relatif optimal entre calcium et vitamine D, tout particulièrement pour la prévention et le traitement de l'ostéoporose, comme expliqué au début de la description.Another object of the invention is to provide such a calcium / vitamin D association in the form of an oral liquid having a dosage optimal relationship between calcium and vitamin D, especially for the prevention and treatment of osteoporosis, as explained at the beginning of the description.
On constate en effet que les associations calcium/vitamine D sous forme unitaire liquide buvable qui ont déjà été proposées ne respectent pas les proportions optimales souhaitables indiquées notamment dans la littérature précitée pour une indication dans la prévention et le traitement de l'ostéoporose. Ceci vient du fait que ces associations sont généralement prescrites soit dans d'autres indications (par exemple la prophylaxie du rachitisme, ou l'ostéomalachie, la spécialité étant alors fortement dosée en vitamine D) ou par le fait qu'il s'agit plus de suppléments vitamino-calciques (suppléments alimentaires ou spécialités "OTC" vendus sans prescription médicale) que de véritables spécialités pharmaceutiques à visée thérapeutique (la teneur en vitamine D est alors relativement faible pour éviter tout risque lié à la toxicité intrinsèque de ce principe actif en cas de surdosage).It is found in fact that the calcium / vitamin D associations in unitary drinkable liquid form which have already been proposed do not respect the optimal desirable proportions indicated in particular in the abovementioned literature for an indication in the prevention and treatment of osteoporosis. This comes from the fact that these associations are generally prescribed either in other indications (for example prophylaxis of rickets, or osteomalachia, the specialty then being highly dosed with vitamin D) or by the fact that it is more vitamin-calcium supplements (food supplements or "OTC" specialties sold without medical prescription) than real pharmaceutical specialties for therapeutic purposes (the vitamin D content is then relatively low to avoid any risk linked to the intrinsic toxicity of this active ingredient in overdose).
A cet effet, l'invention propose une association thérapeutique miné- ralo-vitaminique sous forme de préparation unitaire liquide buvable, notamment pour la prévention et le traitement de l'ostéoporose chez le sujet âgé, cette association comprenant comme principes actifs associés du calcium-élément et au moins une vitamine D, caractérisée en ce qu'elle comprend : un sel de calcium dispersé dans un milieu liquide aqueux, ce sel étant essentiellement non soluble dans le milieu liquide aqueux ; au moins une vitamine D ; un solubilisant de la vitamine D dans le milieu aqueux ; et un gélifiant, propre à augmenter la viscosité du milieu aqueux et ainsi maintenir en suspension homogène dans ce milieu le sel de calcium non soluble.To this end, the invention provides a mineralo-vitamin therapeutic association in the form of a unitary drinkable liquid preparation, in particular for the prevention and treatment of osteoporosis in the elderly, this association comprising as active principles associated with calcium- element and at least one vitamin D, characterized in that it comprises: a calcium salt dispersed in an aqueous liquid medium, this salt being essentially insoluble in the aqueous liquid medium; at least one vitamin D; a vitamin D solubilizer in the aqueous medium; and a gelling agent capable of increasing the viscosity of the aqueous medium and thus maintaining the non-soluble calcium salt in homogeneous suspension in this medium.
Selon diverses caractéristiques avantageuses :According to various advantageous characteristics:
— le rapport du calcium sous forme élémentaire à la vitamine D, exprimé en mg de Ca élément par UI de vitamine D, est compris entre 1 et 1,5, de préférence entre 1,2 et 1,3 ;- The ratio of calcium in elementary form to vitamin D, expressed in mg of elemental Ca per IU of vitamin D, is between 1 and 1.5, preferably between 1.2 and 1.3;
— l'association est conditionnée sous forme de doses journalières unitaires, chaque dose comprenant 800 à 1200 mg de calcium-élément pour 600 à 1000 UI de vitamine D ; — le sel de calcium non soluble est le carbonate de calcium ; — la vitamine D est choisie parmi la vitamine D2 ou ergocalciférol, la vitamine D3 ou cholécalciférol ou un mélange de celles-ci ;- the association is conditioned in the form of unit daily doses, each dose comprising 800 to 1200 mg of calcium element for 600 to 1000 IU of vitamin D; - the non-soluble calcium salt is calcium carbonate; - Vitamin D is chosen from vitamin D2 or ergocalciferol, vitamin D3 or cholecalciferol or a mixture of these;
— le solubilisant de la vitamine D est choisi parmi les polyoxyéthy- lène glycols et leurs esters, les propylène glycols, l'alcool éthylique, les éthers de diéthylène glycols, le glycérol et les glycérides polygly- colysés saturés et insaturés, les saccharides de type fructose liquide, le maltitol liquide, les esters de sorbitanne polyhydroxyéthylé, l'huile de ricin polyoxyéthylénée hydrogénée et non hydrogénée et les maltodextrines, de préférence parmi un ester de sorbitanne po- lyhydroxyéthylé ;The vitamin D solubilizer is chosen from polyoxyethylene glycols and their esters, propylene glycols, ethyl alcohol, diethylene glycol ethers, glycerol and saturated and unsaturated polyglycolysed glycerides, type saccharides liquid fructose, liquid maltitol, polyhydroxyethylated sorbitan esters, hydrogenated and non-hydrogenated polyoxyethylene castor oil and maltodextrins, preferably from a polyhydroxyethylated sorbitan ester;
— le gélifiant est choisi parmi les gommes type gomme guar, gomme xanthane, gomme adragante et gomme arabique, l'agar-agar, le carboxyméthyl amidon sodique, la silice colloïdale anhydre, les dérivés cellulosiques type hydroxypropyl cellulose, hydroxyéthylcel- lulose et carboxyméthylcellulose sodique, les polymères de l'acide acrylique et les silicates d'aluminium et magnésium, de préférence la gomme xanthane ;- the gelling agent is chosen from gums such as guar gum, xanthan gum, tragacanth and gum arabic, agar-agar, carboxymethyl sodium starch, anhydrous colloidal silica, cellulose derivatives such as hydroxypropyl cellulose, hydroxyethylcelululose and sodium carboxymethylcellulose , polymers of acrylic acid and aluminum and magnesium silicates, preferably xanthan gum;
— l'association comprend en outre un conservateur, choisi parmi l'acide parahydroxybenzoïque, ses esters méthyliques et propyliques et les dérivés sodiques de ces esters, l'acide benzoïque et ses sels, l'acide sorbique et ses sels, les bisulfites et les métabisulfites ;The association also comprises a preservative, chosen from parahydroxybenzoic acid, its methyl and propyl esters and the sodium derivatives of these esters, benzoic acid and its salts, sorbic acid and its salts, bisulfites and metabisulfites;
— l'association comprend en outre un édulcorant, choisi parmi l'as- partame, le saccharose, l'acésulfame de potassium, le saccharinate de sodium, le cyclamate de sodium et le fructose ; — l'association présente la formule centésimale suivante : carbonate de calcium 16,67 g (quantité correspondant à calcium-élément : 6,67 g) ; cholécalciférol, quantité correspondant à 5333,33 UI ; ester de sorbitanne polyhydroxyéthylé (Polysorbate 80) 0,05 g ; gomme xanthane 0,75 g ; fructose 8,67 g ; conservateur q.s. ; arôme q.s. ; eau purifiée q.s. 100 ml, le pH final étant compris entre 7 et 9.The association also comprises a sweetener, chosen from aspartame, sucrose, potassium acesulfame, sodium saccharinate, sodium cyclamate and fructose; - the association presents the following percentage formula: calcium carbonate 16.67 g (amount corresponding to calcium element: 6.67 g); cholecalciferol, amount corresponding to 5333.33 IU; polyhydroxyethylated sorbitan ester (Polysorbate 80) 0.05 g; xanthan gum 0.75 g; fructose 8.67 g; curator q.s. ; aroma q.s. ; purified water q.s. 100 ml, the final pH being between 7 and 9.
On va décrire un exemple préférentiel, mais non limitatif, de mise en oeuvre de l'invention. On va tout d'abord détailler chacun des constituants de la formulation, à savoir : vitamine D, sel insoluble de calcium, solubilisant de la vitamine D, agent gélifiant, édulcorant, conservateur et arôme.We will describe a preferred example, but not limiting, of implementation of the invention. We will first detail each of the constituents of the formulation, namely: vitamin D, insoluble calcium salt, solubilizer of vitamin D, gelling agent, sweetener, preservative and flavor.
1°) Vitamine D : Cette vitamine est du cholécalciférol (vitamine D3 Roche), soit sous forme de solution huileuse (huile végétale) titrée à 1 million d'UI/g, soit sous forme granulée, par exemple de type 100 CWS® de Roche titrée à 100 000 Ul/g. Dans les deux cas, la présence de dl-α-tocophérol leur confère une grande stabilité et empêche leur oxydation. 2°) Sel de calcium : Comme on l'a indiqué, ce sel doit être un sel essentiellement insoluble (ni solubilisable) dans cette formulation, de manière à être toujours présent dans le milieu liquide à l'état dispersé, et sans qu'il y ait déplacement de l'équilibre du sel : ainsi le sel ne change pas de nature (d'où une bonne absorption) et la solution ne s'acidifie pas. Le pH final est compris entre 7 et 9.1 °) Vitamin D: This vitamin is cholecalciferol (vitamin D3 Roche), either in the form of an oily solution (vegetable oil) titrated to 1 million IU / g, or in granulated form, for example of the 100 CWS® type. Rock titrated to 100,000 IU / g. In both cases, the presence of dl-α-tocopherol gives them great stability and prevents their oxidation. 2 °) Calcium salt: As indicated, this salt must be a salt that is essentially insoluble (nor soluble) in this formulation, so as to always be present in the liquid medium in the dispersed state, and without there is a shift in the balance of the salt: so the salt does not change in nature (hence good absorption) and the solution does not acidify. The final pH is between 7 and 9.
Ce sel insoluble de calcium est de préférence le carbonate de calcium, du type Scoralite 1B de Scora ; il s'agit d'une poudre blanche de granulométrie très fine de diamètre moyen de 12 μm environ et de densité élevée (d = 1,3 g/cm3 environ). 3°) Solubilisant : Il s'agit de rendre compatible une vitamine lipo- phile (la vitamine D3) avec un environnement aqueux hydrophile c'est- à-dire, en d'autres termes, de trouver un solvant ou un co-solvant de la vitamine D3 qui soit compatible avec cette dernière (c'est-à-dire que la vitamine doit rester soluble et stable dans le solvant) et qui soit compa- tible avec l'eau.This insoluble calcium salt is preferably calcium carbonate, of the Scoralite 1B type from Scora; it is a white powder of very fine particle size with an average diameter of approximately 12 μm and a high density (d = 1.3 g / cm 3 approximately). 3 °) Solubilizer: This involves making a lipophilic vitamin (vitamin D3) compatible with a hydrophilic aqueous environment, that is to say, in other words, finding a solvent or a co-solvent vitamin D3 which is compatible with the latter (that is to say that the vitamin must remain soluble and stable in the solvent) and which is compatible with water.
Le solubilisant doit en outre présenter un goût acceptable et ne doit pas déstabiliser le gélifiant choisi (voir plus bas), ni attaquer les composants du conditionnement de la préparation liquide.The solubilizer must also have an acceptable taste and must not destabilize the chosen gelling agent (see below), nor attack the components of the packaging of the liquid preparation.
Parmi divers solubilisants répondant à ces divers critères, on peut citer notamment :Among various solubilizers meeting these various criteria, there may be mentioned in particular:
— les polyoxyéthylène glycols (PEG) type PEG 400 et leurs esters type laurate de PEG 200 ou stéarate de PEG 40,- polyoxyethylene glycols (PEG) type PEG 400 and their esters type laurate of PEG 200 or stearate of PEG 40,
— les propylène glycols et les éthers du diéthylène glycol type diéthy- lène glycol monoéthyléther (Transcuto^), — l'alcool éthylique, — le glycérol et les glycérides polyglycolysés saturés (type PEG-8 gly- céryl caprylate/caprate (Labrasol®)) et insaturés (type PEG-6 gly- céryl monooléate (Labrafil® M 1944 CS),- propylene glycols and ethers of diethylene glycol such as diethylene glycol monoethyl ether (Transcuto ^), - ethyl alcohol, - glycerol and saturated polyglycolysed glycerides (type PEG-8 glyceryl caprylate / caprate (Labrasol ® )) and unsaturated (type PEG-6 glyceryl monooleate (Labrafil ® M 1944 CS),
— les saccharides type fructose liquide, maltitol liquide (Lycasin® 80/55),- saccharides such as liquid fructose, liquid maltitol (Lycasin ® 80/55),
— les esters de sorbitanne polyhydroxyéthylés type polysorbate 80 — il s'agit du solubilisant actuellement préféré, le polysorbate 80 pouvant être utilisé avec une teneur de 0,03 % à 0,5 % en poids de la préparation finale, de préférence environ 0,05 %, — l'huile de ricin polyoxyéthylénée hydrogénée (type Croduret® 50 spécial), Crémophor® RH 40) et non hydrogénée (type Etocas® 35 HV),- polyhydroxyethylated sorbitan esters of polysorbate 80 type - this is the currently preferred solubilizer, polysorbate 80 can be used with a content of 0.03% to 0.5% by weight of the final preparation, preferably approximately 0, 05%, - hydrogenated polyoxyethylenated castor oil (type Croduret ® 50 special), Crémophor ® RH 40) and non-hydrogenated (type Etocas ® 35 HV),
— la maltodextrine (type Glucidex®).- maltodextrin (Glucidex ® type).
4°) Gélifiant : Le rôle de ce gélifiant est de maintenir le sel de cal- cium en suspension homogène dans le milieu aqueux sans le solubiliser ni déplacer le sel. Pour ce faire, on viscose le milieu aqueux par apport d'un polymère, ce polymère devant présenter une bonne texture pour disperser le carbonate de calcium et le maintenir en dispersion et, également, présenter en bouche un goût et une texture agréable. Parmi les gélifiant qui conviennent, on peut citer :4) Gelling agent: The role of this gelling agent is to maintain the calcium salt in homogeneous suspension in the aqueous medium without dissolving it or displacing the salt. To do this, the aqueous medium is viscosed by the addition of a polymer, this polymer having to have a good texture in order to disperse the calcium carbonate and keep it in dispersion and, also, to present in the mouth a pleasant taste and texture. Among the suitable gelling agents, there may be mentioned:
— les gommes type guar, type xanthane, type adragante et type arabique — le choix de gélifiant actuellement préféré étant la gomme xanthane en proportion de 0,1 à 1 % en poids, de préférence environ 0,75 %, — l'agar-agar,- guar type gums, xanthan type, tragacanth type and arabic type - the currently preferred choice of gelling agent being xanthan gum in a proportion of 0.1 to 1% by weight, preferably approximately 0.75%, - agar- agar,
— le carboxyméthylamidon sodique (type Explotab^,- sodium carboxymethyl starch (type Explotab ^,
— la silice colloïdale anhydre (type Aérosil® 200),- anhydrous colloidal silica (type Aérosil ® 200),
— les dérivés cellulosiques de type hydroxypropylcellulose (Klucet®), hydroxyéthylcellulose (Natrosol®), carboxyméthylcellulose sodique (Blanose®),- cellulosic derivatives of hydroxypropylcellulose type (Klucet ® ), hydroxyethylcellulose (Natrosol ® ), sodium carboxymethylcellulose (Blanose ® ),
— les polymères de l'acide acrylique (type Carbopofè 974P),- polymers of acrylic acid (Carbopofè 974P type),
— le silicate d'aluminium et magnésium (type Veegum® HV).- aluminum and magnesium silicate (Veegum ® HV type).
5°) Edulcorant : Divers types d'édulcorants peuvent être choisis, ce choix n'étant pas critique pour la mise en oeuvre de l'invention. On peut citer notamment : l'aspartame, le saccharose, l'acésulfame de potassium (Sunet ), le saccharinate de sodium, le cyclamate de sodium ou le fructose (Fructofin C type Al 21). Avantageusement, on choisit le fructose, qui est un édulcorant naturel ayant pour avantage de ne pas apporter de saccharose et de ne pas être contre-indiqué chez les sujets diabétiques non insulino-dépendants.5) Sweetener: Various types of sweeteners can be chosen, this choice not being critical for the implementation of the invention. These include: aspartame, sucrose, acesulfame potassium (Sunet), sodium saccharinate, sodium cyclamate or fructose (Fructofin C type Al 21). Advantageously, one chooses fructose, which is a natural sweetener having the advantage of not providing sucrose and of not being contraindicated in non-insulin-dependent diabetic subjects.
6°) Conservateur : Divers conservateurs peuvent être choisis, qui ici encore ne sont pas critiques pour la mise en oeuvre de l'invention, tel que l'acide parahydroxybenzoïque, ses esters méthyliques et propyli- ques et les dérivés sodiques de ces esters, l'acide benzoïque et ses sels, l'acide sorbique et ses sels (notamment le sorbate de potassium), les bisulfites et les métabisulfites.6) Preservative: Various preservatives can be chosen, which here again are not critical for the implementation of the invention, such as parahydroxybenzoic acid, its methyl and propyl esters and the sodium derivatives of these esters, benzoic acid and its salts, sorbic acid and its salts (especially potassium sorbate), bisulfites and metabisulfites.
7°) Arôme : Il est choisi parmi des additifs classiques en fonction du goût (citron, orange, etc.) que l'on souhaite donner à la préparation.7 °) Aroma: It is chosen from conventional additives according to the taste (lemon, orange, etc.) that one wishes to give to the preparation.
Pour la fabrication, le protocole opératoire est le suivant :For manufacturing, the operating protocol is as follows:
— solubiliser la vitamine D3 dans le solubilisant,- dissolve vitamin D3 in the solubilizer,
— transvaser cette solution dans l'eau, et mélanger sous agitation,- transfer this solution to water, and mix with stirring,
— dissoudre le conservateur sous agitation,- dissolve the preservative with stirring,
— dissoudre l'édulcorant sous agitation, — ajouter l'arôme (liquide) sous agitation,- dissolve the sweetener with stirring, - add the aroma (liquid) with stirring,
— disperser le carbonate de calcium sous agitation,- disperse the calcium carbonate with stirring,
— disperser l'agent gélifiant sous agitation,- dispersing the gelling agent with stirring,
— conditionner.- condition.
Une formule générale préférentielle est la suivante (formule centésimale) :A general preferred formula is as follows (centesimal formula):
Carbonate de calcium 16,67 gCalcium carbonate 16.67 g
(Quantité correspondant à calcium-élément : 6,67 g) Cholécalciférol, quantité correspondant à 5333,33 UI Ester de sorbitanne polyhydroxyéthylé (polysorbate 80) 0,05 g(Quantity corresponding to calcium element: 6.67 g) Cholecalciferol, quantity corresponding to 5333.33 IU Polyhydroxyethylated sorbitan ester (polysorbate 80) 0.05 g
Gomme xanthane 0,75 gXanthan gum 0.75 g
Fructose 8,67 gFructose 8.67 g
Conservateur q.s.Curator q.s.
Arôme q.s. Eau purifiée q.s. 100 ml La préparation obtenue présente un pH de 7 à 9 (donc sans aucun caractère acide) et une viscosité η = 2000 mPa.s ± 20 %.Aroma qs Purified water qs 100 ml The preparation obtained has a pH of 7 to 9 (therefore without any acidic character) and a viscosity η = 2000 mPa.s ± 20%.
En variante, les 0,05 g de polysorbate 80 peuvent être remplacés par : PEG 400 (1 g), propylène glycol (1 g), Transcutol® (0,5 g), alcool éthylique (10 g), glycérol (3 g), maltitol liquide (1 g) ou huile de ricin po- lyoxyéthylénée hydrogénée (1 g).Alternatively, the 0.05 g of polysorbate 80 can be replaced by: PEG 400 (1 g), propylene glycol (1 g), Transcutol ® (0.5 g), ethyl alcohol (10 g), glycerol (3 g ), liquid maltitol (1 g) or hydrogenated polyoxyethylene castor oil (1 g).
De même, les 0,75 g de gomme xanthane peuvent être remplacés par : gomme guar (1 g), hydroxypropylcellulose (1 g), hydroxyéthylcel- lulose (1 g), Veegum® HV (5 g), carboxyméthylcellulose sodique (1 g), Carbopol® 974 P (0,3 g) ou agar-agar (0,5 g). Similarly, the 0.75 g of xanthan gum can be replaced by: guar gum (1 g), hydroxypropylcellulose (1 g), hydroxyethylcellulose (1 g), Veegum ® HV (5 g), sodium carboxymethylcellulose (1 g ), Carbopol ® 974 P (0.3 g) or agar-agar (0.5 g).

Claims

REVENDICATIONS
1. Une association thérapeutique minéralo-vitaminique sous forme de préparation unitaire liquide buvable, notamment pour la prévention et le traitement de l'ostéoporose chez le sujet âgé, cette association comprenant comme principes actifs associés du calcium-élément et au moins une vitamine D, caractérisée en ce qu'elle comprend :1. A mineralo-vitamin therapeutic association in the form of a unitary liquid drinkable preparation, in particular for the prevention and treatment of osteoporosis in the elderly, this association comprising as active principles associated with the calcium element and at least one vitamin D, characterized in that it comprises:
— un sel de calcium dispersé dans un milieu liquide aqueux, ce sel étant essentiellement non soluble dans le milieu liquide aqueux, — au moins une vitamine D,A calcium salt dispersed in an aqueous liquid medium, this salt being essentially insoluble in the aqueous liquid medium, at least one vitamin D,
— un solubilisant de la vitamine D dans le milieu aqueux,- a solubilizer of vitamin D in the aqueous medium,
— un gélifiant, propre à augmenter la viscosité du milieu aqueux et ainsi maintenir en suspension homogène dans ce milieu le sel de calcium non soluble.- A gelling agent, capable of increasing the viscosity of the aqueous medium and thus maintaining the non-soluble calcium salt in homogeneous suspension in this medium.
2. L'association de la revendication 1 , où le rapport du calcium sous forme élémentaire à la vitamine D, exprimé en mg de Ca élément par UI de vitamine D, est compris entre 1 et 1,5.2. The combination of claim 1, wherein the ratio of calcium in elemental form to vitamin D, expressed in mg of elemental Ca per IU of vitamin D, is between 1 and 1.5.
3. L'association de la revendication 2, où le rapport du calcium sous forme élémentaire à la vitamine D, exprimé en mg de Ca élément par UI de vitamine D, est compris entre 1,2 et 1,3.3. The combination of claim 2, wherein the ratio of calcium in elemental form to vitamin D, expressed in mg of elemental Ca per IU of vitamin D, is between 1.2 and 1.3.
4. L'association de la revendication 1 , caractérisée en ce qu'elle est conditionnée sous forme de doses journalières unitaires, chaque dose comprenant 800 à 1200 mg de calcium-élément pour 600 à 1000 UI de vitamine D.4. The combination of claim 1, characterized in that it is packaged in the form of daily unit doses, each dose comprising 800 to 1200 mg of calcium element for 600 to 1000 IU of vitamin D.
5. L'association de la revendication 1, où le sel de calcium non soluble est le carbonate de calcium.5. The combination of claim 1, wherein the insoluble calcium salt is calcium carbonate.
6. L'association de la revendication 1 , où la vitamine D est choisie parmi la vitamine D2 ou ergocalciférol, la vitamine D3 ou cholécalciférol ou un mélange de celles-ci. 6. The combination of claim 1, wherein vitamin D is chosen from vitamin D2 or ergocalciferol, vitamin D3 or cholecalciferol or a mixture of these.
7. L'association de la revendication 1 , où le solubilisant de la vitamine D est choisi parmi les polyoxyéthylène glycols et leurs esters, les propylène glycols, l'alcool éthylique, les éthers de diéthylène glycols, le glycérol et les glycérides polyglycolysés saturés et insaturés, les saccha- rides de type fructose liquide, le maltitol liquide, les esters de sorbitanne polyhydroxyéthylé, l'huile de ricin polyoxyéthylénée hydrogénée et non hydrogénée et les maltodextrines, de préférence un ester de sorbitanne polyhydroxyéthylé.7. The combination of claim 1, wherein the vitamin D solubilizer is chosen from polyoxyethylene glycols and their esters, propylene glycols, ethyl alcohol, ethers of diethylene glycols, glycerol and saturated polyglycolysed glycerides and unsaturated, liquid fructose type saccharides, liquid maltitol, polyhydroxyethylated sorbitan esters, hydrogenated and non-hydrogenated polyoxyethylene castor oil and maltodextrins, preferably a polyhydroxyethylated sorbitan ester.
8. L'association de la revendication 1 , où le gélifiant est choisi parmi les gommes type gomme guar, gomme xanthane, gomme adragante et gomme arabique, l'agar-agar, le carboxyméthyl amidon sodique, la silice colloïdale anhydre, les dérivés cellulosiques type hydroxypropyl- cellulose, hydroxyéthylcellulose et carboxyméthylcellulose sodique, les polymères de l'acide acrylique et les silicates d'aluminium et magnésium, de préférence la gomme xanthane.8. The combination of claim 1, wherein the gelling agent is chosen from gums such as guar gum, xanthan gum, tragacanth and gum arabic, agar-agar, sodium carboxymethyl starch, colloidal anhydrous silica, cellulose derivatives hydroxypropylcellulose, hydroxyethylcellulose and sodium carboxymethylcellulose, polymers of acrylic acid and aluminum and magnesium silicates, preferably xanthan gum.
9. L'association de la revendication 1 , comprenant en outre un conservateur, choisi parmi l'acide parahydroxybenzoïque, ses esters mé- thyliques et propyliques et les dérivés sodiques de ces esters, l'acide benzoïque et ses sels, l'acide sorbique et ses sels, les bisulfites et les métabisulfites.9. The combination of claim 1, further comprising a preservative, chosen from parahydroxybenzoic acid, its methyl and propylic esters and the sodium derivatives of these esters, benzoic acid and its salts, sorbic acid and its salts, bisulfites and metabisulfites.
10. L'association de la revendication 1, comprenant en outre un édulcorant, choisi parmi l'aspartame, le saccharose, l'acésulfame de potassium, le saccharinate de sodium, le cyclamate de sodium et le fructose.10. The combination of claim 1, further comprising a sweetener, selected from aspartame, sucrose, potassium acesulfame, sodium saccharinate, sodium cyclamate and fructose.
11. L'association de la revendication 1 , de formule centésimale :11. The association of claim 1, of centesimal formula:
Carbonate de calcium 16,67 gCalcium carbonate 16.67 g
(Quantité correspondant à calcium-élément : 6,67 g) Cholécalciférol, quantité correspondant à 5333,33 UI(Quantity corresponding to calcium element: 6.67 g) Cholecalciferol, quantity corresponding to 5333.33 IU
Ester de sorbitanne polyhydroxyéthylé (polysorbate 80) 0,05 g Gomme xanthane 0,75 g Fructose 8,67 gPolyhydroxyethylated sorbitan ester (polysorbate 80) 0.05 g Xanthan gum 0.75 g Fructose 8.67 g
Conservateur q.s.Curator q.s.
Arôme q.s.Aroma q.s.
Eau purifiée q.s. 100 ml, le pH final étant compris entre 7 et 9. Purified water q.s. 100 ml, the final pH being between 7 and 9.
EP98913826A 1997-03-14 1998-03-04 Therapeutic combination of mineral and vitamin in units of liquid preparation for oral administration Withdrawn EP0971719A1 (en)

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FR9703061A FR2760639B1 (en) 1997-03-14 1997-03-14 MINERALO-VITAMIN THERAPEUTIC ASSOCIATION IN THE FORM OF A UNITABLE ORAL LIQUID PREPARATION
PCT/FR1998/000425 WO1998041217A1 (en) 1997-03-14 1998-03-04 Therapeutic combination of mineral and vitamin in units of liquid preparation for oral administration

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DE102004051879A1 (en) * 2004-10-26 2006-04-27 Bayerl, Wolfgang P., Dr. Curing agent, useful e.g. for the prophylaxis and therapy of osteoporosis, as food auxiliary agent intended to stimulate bone formation, comprises a combination of silicon dioxide with natural minerals and vitamin D
GB0507167D0 (en) 2005-04-08 2005-05-18 Glaxosmithkline Consumer Healt Composition
CA2924200C (en) * 2005-10-12 2017-09-05 Proventiv Therapeutics, Llc Methods and articles for treating 25-hydroxyvitamin d insufficiency and deficiency
CN102232967A (en) * 2010-04-21 2011-11-09 武汉同济现代医药有限公司 Novel oral effervescent agent for calcium supply and preparation method thereof
ES2885523T3 (en) 2011-11-23 2021-12-14 Therapeuticsmd Inc Natural combination hormone replacement formulations and therapies
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