FR2760639A1 - MINERALO-VITAMIN THERAPEUTIC ASSOCIATION IN THE FORM OF A UNITABLE ORAL LIQUID PREPARATION - Google Patents
MINERALO-VITAMIN THERAPEUTIC ASSOCIATION IN THE FORM OF A UNITABLE ORAL LIQUID PREPARATION Download PDFInfo
- Publication number
- FR2760639A1 FR2760639A1 FR9703061A FR9703061A FR2760639A1 FR 2760639 A1 FR2760639 A1 FR 2760639A1 FR 9703061 A FR9703061 A FR 9703061A FR 9703061 A FR9703061 A FR 9703061A FR 2760639 A1 FR2760639 A1 FR 2760639A1
- Authority
- FR
- France
- Prior art keywords
- vitamin
- calcium
- combination
- salt
- chosen
- 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.)
- Granted
Links
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- 238000002360 preparation method Methods 0.000 title claims description 13
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- 239000011782 vitamin Substances 0.000 title claims description 8
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- 229930003316 Vitamin D Natural products 0.000 claims abstract description 39
- 235000019166 vitamin D Nutrition 0.000 claims abstract description 39
- 239000011710 vitamin D Substances 0.000 claims abstract description 39
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- 239000011575 calcium Substances 0.000 claims abstract description 24
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- 229910052791 calcium Inorganic materials 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 15
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- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 8
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- 239000011653 vitamin D2 Substances 0.000 claims description 4
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 claims description 4
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- 230000009469 supplementation Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
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- 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
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Abstract
Description
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. 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.
Affect of Calcium and Cholecalciferol Treatment for Three Years on
Hip Fractures in Elderly Women, British Medical Journal, 308, 10811082 (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'article intitulé Supplementation with Vitamin D3 and Calcium Prevents
Hip Fractures in Elderly Women, Nutrition Reviews, Vol. 51, 6, pp.Affect of Calcium and Cholecalciferol Treatment for Three Years on
Hip Fractures in Elderly Women, British Medical Journal, 308, 10811082 (April 23, 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 titled Supplementation with Vitamin D3 and Calcium Prevents
Hip Fractures in Elderly Women, Nutrition Reviews, Vol. 51, 6, 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 indication dans la prévention et le traitement de l'ostéoporose, aux alentours de 1000 à 1200 mg de calcium élément et 800 UI de vitamine D3.183-185. 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.
On connaît de très nombreuses formes galéniques associant calcium et vitamine D. 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 pelliculés, 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). 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 vitaminocalciques 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. 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.
Mais, ici encore, le sel de calcium est toujours sous forme soluble ou solubilisée, avec pour conséquence un pH faible conduisant aux inconvénients cités plus haut.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 minéralo-vitaminique combinant calcium et vitamine D, qui soit présentée sous forme galénique de préparation unitaire liquide buvable dépourvue de forte acidité de façon à procurer une bonne tolérance et une bonne absorption des principes actifs. One of the aims of the invention is to propose a mineralo-vitamin association combining calcium and vitamin D, which is presented in galenical form of unitary drinkable liquid preparation devoid of high acidity so as to provide good tolerance and good absorption of active subtances.
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, 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. 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, without the patient having to carry out any manipulation, as would be the case for example. with effervescent granules or soluble powders.
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. 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 propose such a calcium / vitamin D association in drinkable liquid form having an optimal relative dosage between calcium and vitamin D, very particularly 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 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 : 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 en solution huileuse ; 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 the 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 in oily solution; 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 - 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 - l'association est conditionnée sous forme de doses journalières uni
taires, 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 - le solubilisant de la vitamine D est choisi parmi les polyoxyéthy
lène glycols et leurs esters, les propylène glycols, les éthers de
diéthylène glycols, le glycérol et les glycérides polyglycolysés satu
rés 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 maltodex
trines, de préférence parmi un ester de sorbitanne polyhydroxy
éthylé; - 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 hydroxypropylcellulose, hydroxyéthylcel
lulose et carboxyméthylcellulose sodique, les polymères de l'acide
acrylique et les silicates d'aluminium et magnésium, de préférence
la gomme xanthane; - l'association comprend en outre un conservateur, choisi parmi l'aci
de 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 - 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, solution huileuse 5,33 mg (quantité corres
pondant 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.According to various advantageous characteristics - the ratio of calcium in elementary form to vitamin D,
expressed in mg of elemental Ca per IU of vitamin D, is understood
between 1 and 1.5, preferably between 1.2 and 1.3 - the combination is packaged in the form of single daily doses
with each dose comprising 800 to 1,200 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 polyoxyethy
lene glycols and their esters, propylene glycols, ethers of
diethylene glycols, glycerol and saturated polyglycolysed glycerides
res and unsaturated, liquid fructose saccharides, maltitol
liquid, polyhydroxyethylated sorbitan esters, castor oil
hydrogenated and non-hydrogenated polyoxyethylenated and maltodex
triines, preferably from a polyhydroxy sorbitan ester
ethyl; - the gelling agent is chosen from gums such as guar gum, gum
xanthan, tragacanth and gum arabic, agar-agar,
sodium carboxymethyl starch, anhydrous colloidal silica,
hydroxypropylcellulose, hydroxyethylcel cellulose derivatives
lulose and sodium carboxymethylcellulose, acid polymers
acrylic and aluminum and magnesium silicates, preferably
xanthan gum; - the association also includes a curator, chosen from the aci
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 combination also includes a sweetener, chosen from as
partame, sucrose, acesulfame potassium, saccharinate
sodium, sodium cyclamate and fructose - the association presents the following centesimal formula: carbonate
calcium 16.67 g (amount corresponding to calcium element
6.67 g); cholecalciferol, oily solution 5.33 mg (corresponding quantity
ponding at: 5333.33 IU); polyhydroxyethylated sorbitan ester
(Polysorbate 80) 0.05 g; xanthan gum 0.75 g; fructose 8.67 g;
preservative qs; aroma qs; purified water qs 100 ml.
#
On va décrire un exemple préférentiel, mais non limitatif, de mise en oeuvre de l'invention.#
We will describe a preferred example, but not limiting, of implementation of the 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 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.
10) Vitamine D : Cette vitamine est du cholécalciférol (vitamine D3
Roche) en solution huileuse (huile végétale) titrée à 1 million d'U1/g. 10) Vitamin D: This vitamin is cholecalciferol (vitamin D3
Roche) in oily solution (vegetable oil) titrated to 1 million U1 / g.
La présence de dl-a-tocophérol lui confère une grande stabilité et empêche son oxydation.The presence of dl-a-tocopherol gives it great stability and prevents its oxidation.
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. 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.
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 llm environ et de densité élevée (d =1,3 g/cm3 environ). 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 ) Solubilisant: Il s'agit de rendre compatible une vitamine lipophile (la vitamine D3 en solution huileuse) 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 compatible avec l'eau. 3) Solubilizer: This involves making a lipophilic vitamin (vitamin D3 in oily solution) 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 sachet 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 sachet of the packaging of the liquid preparation.
Parmi divers solubilisants répondant à ces divers critères, on peut citer notamment - les polyoxyéthylène glycols (PEG) type PEG 400 et leurs esters type
laurate de PEG 200 ou stéarate de PEG 40, - les propylène glycols et les éthers du diéthylène glycol type diéthy
lène glycol monoéthyléther (Transcuto), - le glycérol et les glycérides polyglycolysés saturés (type PEG-8 gly
céryl caprylate/caprate (Labrasol)) et insaturés (type PEG-6 gly
céryl monooléate (LabrafiP M 1944 CS), - les saccharides type fructose liquide, maltitol liquide (LycasinG3
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 So, - l'huile de ricin polyoxyéthylénée hydrogénée (type Croduret 50
spécial), Crémophor RH 40) et non hydrogénée (type Etocas
35 HV), - la maltodextrine (type Glucidex). Among various solubilizers meeting these various criteria, there may be mentioned in particular - polyoxyethylene glycols (PEG) type PEG 400 and their esters type
PEG 200 laurate or PEG 40 stearate, - propylene glycols and diethylene glycol ethers, diethyl type
lene glycol monoethyl ether (Transcuto), - glycerol and saturated polyglycolysed glycerides (type PEG-8 gly
ceryl caprylate / caprate (Labrasol)) and unsaturated (type PEG-6 gly
ceryl monooleate (LabrafiP M 1944 CS), - saccharides such as liquid fructose, liquid maltitol (LycasinG3
80/55), - polyhydroxyethylated sorbitan esters of polysorbate type 80
it 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 about 0.05 So, - the hydrogenated polyoxyethylenated castor oil (type Croduret 50
special), Crémophor RH 40) and not hydrogenated (Etocas type
35 HV), - maltodextrin (type Glucidex).
4 ) Gélifiant : Le rôle de ce gélifiant est de maintenir le sel de calcium 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. 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.
Parmi les gélifiant qui conviennent, on peut citer: - les gommes type guar, type xanthane, type adragante et type ara
bique - le choix de gélifiant actuellement préféré étant la gomme
xanthane en proportion de 0,1 à 1 Go en poids, de préférence envi
ron 0,75 %, - l'agar-agar, - le carboxyméthylamidon sodique (type Explotab, - la silice colloïdale anhydre (type AérosilX 200), - les dérivés cellulosiques de type hydroxypropylcellulose (Klucel9),
hydroxyéthylcellulose (Natrosol), carboxyméthylcellulose sodique (Blanose3), - les polymères de l'acide acrylique (type Carbopol 974P), - le silicate d'aluminium et magnésium (type VeegumX HV). Among the gelling agents which are suitable, there may be mentioned: - guar type gums, xanthan type, tragacanth type and macaw type
bique - the currently preferred choice of gelling agent is gum
xanthan in proportion of 0.1 to 1 GB by weight, preferably approx.
ron 0.75%, - agar-agar, - sodium carboxymethyl starch (type Explotab, - anhydrous colloidal silica (type AerosilX 200), - cellulose derivatives of hydroxypropylcellulose type (Klucel9),
hydroxyethylcellulose (Natrosol), sodium carboxymethylcellulose (Blanose3), - polymers of acrylic acid (type Carbopol 974P), - aluminum and magnesium silicate (type VeegumX HV).
5 ) Édulcorant: Divers types d'édulcorants peuvent être choisis, ce choix n'étant pas critique pour la mise en oeuvre de l'invention. 5) Sweetener: Various types of sweeteners can be chosen, this choice not being critical for the implementation of the invention.
On peut citer notamment : l'aspartame, le saccharose, l'acésulfame de potassium (Sunetag), le saccharinate de sodium, le cyclamate de sodium ou le fructose (FructofinX C type A121). 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. Mention may in particular be made of: aspartame, sucrose, potassium acesulfame (Sunetag), sodium saccharinate, sodium cyclamate or fructose (FructofinX C type A121). Advantageously, one chooses fructose, which is a natural sweetener having the advantage of not providing sucrose and of not being contraindicated in diabetic non-insulin-dependent 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 propyliques 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 propylic esters and the sodium derivatives of these esters, the acid 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: - solubiliser la vitamine D3 en solution huileuse dans le solubilisant, - transvaser cette solution dans l'eau, et mélanger sous agitation, - dissoudre le conservateur sous agitation, - dissoudre l'édulcorant sous agitation, - ajouter l'arôme (liquide) sous agitation, - disperser le carbonate de calcium sous agitation, - disperser l'agent gélifiant sous agitation, - conditionner en sachet. For manufacturing, the operating protocol is as follows: - dissolve vitamin D3 in oily solution in the solubilizer, - transfer this solution to water, and mix with stirring, - dissolve the preservative with stirring, - dissolve the sweetener under stirring, - add the aroma (liquid) with stirring, - disperse the calcium carbonate with stirring, - disperse the gelling agent with stirring, - condition in a sachet.
Une formule générale préférentielle est la suivante (formule cen tésimale)
Carbonate de calcium 16,67 g
(Quantité correspondant à calcium-élément: 6,67 g)
Cholécalciférol, solution huileuse 5,33 mg
(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.A preferred general formula is as follows (centennial formula)
Calcium carbonate 16.67 g
(Quantity corresponding to calcium element: 6.67 g)
Cholecalciferol, oily solution 5.33 mg
(Quantity corresponding to: 5333.33 IU)
Polyhydroxyethylated sorbitan ester (polysorbate 80) 0.05 g
Xanthan gum 0.75 g
Fructose 8.67 g
Conservative qs
Arôme q.s. Aroma q.s.
Eau purifiée q.s. 100 ml
La préparation obtenue présente un pH de 8 environ (donc sans aucun caractère acide) et une viscosité n = 2000 mPa.s.Purified water qs 100 ml
The preparation obtained has a pH of approximately 8 (therefore without any acidic character) and a viscosity n = 2000 mPa.s.
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), glycérol (3 g), maltitol liquide (1 g) ou huile de ricin polyoxyéthylénée hydrogé née (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), glycerol (3 g), liquid maltitol (1 g) or polyoxyethylene hydrogenated castor oil born (1 g).
De même, les 0,75 g de gomme xanthane peuvent être remplacés par : gomme guar (1 g), hydroxypropylcellulose (1 g), hydroxyéthylcellulose (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 (11)
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
| JP54018498A JP2001521495A (en) | 1997-03-14 | 1998-03-04 | Therapeutic combinations of minerals and vitamins in a single formulation of beverage liquid |
| EP98913826A EP0971719A1 (en) | 1997-03-14 | 1998-03-04 | Therapeutic combination of mineral and vitamin in units of liquid preparation for oral administration |
| CN98803347A CN1250374A (en) | 1997-03-14 | 1998-03-04 | Therapeutic combination of mineral and vitamin in units of liquid preparation for oral administration |
| EA199900830A EA199900830A1 (en) | 1997-03-14 | 1998-03-04 | THERAPEUTIC MINERALOVITAMIN ASSOCIATION IN THE FORM OF UNITARY LIQUID PREPARATION FOR DRINKING |
| CA002283691A CA2283691A1 (en) | 1997-03-14 | 1998-03-04 | Therapeutic combination of mineral and vitamin in units of liquid preparation for oral administration |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9703061A FR2760639B1 (en) | 1997-03-14 | 1997-03-14 | MINERALO-VITAMIN THERAPEUTIC ASSOCIATION IN THE FORM OF A UNITABLE ORAL LIQUID PREPARATION |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2760639A1 true FR2760639A1 (en) | 1998-09-18 |
| FR2760639B1 FR2760639B1 (en) | 2000-09-22 |
Family
ID=9504760
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR9703061A Expired - Fee Related FR2760639B1 (en) | 1997-03-14 | 1997-03-14 | MINERALO-VITAMIN THERAPEUTIC ASSOCIATION IN THE FORM OF A UNITABLE ORAL LIQUID PREPARATION |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0971719A1 (en) |
| JP (1) | JP2001521495A (en) |
| CN (1) | CN1250374A (en) |
| CA (1) | CA2283691A1 (en) |
| EA (1) | EA199900830A1 (en) |
| FR (1) | FR2760639B1 (en) |
| WO (1) | WO1998041217A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006108692A3 (en) * | 2005-04-08 | 2007-12-06 | Glaxosmithkline Consumer Healt | Dosage form for oral administration of a vitamin |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITFI970184A1 (en) * | 1997-07-30 | 1999-01-30 | Menarini Farma Ind | PHARMACEUTICAL COMPOSITIONS CONTAINING VITAMIN D AND CALCIUM, THEIR PREPARATION AND THERAPEUTIC USE |
| 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 |
| EP1945185B1 (en) * | 2005-10-12 | 2016-02-03 | 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 |
| RS62297B1 (en) | 2011-11-23 | 2021-09-30 | Therapeuticsmd Inc | Natural combination hormone replacement formulations and therapies |
| US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
| US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| JP2017516768A (en) | 2014-05-22 | 2017-06-22 | セラピューティックスエムディー インコーポレーテッドＴｈｅｒａｐｅｕｔｉｃｓｍｄ， Ｉｎｃ． | Natural combination hormone replacement therapy and therapy |
| US11633405B2 (en) | 2020-02-07 | 2023-04-25 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical formulations |
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|---|---|---|---|---|
| GB899656A (en) * | 1958-02-11 | 1962-06-27 | Wander A G A | Method for producing sterile vitamin d solutions containing calcium salts |
| EP0227174A2 (en) * | 1985-12-26 | 1987-07-01 | The Procter & Gamble Company | Beverages and beverage concentrates nutritionally supplemented with calcium |
| GB2196523A (en) * | 1986-09-12 | 1988-05-05 | Beecham Group Plc | Non-fat beverage |
| WO1990009797A1 (en) * | 1989-02-27 | 1990-09-07 | Gunnar Kjems | Orally administerable calcium supplement for cattle |
| WO1992019251A1 (en) * | 1991-05-06 | 1992-11-12 | The Procter & Gamble Company | Combined calcium and vitamin d supplements |
| WO1996009036A1 (en) * | 1994-09-23 | 1996-03-28 | Laboratoire Innothera, Societe Anonyme | Therapeutic vitamin-calcium combination in unitary galenic tablet form, method for preparing same and use thereof |
| WO1996031130A2 (en) * | 1995-04-07 | 1996-10-10 | Abbott Laboratories | Calcium supplements and calcium containing beverages comprising vitamin d |
-
1997
- 1997-03-14 FR FR9703061A patent/FR2760639B1/en not_active Expired - Fee Related
-
1998
- 1998-03-04 EP EP98913826A patent/EP0971719A1/en not_active Withdrawn
- 1998-03-04 JP JP54018498A patent/JP2001521495A/en active Pending
- 1998-03-04 CA CA002283691A patent/CA2283691A1/en not_active Abandoned
- 1998-03-04 WO PCT/FR1998/000425 patent/WO1998041217A1/en not_active Ceased
- 1998-03-04 EA EA199900830A patent/EA199900830A1/en unknown
- 1998-03-04 CN CN98803347A patent/CN1250374A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB899656A (en) * | 1958-02-11 | 1962-06-27 | Wander A G A | Method for producing sterile vitamin d solutions containing calcium salts |
| EP0227174A2 (en) * | 1985-12-26 | 1987-07-01 | The Procter & Gamble Company | Beverages and beverage concentrates nutritionally supplemented with calcium |
| GB2196523A (en) * | 1986-09-12 | 1988-05-05 | Beecham Group Plc | Non-fat beverage |
| WO1990009797A1 (en) * | 1989-02-27 | 1990-09-07 | Gunnar Kjems | Orally administerable calcium supplement for cattle |
| WO1992019251A1 (en) * | 1991-05-06 | 1992-11-12 | The Procter & Gamble Company | Combined calcium and vitamin d supplements |
| WO1996009036A1 (en) * | 1994-09-23 | 1996-03-28 | Laboratoire Innothera, Societe Anonyme | Therapeutic vitamin-calcium combination in unitary galenic tablet form, method for preparing same and use thereof |
| WO1996031130A2 (en) * | 1995-04-07 | 1996-10-10 | Abbott Laboratories | Calcium supplements and calcium containing beverages comprising vitamin d |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006108692A3 (en) * | 2005-04-08 | 2007-12-06 | Glaxosmithkline Consumer Healt | Dosage form for oral administration of a vitamin |
| EA013381B1 (en) * | 2005-04-08 | 2010-04-30 | Глаксосмитклайн Консьюмер Хелткер Гмбх Унд Ко. Кг | Composition |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2283691A1 (en) | 1998-09-24 |
| JP2001521495A (en) | 2001-11-06 |
| CN1250374A (en) | 2000-04-12 |
| FR2760639B1 (en) | 2000-09-22 |
| WO1998041217A1 (en) | 1998-09-24 |
| EA199900830A1 (en) | 2000-04-24 |
| EP0971719A1 (en) | 2000-01-19 |
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