EP1603574A1 - Medicament or nutriceutical combining a soluble poorly-absorbed saccharide and an antiflatulent from the siloxane group - Google Patents

Medicament or nutriceutical combining a soluble poorly-absorbed saccharide and an antiflatulent from the siloxane group

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Publication number
EP1603574A1
EP1603574A1 EP03717376A EP03717376A EP1603574A1 EP 1603574 A1 EP1603574 A1 EP 1603574A1 EP 03717376 A EP03717376 A EP 03717376A EP 03717376 A EP03717376 A EP 03717376A EP 1603574 A1 EP1603574 A1 EP 1603574A1
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European Patent Office
Prior art keywords
lactulose
simeticone
antiflatulent
pharmaceutical
saccharide
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EP03717376A
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German (de)
French (fr)
Inventor
Jean-Luc Derre
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Individual
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Individual
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Publication of EP1603574A1 publication Critical patent/EP1603574A1/en
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    • 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
    • A61K31/695—Silicon compounds
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose

Definitions

  • Constipation is a common disorder affecting a large number of individuals.
  • constipation is defined by a reduced number of bowel movements, equal to or less than 3 per week. However, be aware that constipation often means hard but daily bowel movements, hard-to-pass stools or incomplete exoneration. Drug treatment for constipation should only be used as an adjunct to diet and diet therapy:
  • laxative drugs are useful or even essential in the most serious cases, such as chronic functional constipation or in special situations (such as preparation for certain radiological examinations).
  • the saccharide most used therapeutically in the treatment of constipation is lactulose.
  • Lactulose administered orally generally in the form of a concentrated solution, passes through the upper parts of the digestive tract (stomach, small intestine) without modification and without absorption.
  • lactulose and related substances are generally considered by gastroenterologists to be "mild” laxatives.
  • lactulose is transformed under the effect of the local saccharolytic bacterial flora into short-chain organic acids (mainly lactic acid, accompanied by small amounts of acetic, formic acids, etc.) and this acidification of the intestinal contents stimulates peristalsis intestinal.
  • short-chain organic acids mainly lactic acid, accompanied by small amounts of acetic, formic acids, etc.
  • a recent communication from the INSERM U 290 team on the occasion of the Francophone Days of Digestive Pathology (March 1998) even specified its mechanism of action at the level of the colon, by demonstrating on 18 healthy volunteers that lactulose causes a tonic contraction prolonged; this motor effect should affect colonic propulsion and therefore explain the laxative effect of lactulose.
  • the lactulose will thus reproduce a "carbohydrate malabsorption syndrome" accompanied by an acceleration of the transit which constitutes the therapeutic effect sought.
  • lactulose The colonic metabolism of lactulose and related substances is unfortunately accompanied by the formation of intestinal gases (essentially hydrogen, but also C0 2 or even methane) which is the cause of the most frequent undesirable effects of lactulose (abdominal discomfort with meteorism and flatulence).
  • BIAM Computerized Automatic Drug Database
  • Methodeorism and “Flatulence” as “certain and frequent” side effects of lactulose.
  • These digestive side effects are also mentioned in The Drug Dictionary.
  • the reference article on lactulose mentions: “In humans, however, there are minor side effects; they are quite frequent and can be observed even at low doses (20 to 40 g I day). These are digestive disorders: diarrhea, sometimes accompanied by abdominal pain, and flatulence.
  • the “breath-test” represents the best objective demonstration of the production of intestinal gases and in particular of H 2 , starting on average 2 hours after ingestion of a single intake of lactulose of 10 g.
  • the undesirable digestive effects of lactulose and related substances appear when the saccharide reaches the level of the ascending colon, that is to say 2 to 3 hours after taking the drug.
  • the administration of symptomatic treatment to combat these undesirable effects is doomed to failure, taking into account the time of action of the antiflatulent product in colonic site, also of the order of 2 to 3 hours.
  • the new composition which is the subject of this patent combines, in defined proportions, a soluble saccharide, little or not absorbed (lactulose, lactitol, trehalose ...) with an antiflatulent with recognized efficacy in order to avoid this type of problem.
  • the advantage of this new composition lies in the fact that the simultaneous taking of the laxative active principle (lactulose, lactitol, trehalose ...) and the antiflatulent active principle will allow them to follow the same digestive transit, the antiflatulent active principle then having a optimal action on gases formed by the fermentation of the laxative active ingredient in the colon.
  • the new composition may be in the form of a drug or “food” (food product favorable to health, also called “functional food”), the new composition then being added to a traditional food (fruit compote, yoghurt, etc.) in order to obtain a "food”.
  • food food product favorable to health, also called “functional food”
  • traditional food fruit compote, yoghurt, etc.
  • the antiflatulent active principle must have the following characteristics: ⁇ possess recognized clinical efficacy in digestive disorders linked to an excess of gas; o do not interfere with the mode of action of the laxative, in particular respect the colonic metabolism and therefore the fermentation phenomenon at the base of the laxative action of the saccharide; • have no constipating effect, which would counteract the action of the laxative;
  • the antiflatulent active principle will be chosen from the chemical family of siloxanes and more particularly from polydimethylsiloxanes (simeticone, dimeticone, etc.).
  • Simeticone belongs to the class of linear polydimethylsiloxanes, widely used in human medicine for many years. It is the compound most used in therapy within the chemical family of siloxanes. Simeticone is dimeticone to which silica gel is added to promote its dispersion in an aqueous medium; simeticone is listed in the American Pharmacopoeia.
  • simeticone or activated dimeticone
  • simeticone works by dispersing and preventing the formation of gas bubbles surrounded by mucus in the gastrointestinal tract. By reducing the size of air bubbles, simeticone allows gases to pass through the gastrointestinal tract to be eliminated there.
  • simeticone also seems to act by promoting intestinal gas absorption.
  • Simeticone is indicated for the treatment of flatulence and abdominal discomfort due to excess gastrointestinal gas.
  • Simeticone is used as an antiflatulent in doses generally ranging from 250 mg to 2 g per day.
  • Simeticone therefore has excellent safety in use and animal toxicological studies have not made it possible to determine its lethal dose, given its large margin of safety. Simeticone is also a food additive considered to be “GRAS” (“Generally Recognized As Safe”).
  • simeticone Another proof of the safety of simeticone is the fact that several drugs based on simeticone are used in the USA in newborns.
  • simeticone does not modify digestive transit.
  • simeticone is a substance with high chemical inertness, thus limiting the risks of drug interactions, but also the risks of disturbing the phenomenon of colonic fermentation at the base of the laxative action of the saccharide.
  • the safety data from simeticone can be transposed to dimeticone.
  • a drug based on dimeticone having as indication “symptomatic treatment of gastralgia and treatment of intestinal meteorism” has a maximum dosage corresponding to a dose of 13.5 g of dimeticone per day, without limitation of the duration of treatment. Also, to take into account the disparities in national legislations and the therapeutic habits of each country, the doses of antiflatulent will be expressed in "range" of doses (with indication of two extreme values) and not in fixed doses,
  • the new pharmaceutical or dietetic composition is characterized in that it combines a soluble saccharide, little or not absorbed by the body and an antiflatulent with the recognized effectiveness of the family of siloxanes, in proportions such as:
  • the final concentration of the saccharide in the new composition is greater than 80% (w / w) for a solid composition or greater than 40% (w / v) for a liquid or semi-liquid composition, in order to limit the volume of the therapeutically effective daily intake (the volume of the therapeutically effective daily intake constituting one of the major obstacles to good compliance with treatment with saccharides);
  • the amount of antiflatulent per 100 g of saccharide in the new composition is between 0.5 g and 100 g, taking into account the usual and maximum dosages of each active ingredient and depending on the desired therapeutic effect.
  • simeticone, dimeticone or any other polydimethylsiloxane which has demonstrated its antiflatulent efficacy and its safety in humans will be used interchangeably.
  • drugs or "alicaments” with essentially laxative aims, devoid of the usual digestive undesirable effects linked to the use of lactulose or related substances - discomfort abdominal with meteorism and flatulence.
  • these drugs or "alicaments” can be used to promote the development of the saccharolytic intestinal flora, considered as the flora "beneficial" to health.
  • drugs or "alicaments” with an essentially antiflatulent aim intended for patients suffering from functional digestive disorders such as functional colopathy or "bowel syndrome"
  • irritable where intestinal gases have now been shown to play a predominant role, generally associated with constipation, prohibiting the use of“ traditional ”therapies such as activated charcoal or clays which cause a slowing of intestinal transit and therefore worsen constipation pre-existing.
  • the drugs manufactured according to the present invention and combining polydimethylsiloxane and soluble saccharide little or not absorbed may claim therapeutic indications of the type "Symptomatic treatment of functional colopathy with constipation".
  • the pharmaceutical or dietetic composition which is the subject of the present invention will be used for the manufacture of medicaments or “alicaments” useful for preventing and / or treating digestive disorders (such as constipation and / or bloating) or for regenerating the intestinal flora or still to treat hepatic encephalopathy.
  • the new composition may be in liquid or semi-liquid form in which the active ingredients are mixed with one or more excipients (emulsifying agents, stabilizers, thickeners - carbomer type 934P - synthetic high molecular weight copolymer of acrylic acid and d 'a polyalkyl sugar-, sodium carmellose -cellulose carboxymethyl ether, sodium salt-, xanthan gum, purified water .10) giving it a form of stabilized emulsion or oral jelly.
  • excipients emulsifying agents, stabilizers, thickeners - carbomer type 934P - synthetic high molecular weight copolymer of acrylic acid and d 'a polyalkyl sugar-, sodium carmellose -cellulose carboxymethyl ether, sodium salt-, xanthan gum, purified water .
  • the new composition may also be in solid form (powder for oral solution, dispersing powder, tablet, etc.) in which the saccharide is provided in crystallized form and the antiflatulent is provided in liquid form using the saccharide as a support or in solid form (simeticone or dimeticone previously fixed on an inert support).
  • compositions associating a soluble saccharide, little or not absorbed may further comprise a or several excipients (preservative, color, flavor %) and / or one or more other active ingredients, for digestive purposes or not.
  • Stabilized liquid pharmaceutical composition for essentially laxative purposes, the formulation of which is as follows: Lactulose (brought in the form of liquid lactulose Ph. Europ) 10 g
  • Excipient purified water, 934P carbomer, sodium carmellose, xanthan gum, flavor 7.3 qs a 15 ml sachet (average dosage: 1 to 3 sachets / day)
  • Stabilized liquid pharmaceutical composition with an essentially antiflatulent aim the formulation of which is:
  • Solid pharmaceutical composition for essentially laxative purposes the formulation of which is: Lactitol (supplied in crystallized form) 10 g Simeticone (supplied in the form of simeticone fixed on an inert support) 250 mg
  • Excipient (flavor .7) qs a sachet of powder for oral solution (average dosage: 1 to 3 sachets / day)
  • Dietary composition intended essentially to promote the development of intestinal flora beneficial to health, the formulation of which is:
  • Apple compote rich in pectin without adding sugar to a 125 g jar (recommended consumption: 2 to 3 jars / day)

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a novel composition which combines defined proportions of a soluble saccharide which is poorly absorbed by the organism (the most widely known being disaccharides such as lactulose, lactitol, trehalose) and an antiflatulent from the siloxane group (the most widely known being polydimethylsiloxanes such as simeticone, dimeticone). The inventive composition takes the form of a medicament or nutriceutical which is essentially intended to treat constipation without causing the adverse digestive effects such as meteroism and flatulence associated with poorly-absorbed soluble saccharides. The composition is also intended for the regeneration of intestinal flora and for the symptomatic treatment of functional digestive disorders involving bloating and constipation. The antiflatulent/saccharide ratio can be varied in order to produce essentially-laxative compositions with low ratios and essentially-antiflatuelnt compositions with higher ratios. Moreover, the ratio can be varied within the range of low ratios in order to produce different formulations which are intended for the initial and maintenance treatment of constipation. The novel composition can also comprise one or more excipients and/or one or more other active principles and can take the form of a stabilised liquid or a solid.

Description

MEDICAMENT OU ALICAMENT ASSOCIANT MEDICINE OR RELATED ALICAMENT
UN SACCHARIDE SOLUBLE MAL ABSORBE ETA poorly absorbed and soluble solubar
UN ANTIFLATULENT DE LA FAMILLE DES SILOXANESAN ANTIFLATULENT OF THE SILOXANE FAMILY
DOMAINE TECHNIQUE ( PATHOLOGIE)TECHNICAL AREA (PATHOLOGY)
La constipation est un trouble fréquent affectant un grand nombre d'individus.Constipation is a common disorder affecting a large number of individuals.
Médicalement, la constipation est définie par un nombre réduit de défécations, égal ou inférieur à 3 par semaine. Cependant, il convient de savoir que les patients entendent par constipation souvent des selles dures mais quotidiennes, des selles difficiles à émettre ou une exonération incomplète. Le traitement médicamenteux de la constipation ne doit être qu'un adjuvant au traitement hygiéno- diététique:Medically, constipation is defined by a reduced number of bowel movements, equal to or less than 3 per week. However, be aware that constipation often means hard but daily bowel movements, hard-to-pass stools or incomplete exoneration. Drug treatment for constipation should only be used as an adjunct to diet and diet therapy:
• enrichissement de l'alimentation en fibres végétales et en boissons ;• enrichment of the diet with vegetable fibers and beverages;
• conseils d'activité physique et de rééducation de l'exonération.• advice on physical activity and exemption rehabilitation.
Cependant, les médicaments laxatifs sont utiles voire indispensables dans les cas les plus sérieux, comme la constipation fonctionnelle chronique ou dans des situations particulières (comme la préparation à certains examens radiologiques).However, laxative drugs are useful or even essential in the most serious cases, such as chronic functional constipation or in special situations (such as preparation for certain radiological examinations).
TECHNIQUES ANTERIEURES ( THERAPEUTIQUES EXISTANTES )PRIOR TECHNIQUES (EXISTING THERAPEUTICS)
De nombreuses substances laxatives existent sur le marché et la plupart d'entre elles sont connus depuis très longtemps. Elles peuvent être d'origine végétale, minérale ou synthétique. Malheureusement, à long terme, leur usage entraîne souvent des effets délétères (agression de la muqueuse intestinale -en particulier de la muqueuse colique-, ...) qu'il est intéressant d'éliminer.Many laxative substances exist on the market and most of them have been known for a very long time. They can be of vegetable, mineral or synthetic origin. Unfortunately, in the long term, their use often leads to deleterious effects (aggression on the intestinal mucosa - in particular the colonic mucosa -, ...) which it is worth eliminating.
A cette fin, l'usage relativement récent de saccharides solubles dans l'eau mais mal absorbés par notre organisme au niveau de l'intestin grêle a constitué un progrès indéniable. Dans le cadre de cette invention, comme saccharide soluble, mal absorbé, on utilisera indifféremment des disaccharides de synthèse non absorbés comme le lactulose ou le lactitol ou des disaccharides naturels peu absorbés comme le trehalose ou tout autre saccharide soluble, peu ou pas absorbé par l'organismeTo this end, the relatively recent use of saccharides soluble in water but poorly absorbed by our organism in the small intestine has constituted undeniable progress. In the context of this invention, as soluble saccharide, poorly absorbed, use will be made of synthetic disaccharides which are not absorbed such as lactulose or lactitol or natural disaccharides which are poorly absorbed such as trehalose or any other soluble saccharide which is little or not absorbed by the 'organization
(substances récentes comme les fructo-oligosaccharides, ...).(recent substances such as fructo-oligosaccharides, ...).
Sur le plan international, le saccharide le plus utilisé en thérapeutique dans le traitement de la constipation est le lactulose.Internationally, the saccharide most used therapeutically in the treatment of constipation is lactulose.
La parenté structurale de tous les saccharides à visée laxative et la similitude de leur mode d'action justifient de ne développer ici que ce qui concerne le lactulose et dans une moindre mesure le lactitol, ces deux substances ayant fait l'objet de nombreuses publications. Le lactulose ou 4-O-β-D-galactopyranosyl-D-fructose a été préparé pour la 1θre fois en 1930 et a été proposé dans les années 1960 pour le traitement de la constipation. De nombreuses études toxicologiques, pharmacologiques ou cliniques ont démontré son efficacité et sa sécurité d'emploi. Des spécialités pharmaceutiques ont été commercialisées dans de nombreux pays, généralement sous forme liquide concentrée (sirop dosé à 10 g/ 15 ml).The structural relationship of all saccharides for laxative purposes and the similarity of their mode of action justify developing here only what concerns lactulose and to a lesser extent lactitol, these two substances having been the subject of numerous publications. Lactulose or 4-O-β-D-galactopyranosyl-D-fructose was prepared for the first time in 1930 and was proposed in the 1960s for the treatment of constipation. Numerous toxicological, pharmacological or clinical studies have demonstrated its efficacy and safety in use. Pharmaceutical specialties have been marketed in many countries, generally in concentrated liquid form (syrup dosed at 10 g / 15 ml).
Son intérêt thérapeutique a justifié son inscription dans les Pharmacopées les plus importantes (américaine, européenne, japonaise ...).Its therapeutic interest justified its inclusion in the most important Pharmacopoeias (American, European, Japanese ...).
Le lactulose administré par voie orale, généralement sous forme de solution concentrée, traverse sans modification et sans résorption les parties hautes du tube digestif (estomac, intestin grêle).Lactulose administered orally, generally in the form of a concentrated solution, passes through the upper parts of the digestive tract (stomach, small intestine) without modification and without absorption.
Le mécanisme d'action laxative du lactulose est original et complexe, mettant en jeu plusieurs processus, ce qui explique que le lactulose et les substances apparentées n'appartiennent pas à une classe distincte de laxatifs mais sont rangés dans la classification internationale des médicaments EPHMRA commeThe mechanism of laxative action of lactulose is original and complex, involving several processes, which explains why lactulose and related substances do not belong to a separate class of laxatives but are classified in the international classification of medicines EPHMRA as
« autres laxatifs »."Other laxatives".
Cependant, le lactulose et les substances apparentées sont généralement considérés par les gastro- entérologues comme des laxatifs « doux ».However, lactulose and related substances are generally considered by gastroenterologists to be "mild" laxatives.
Au niveau du colon : « le lactulose augmente l'hydratation et donc le volume du contenu colique par effet osmotique ;At the level of the colon: “lactulose increases hydration and therefore the volume of colonic content by osmotic effect;
• le lactulose se transforme sous l'effet de la flore bactérienne saccharolytique locale en acides organiques à courte chaîne (principalement acide lactique, accompagné de petites quantités d'acides acétique, formique ....) et cette acidification du contenu intestinal stimule le péristaltisme intestinal. Une communication récente de l'équipe INSERM U 290 à l'occasion des Journées Francophones de Pathologie Digestive (Mars 1998) a même précisé son mécanisme d'action au niveau du colon, en démontrant sur 18 volontaires sains que le lactulose entraîne une contraction tonique prolongée ; cet effet moteur devrait retentir sur la propulsion colique et donc expliquer l'effet laxatif du lactulose.• lactulose is transformed under the effect of the local saccharolytic bacterial flora into short-chain organic acids (mainly lactic acid, accompanied by small amounts of acetic, formic acids, etc.) and this acidification of the intestinal contents stimulates peristalsis intestinal. A recent communication from the INSERM U 290 team on the occasion of the Francophone Days of Digestive Pathology (March 1998) even specified its mechanism of action at the level of the colon, by demonstrating on 18 healthy volunteers that lactulose causes a tonic contraction prolonged; this motor effect should affect colonic propulsion and therefore explain the laxative effect of lactulose.
Au niveau du colon, le lactulose va reproduire ainsi un « syndrome de malabsorption des glucides » accompagné d'une accélération du transit qui constitue l'effet thérapeutique recherché.At the level of the colon, the lactulose will thus reproduce a "carbohydrate malabsorption syndrome" accompanied by an acceleration of the transit which constitutes the therapeutic effect sought.
Le métabolisme colique du lactulose et des substances apparentées s'accompagne malheureusement de la formation de gaz intestinaux (essentiellement de l'hydrogène, mais aussi du C02 voire du méthane) à l'origine des effets indésirables les plus fréquents du lactulose (inconfort abdominal avec météorisme et flatulence). La BIAM (Banque de données Informatisée Automatique du Médicament) classe « Météorisme » et « Flatulence » comme des effets secondaires « certains et fréquents » du lactulose. Ces effets indésirables digestifs sont également mentionnés dans Le Dictionnaire des Médicaments. De plus, l'article de référence sur le lactulose (réf. 1) mentionne : « Chez l'homme, il y a cependant des effets secondaires sans gravité ; ils sont assez fréquents et peuvent être observés même à des doses faibles (20 à 40 g I jour). Il s'agit de troubles digestifs : diarrhée, parfois accompagnée de douleurs abdominales, et flatulences. ». Ce même article précise que « le lactitol a les mêmes caractéristiques de tolérance que le lactulose ». L'étude clinique qui semble évaluer le plus précisément la tolérance d'un disaccharide de synthèse est l'étude de Goovaerts L et Ravelli GP (réf. 2). Dans cette étude, la tolérance du lactitol est évaluée sur 136 patients : au cours de la 1ère semaine de traitement à la posologie usuelle (20 g / jour), 27,2 % des patients se plaignent de météorisme et/ou de flatulence. Parmi les patients poursuivant le traitement sans diminuer la dose, 27,9 % des patients se plaignent également de météorisme et/ou de flatulence au cours de la 2ème et 3éme semaine de traitement. Par ailleurs, 7 patients (5,1 %) ont arrêté le traitement pour des raisons liées à la tolérance digestive. Cette étude a le mérite d'évaluer la fréquence des effets indésirables digestifs liés à un excès de gaz (plus d'un patient sur 4) et aussi de combattre une « idée reçue » selon laquelle la tolérance digestive des disaccharides de synthèse s'améliorerait au cours du traitement.The colonic metabolism of lactulose and related substances is unfortunately accompanied by the formation of intestinal gases (essentially hydrogen, but also C0 2 or even methane) which is the cause of the most frequent undesirable effects of lactulose (abdominal discomfort with meteorism and flatulence). BIAM (Computerized Automatic Drug Database) classifies “Meteorism” and “Flatulence” as “certain and frequent” side effects of lactulose. These digestive side effects are also mentioned in The Drug Dictionary. In addition, the reference article on lactulose (ref. 1) mentions: “In humans, however, there are minor side effects; they are quite frequent and can be observed even at low doses (20 to 40 g I day). These are digestive disorders: diarrhea, sometimes accompanied by abdominal pain, and flatulence. ". This same article specifies that "lactitol has the same tolerance characteristics as lactulose". The clinical study which seems to assess the tolerance of a synthetic disaccharide most precisely is the study by Goovaerts L and Ravelli GP (ref. 2). In this study, the tolerance of lactitol is evaluated on 136 patients: during the 1 st week of treatment at the usual dosage (20 g / day), 27.2% of the patients complain of meteorism and / or flatulence. Among patients continuing treatment without decreasing the dose, 27.9% of patients also complain of bloating and / or flatulence during the 2 nd and 3 rd week of treatment. In addition, 7 patients (5.1%) stopped treatment for reasons related to digestive tolerance. This study has the merit of evaluating the frequency of digestive undesirable effects linked to an excess of gas (more than 1 in 4 patients) and also of fighting a "preconceived idea" according to which the digestive tolerance of synthetic disaccharides would improve during treatment.
Enfin, des publications récentes comparant la tolérance digestive du trehalose et des fructo- oligosaccharides à celle du lactulose concluent à des effets indésirables digestifs de même nature, de même intensité et de même fréquence. En résumé, les substances apparentées au lactulose (lactitol, trehalose, fructo-oligosaccharides ...) présentent les mêmes effets indésirables digestifs dus à la production de gaz intestinaux.Finally, recent publications comparing the digestive tolerance of trehalose and fructo-oligosaccharides to that of lactulose conclude that digestive undesirable effects of the same nature, the same intensity and the same frequency. In summary, lactulose-like substances (lactitol, trehalose, fructo-oligosaccharides ...) have the same digestive undesirable effects due to the production of intestinal gases.
Ces effets indésirables sans gravité ne doivent pas faire oublier que le lactulose et les substances apparentées présentent une toxicité très faible (LD 50 du lactulose = 28 ml / kg de poids) et donc une marge de sécurité importante. Aux USA, le lactitol est d'ailleurs un additif alimentaire considéré comme « GRAS » (« Generally Recognized As Safe »).These non-serious undesirable effects should not make us forget that lactulose and related substances have very low toxicity (LD 50 of lactulose = 28 ml / kg of weight) and therefore a significant safety margin. In the USA, lactitol is also a food additive considered as "GRAS" ("Generally Recognized As Safe").
Cette production en excès de gaz intestinaux après ingestion orale de lactulose a servi de base à une épreuve portant le nom de « breath-test » ou « test respiratoire à l'hydrogène » utilisée en Exploration Fonctionnelle Digestive comme méthode de diagnostic (mesure du temps nécessaire au lactulose pour parvenir en site colique, c'est à dire mesure du temps de transit oro-caecal) ou en Recherche Clinique comme méthode d'évaluation pour les médicaments antiflatulents (capacité pour un médicament revendiquant un effet antiflatulent à réduire la quantité de H2 expiré mesurée par le « breath-test »). Tous les antiflatulents -le charbon activé, le simeticone, les argiles, les extraits enzymatiques pancréatiques ...- ont subi l'épreuve du « breath-test ». Il faut souligner que dans ce cadre de Recherche Clinique, le lactulose joue un rôle strictement expérimental (le lactulose permettant de reproduire artificiellement la production colique de gaz intestinaux) sans aucune finalité thérapeutique.This excess production of intestinal gas after oral ingestion of lactulose served as the basis for a test called "breath-test" or "hydrogen breath test" used in Digestive Functional Exploration as a diagnostic method (time measurement necessary for lactulose to reach the colonic site, i.e. measurement of the oro-caecal transit time) or in Clinical Research as an evaluation method for antiflatulent drugs (ability for a drug claiming an antiflatulent effect to reduce the amount of H 2 expired measured by the “breath-test”). All antiflatulents - activated charcoal, simeticone, clays, pancreatic enzyme extracts ... - have undergone the breath-test. It should be emphasized that in this context of Clinical Research, lactulose plays a strictly experimental role (lactulose making it possible to artificially reproduce the colonic production of intestinal gases) without any therapeutic purpose.
Le « breath-test » représente la meilleure démonstration objective de la production de gaz intestinaux et en particulier de H2 , débutant en moyenne 2 heures après ingestion d'une prise unique de lactulose de 10 g.The “breath-test” represents the best objective demonstration of the production of intestinal gases and in particular of H 2 , starting on average 2 hours after ingestion of a single intake of lactulose of 10 g.
Ces effets indésirables digestifs sont à l'origine d'une mauvaise observance du traitement, compromettant l'efficacité de celui-ci et entraînant un recours à des thérapeutiques plus onéreuses et ayant souvent un rapport bénéfice - risque moins favorable.These digestive undesirable effects are at the origin of poor adherence to treatment, compromising its effectiveness and leading to the use of more expensive therapies and often having a less favorable risk - benefit ratio.
En effet, les effets indésirables digestifs du lactulose et des substances apparentées apparaissent lorsque le saccharide arrive au niveau du colon ascendant, c'est à dire 2 à 3 heures après la prise du médicament. A ce moment, l'administration d'un traitement symptomatique pour lutter contre ces effets indésirables est vouée à l'échec, compte tenu du délai d'action du produit antiflatulent en site colique, également de l'ordre de 2 à 3 heures.Indeed, the undesirable digestive effects of lactulose and related substances appear when the saccharide reaches the level of the ascending colon, that is to say 2 to 3 hours after taking the drug. At this time, the administration of symptomatic treatment to combat these undesirable effects is doomed to failure, taking into account the time of action of the antiflatulent product in colonic site, also of the order of 2 to 3 hours.
EXPOSE DE L' INVENTIONSTATEMENT OF THE INVENTION
La composition nouvelle objet du présent brevet associe dans des proportions définies un saccharide soluble, peu ou pas absorbé (lactulose, lactitol, trehalose ...) à un antiflatulent à l'efficacité reconnue afin d'éviter ce type de problème. L'intérêt de cette composition nouvelle réside dans le fait que la prise simultanée du principe actif laxatif (lactulose, lactitol, trehalose ...) et du principe actif antiflatulent leur permettra de suivre le même transit digestif, le principe actif antiflatulent ayant alors une action optimale sur les gaz formés par la fermentation du principe actif laxatif au niveau du colon.The new composition which is the subject of this patent combines, in defined proportions, a soluble saccharide, little or not absorbed (lactulose, lactitol, trehalose ...) with an antiflatulent with recognized efficacy in order to avoid this type of problem. The advantage of this new composition lies in the fact that the simultaneous taking of the laxative active principle (lactulose, lactitol, trehalose ...) and the antiflatulent active principle will allow them to follow the same digestive transit, the antiflatulent active principle then having a optimal action on gases formed by the fermentation of the laxative active ingredient in the colon.
Compte tenu de la pathologie digestive à laquelle elle s'adresse, la nouvelle composition pourra se présenter sous forme de médicament ou d'« alicament » (produit alimentaire favorable à la santé, aussi appelé « aliment fonctionnel »), la composition nouvelle étant alors additionnée à un aliment traditionnel (compote de fruits, yoghourt, ....) afin d'obtenir un « alicament ».In view of the digestive pathology to which it is addressed, the new composition may be in the form of a drug or “food” (food product favorable to health, also called “functional food”), the new composition then being added to a traditional food (fruit compote, yoghurt, etc.) in order to obtain a "food".
Dans le cadre de l'invention, le principe actif antiflatulent devra présenter les caractéristiques suivantes : © posséder une efficacité clinique reconnue sur les troubles digestifs liés à un excès de gaz ; o ne pas interférer sur le mode d'action du laxatif, en particulier respecter le métabolisme colique et donc le phénomène de fermentation à la base de l'action laxative du saccharide ; • ne pas avoir d'effet constipant, qui contrarierait l'action du laxatif ;In the context of the invention, the antiflatulent active principle must have the following characteristics: © possess recognized clinical efficacy in digestive disorders linked to an excess of gas; o do not interfere with the mode of action of the laxative, in particular respect the colonic metabolism and therefore the fermentation phenomenon at the base of the laxative action of the saccharide; • have no constipating effect, which would counteract the action of the laxative;
• ne pas être résorbé par la muqueuse digestive, afin de pouvoir atteindre son site d'action (le colon) et jouer ainsi une action optimale dans la lumière intestinale ;• not be absorbed by the digestive mucosa, in order to be able to reach its site of action (the colon) and thus play an optimal action in the intestinal lumen;
• présenter une grande inertie chimique, évitant les interactions médicamenteuses ;• have high chemical inertness, avoiding drug interactions;
• bénéficier d'une grande sécurité d'emploi (absence d'effets indésirables) ; • si possible, être accepté comme additif alimentaire.• benefit from great job security (absence of undesirable effects); • if possible, be accepted as a food additive.
Pour toutes ces raisons, le principe actif antiflatulent sera choisi dans la famille chimique des siloxanes et plus particulièrement au sein des polydimethylsiloxanes (simeticone, dimeticone ...).For all these reasons, the antiflatulent active principle will be chosen from the chemical family of siloxanes and more particularly from polydimethylsiloxanes (simeticone, dimeticone, etc.).
Le simeticone appartient à la classe des polydimethylsiloxanes linéaires, largement utilisés en médecine humaine depuis de nombreuses années. Il s'agit du composé le plus utilisé en thérapeutique au sein de la famille chimique des siloxanes. Le simeticone est du dimeticone auquel on additionne du gel de silice pour favoriser sa dispersion en milieu aqueux ; le simeticone figure à la Pharmacopée américaine.Simeticone belongs to the class of linear polydimethylsiloxanes, widely used in human medicine for many years. It is the compound most used in therapy within the chemical family of siloxanes. Simeticone is dimeticone to which silica gel is added to promote its dispersion in an aqueous medium; simeticone is listed in the American Pharmacopoeia.
La parenté structurale du simeticone et du dimeticone et la similitude de leur mode d'action justifient de ne développer ici que ce qui concerne le simeticone, celui-ci ayant fait l'objet de publications plus nombreuses. Le simeticone (ou dimeticone activé) est un agent tensioactif qui agit comme un « anti-mousse ». Il n'est pas résorbé par la muqueuse digestive et son action antimousse locale est visualisée lorsqu'il est utilisé comme préparation à la radiographie, l'échographie ou l'endoscopie du tube digestif.The structural relationship of simeticone and dimeticone and the similarity of their mode of action justify developing here only what concerns simeticone, the latter having been the subject of more numerous publications. Simeticone (or activated dimeticone) is a surfactant that acts as an "anti-foam". It is not absorbed by the digestive mucosa and its local anti-foaming action is visualized when it is used as a preparation for radiography, ultrasound or endoscopy of the digestive tract.
L'action antimousse du simeticone agit en dispersant et prévenant la formation de bulles de gaz entourés de mucus dans le tractus gastro-intestinal. En réduisant la taille des bulles d'air, le simeticone permet aux gaz de traverser le tractus gastro-intestinal pour y être éliminés.The anti-foam action of simeticone works by dispersing and preventing the formation of gas bubbles surrounded by mucus in the gastrointestinal tract. By reducing the size of air bubbles, simeticone allows gases to pass through the gastrointestinal tract to be eliminated there.
Au niveau colique, le simeticone semble agir également en favorisant la résorption intestinale des gaz.At the colonic level, simeticone also seems to act by promoting intestinal gas absorption.
Le simeticone est indiqué dans le traitement des flatulences et de l'inconfort abdominal dû à un excès de gaz gastro-intestinaux.Simeticone is indicated for the treatment of flatulence and abdominal discomfort due to excess gastrointestinal gas.
La FDA (Food and Drug Administration) a examiné en 1996 puis en 1999 l'ensemble des principes actifs présentés comme ayant des propriétés antiflatulentes. De cet examen, il ressort que le simeticone est la seule substance à pouvoir revendiquer cette propriété (réf. 3 et 4).The FDA (Food and Drug Administration) examined in 1996 and in 1999 all of the active ingredients presented as having antiflatulent properties. From this review, it appears that simeticone is the only substance able to claim this property (ref. 3 and 4).
De nombreuses spécialités à base de simeticone sont commercialisées dans de nombreux pays.Many simeticone-based specialties are marketed in many countries.
Le simeticone est utilisé comme antiflatulent à des doses variant généralement de 250 mg à 2 g par jour.Simeticone is used as an antiflatulent in doses generally ranging from 250 mg to 2 g per day.
Aux Etats Unis, pour les médicaments OTC (Over-the-Counter, c'est à dire vendus librement au public) à base de simeticone, la dose journalière maximale est de 500 mg (au Canada, 640 mg). En revanche, pour les médicaments à base de simeticone prescrits par le Corps Médical, il n'y a pas de limite pour la dose journalière.In the United States, for OTC (Over-the-Counter, i.e. freely sold to the public) drugs based on simeticone, the maximum daily dose is 500 mg (in Canada, 640 mg). On the other hand, for simeticone-based drugs prescribed by the medical profession, there is no limit for the daily dose.
Le simeticone a donc une excellente sécurité d'emploi et les études toxicologiques animales n'ont pas permis de déterminer sa dose létale, tant sa marge de sécurité est grande. Le simeticone est également un additif alimentaire considéré comme « GRAS » (« Generally Recognized As Safe »).Simeticone therefore has excellent safety in use and animal toxicological studies have not made it possible to determine its lethal dose, given its large margin of safety. Simeticone is also a food additive considered to be “GRAS” (“Generally Recognized As Safe”).
Une autre preuve de la sécurité d'emploi du simeticone est le fait que plusieurs médicaments à base de simeticone sont utilisés aux USA chez le nouveau-né.Another proof of the safety of simeticone is the fact that several drugs based on simeticone are used in the USA in newborns.
Par ailleurs, le simeticone ne modifie pas le transit digestif.Furthermore, simeticone does not modify digestive transit.
Enfin, le simeticone est une substance présentant une grande inertie chimique limitant ainsi les risques d'interactions médicamenteuses, mais aussi les risques de perturbation du phénomène de fermentation colique à la base de l'action laxative du saccharide.Finally, simeticone is a substance with high chemical inertness, thus limiting the risks of drug interactions, but also the risks of disturbing the phenomenon of colonic fermentation at the base of the laxative action of the saccharide.
Les données de sécurité du simeticone sont transposables au dimeticone.The safety data from simeticone can be transposed to dimeticone.
En France, un médicament à base de dimeticone ayant comme indication « traitement symptomatique des gastralgies et traitement du météorisme intestinal » a une posologie maximale correspondant à une prise de 13,5 g de dimeticone par jour, sans limitation de la durée du traitement. Aussi, pour tenir compte des disparités des législations nationales et des habitudes thérapeutiques de chaque pays, les doses d'antiflatulent seront exprimées en « fourchette » de doses (avec indication de deux valeurs extrêmes) et non en doses fixes,In France, a drug based on dimeticone having as indication “symptomatic treatment of gastralgia and treatment of intestinal meteorism” has a maximum dosage corresponding to a dose of 13.5 g of dimeticone per day, without limitation of the duration of treatment. Also, to take into account the disparities in national legislations and the therapeutic habits of each country, the doses of antiflatulent will be expressed in "range" of doses (with indication of two extreme values) and not in fixed doses,
Ainsi, la composition pharmaceutique ou diététique nouvelle est caractérisée en ce qu'elle associe un saccharide soluble, peu ou pas absorbé par l'organisme et un antiflatulent à l'efficacité reconnue de la famille des siloxanes, dans des proportions telles que :Thus, the new pharmaceutical or dietetic composition is characterized in that it combines a soluble saccharide, little or not absorbed by the body and an antiflatulent with the recognized effectiveness of the family of siloxanes, in proportions such as:
• la concentration finale du saccharide dans la composition nouvelle est supérieure à 80 % (p/p) pour une composition solide ou supérieure à 40 % (p/v) pour une composition liquide ou semi-liquide, afin de limiter le volume de la prise quotidienne thérapeutiquement efficace (le volume de la prise quotidienne thérapeutiquement efficace constituant l'un des obstacles majeurs à la bonne observance du traitement par les saccharides) ;The final concentration of the saccharide in the new composition is greater than 80% (w / w) for a solid composition or greater than 40% (w / v) for a liquid or semi-liquid composition, in order to limit the volume of the therapeutically effective daily intake (the volume of the therapeutically effective daily intake constituting one of the major obstacles to good compliance with treatment with saccharides);
• la quantité d'antiflatulent pour 100 g de saccharide dans la composition nouvelle est comprise entre 0,5 g et 100 g, compte tenu des posologies usuelles et maximales de chaque principe actif et en fonction de l'effet thérapeutique recherché.• the amount of antiflatulent per 100 g of saccharide in the new composition is between 0.5 g and 100 g, taking into account the usual and maximum dosages of each active ingredient and depending on the desired therapeutic effect.
Dans le cadre de l'invention, on utilisera indifféremment du simeticone, du dimeticone ou tout autre polydiméthylsiloxane ayant démontré son efficacité antiflatulente et sa sécurité chez l'Homme.In the context of the invention, simeticone, dimeticone or any other polydimethylsiloxane which has demonstrated its antiflatulent efficacy and its safety in humans will be used interchangeably.
MEILLEURE MANIERE DE REALISER L'INVENTIONBEST WAY TO IMPLEMENT THE INVENTION
En faisant varier le ratio des quantités Antiflatulent (simeticone, dimeticone ...) / Saccharide (lactulose, lactitol, trehalose ...) à l'intérieur d'une fourchette allant de 0,5:100 à 100:100 -ratio exprimé en gramme d'Antiflatulent par gramme de Saccharide-, on préparera dans le cadre de la présente invention :By varying the ratio of the Antiflatulent (simeticone, dimeticone ...) / Saccharide (lactulose, lactitol, trehalose ...) quantities within a range from 0.5: 100 to 100: 100 - expressed ratio in grams of Antiflatulent per gram of Saccharide, the following will be prepared in the context of the present invention:
• pour les faibles ratios (par exemple entre 0,5:100 et 7:100), des médicaments ou « alicaments » à visée essentiellement laxative, dénués des effets indésirables digestifs habituels liés à l'usage du lactulose ou des substances apparentées -inconfort abdominal avec météorisme et flatulence-. De même, ces médicaments ou « alicaments » pourront être utilisés pour favoriser le développement de la flore intestinale saccharolytique, considérée comme la flore « bénéfique » à la santé.• for low ratios (for example between 0.5: 100 and 7: 100), drugs or "alicaments" with essentially laxative aims, devoid of the usual digestive undesirable effects linked to the use of lactulose or related substances - discomfort abdominal with meteorism and flatulence. Likewise, these drugs or "alicaments" can be used to promote the development of the saccharolytic intestinal flora, considered as the flora "beneficial" to health.
• pour les ratios plus élevés (par exemple entre 7:100 et 100:100), des médicaments ou « alicaments » à visée essentiellement antiflatulente destinés aux patients souffrant de troubles fonctionnels digestifs (à type de colopathie fonctionnelle ou « syndrome de l'intestin irritable » où il est maintenant démontré que les gaz intestinaux jouent un rôle prépondérant, généralement associés à une constipation, interdisant le recours à des thérapeutiques « traditionnelles » comme le charbon activé ou les argiles qui provoquent un ralentissement du transit intestinal et donc aggravent la constipation préexistante). Dans ce cadre, les médicaments fabriqués selon la présente invention et associant polydiméthylsiloxane et saccharide soluble peu ou pas absorbé pourront revendiquer des indications thérapeutiques du type « traitement symptomatique de la colopathie fonctionnelle avec constipation ».• for the higher ratios (for example between 7: 100 and 100: 100), drugs or "alicaments" with an essentially antiflatulent aim intended for patients suffering from functional digestive disorders (such as functional colopathy or "bowel syndrome") irritable ”where intestinal gases have now been shown to play a predominant role, generally associated with constipation, prohibiting the use of“ traditional ”therapies such as activated charcoal or clays which cause a slowing of intestinal transit and therefore worsen constipation pre-existing). In this context, the drugs manufactured according to the present invention and combining polydimethylsiloxane and soluble saccharide little or not absorbed may claim therapeutic indications of the type "Symptomatic treatment of functional colopathy with constipation".
Au sein des faibles ratios, en faisant varier le ratio Antiflatulent / Saccharide à l'intérieur de la « fourchette » allant de 0,5:100 à 7:100, on préparera des formulations différentes destinées soit au « traitement d'attaque », soit au « traitement d'entretien » de la constipation, la posologie du principe actif laxatif et la fréquence de ses effets indésirables digestifs évoluant généralement en cours de traitement. Par exemple, on préparera deux formulations différentes dans lesquelles la quantité de simeticone est de 2,5 g à 7 g pour 100 g de lactulose pour la formulation destinée au « traitement d'attaque » de la constipation et de 0,5 g à 2,5 g pour 100 g de lactulose pour la formulation destinée au « traitement d'entretien » de la constipation.Within low ratios, by varying the Antiflatulent / Saccharide ratio within the "range" going from 0.5: 100 to 7: 100, different formulations will be prepared intended either for "attack treatment", or "maintenance treatment" of constipation, the dosage of the active ingredient laxative and the frequency of its digestive side effects generally evolving during treatment. For example, two different formulations will be prepared in which the amount of simeticone is 2.5 g to 7 g per 100 g of lactulose for the formulation intended for the “attack treatment” of constipation and 0.5 g to 2 , 5 g per 100 g of lactulose for the formulation intended for the “maintenance treatment” of constipation.
POSSIBILITES D' APPLICATION INDUSTRIELLEPOSSIBILITIES OF INDUSTRIAL APPLICATION
La composition pharmaceutique ou diététique objet de la présente invention sera utilisée pour la fabrication de médicaments ou d'« alicaments » utiles pour prévenir et/ou traiter les troubles digestifs (à type de constipation et/ou ballonnement) ou pour régénérer la flore intestinale ou encore pour traiter Pencéphalopathie hépatique.The pharmaceutical or dietetic composition which is the subject of the present invention will be used for the manufacture of medicaments or “alicaments” useful for preventing and / or treating digestive disorders (such as constipation and / or bloating) or for regenerating the intestinal flora or still to treat hepatic encephalopathy.
La composition nouvelle pourra se présenter sous forme liquide ou semi-liquide dans laquelle les principes actifs sont mélangés à un ou plusieurs excipients (agents émulsifiants, stabilisants, épaississants -type carbomere 934P -copolymère synthétique de haut poids moléculaire de l'acide acrylique et d'un polyalkyl sucre-, carmellose sodique -cellulose carboxyméthyl élher, sel de sodium-, gomme xanthane, eau purifiée ....) lui conférant une forme d'émulsion stabilisée ou de gelée orale.The new composition may be in liquid or semi-liquid form in which the active ingredients are mixed with one or more excipients (emulsifying agents, stabilizers, thickeners - carbomer type 934P - synthetic high molecular weight copolymer of acrylic acid and d 'a polyalkyl sugar-, sodium carmellose -cellulose carboxymethyl ether, sodium salt-, xanthan gum, purified water ....) giving it a form of stabilized emulsion or oral jelly.
La composition nouvelle pourra se présenter aussi sous forme solide (poudre pour solution buvable, poudre à disperser, comprimé ...) dans laquelle le saccharide est apporté sous forme cristallisée et l'antiflatulent est apporté sous forme liquide en utilisant le saccharide comme support ou sous forme solide (simeticone ou dimeticone préalablement fixé sur un support inerte).The new composition may also be in solid form (powder for oral solution, dispersing powder, tablet, etc.) in which the saccharide is provided in crystallized form and the antiflatulent is provided in liquid form using the saccharide as a support or in solid form (simeticone or dimeticone previously fixed on an inert support).
Enfin, les compositions pharmaceutiques ou diététiques associant un saccharide soluble, peu ou pas absorbé (lactulose, lactitol, trehalose ...) à un antiflatulent aux propriétés reconnues de la famille des siloxanes (simeticone, dimeticone ...) pourront comprendre en outre un ou plusieurs excipients (conservateur, colorant, arôme ...) et/ou un ou plusieurs autres principes actifs, à visée digestive ou non.Finally, pharmaceutical or dietetic compositions associating a soluble saccharide, little or not absorbed (lactulose, lactitol, trehalose ...) with an antiflatulent with recognized properties of the siloxane family (simeticone, dimeticone ...) may further comprise a or several excipients (preservative, color, flavor ...) and / or one or more other active ingredients, for digestive purposes or not.
Exemples de médicaments ou « alicaments » fabriqués selon la présente invention :Examples of medicaments or "medicaments" produced according to the present invention:
Composition pharmaceutique liquide stabilisée à visée essentiellement laxative dont la formulation est la suivante : Lactulose (apporté sous forme de lactulose liquide Ph. Europ) 10 gStabilized liquid pharmaceutical composition for essentially laxative purposes, the formulation of which is as follows: Lactulose (brought in the form of liquid lactulose Ph. Europ) 10 g
Simeticone (apporté sous forme d'émulsion à 30% USP) 250 mgSimeticone (supplied as an emulsion at 30% USP) 250 mg
Excipient (eau purifiée, carbomere 934P, carmellose sodique, gomme xanthane, arôme...) qsp un sachet de 15 ml (posologie moyenne : 1 à 3 sachets /jour)Excipient (purified water, 934P carbomer, sodium carmellose, xanthan gum, flavor ...) qs a 15 ml sachet (average dosage: 1 to 3 sachets / day)
Composition pharmaceutique liquide stabilisée à visée essentiellement antiflatulente dont la formulation est :Stabilized liquid pharmaceutical composition with an essentially antiflatulent aim, the formulation of which is:
Simeticone (apporté sous forme d'émulsion à 30% USP) 400 mgSimeticone (supplied as an emulsion at 30% USP) 400 mg
Lactulose (apporté sous forme de lactulose liquide Ph. Europ) 5 g Excipient (eau purifiée, carbomere 934P, carmellose sodique, gomme xanthane, arôme...) qsp une dose-mesure de 10 ml (posologie moyenne : 2 à 3 doses-mesures /jour)Lactulose (brought in the form of liquid lactulose Ph. Europ) 5 g Excipient (purified water, 934P carbomer, sodium carmellose, xanthan gum, aroma ...) qs a dose-measure of 10 ml (average dosage: 2 to 3 doses- measurements / day)
Composition pharmaceutique solide à visée essentiellement laxative dont la formulation est : Lactitol (apporté sous forme cristallisé) 10 g Simeticone (apporté sous forme de simeticone fixé sur support inerte) 250 mgSolid pharmaceutical composition for essentially laxative purposes, the formulation of which is: Lactitol (supplied in crystallized form) 10 g Simeticone (supplied in the form of simeticone fixed on an inert support) 250 mg
Excipient (arôme ....) qsp un sachet de poudre pour solution buvable (posologie moyenne : 1 à 3 sachets /jour)Excipient (flavor ....) qs a sachet of powder for oral solution (average dosage: 1 to 3 sachets / day)
Composition diététique destinée essentiellement à favoriser le développement de la flore intestinale bénéfique pour la santé dont la formulation est :Dietary composition intended essentially to promote the development of intestinal flora beneficial to health, the formulation of which is:
Lactitol 5 gLactitol 5 g
Simeticone 50 mgSimeticone 50 mg
Compote de pomme riche en pectine sans addition de sucre qsp un pot de 125 g (consommation recommandée : 2 à 3 pots /jour)Apple compote rich in pectin without adding sugar to a 125 g jar (recommended consumption: 2 to 3 jars / day)
Bibliographie :Bibliography:
1. Prat F, Lambert R : Le lactulose. Gastroenterol Clin Biol, 1990 ; 14 : 567-5751. Prat F, Lambert R: Lactulose. Gastroenterol Clin Biol, 1990; 14: 567-575
2. Goovaerts L, Ravelli GP : Lactitol for the treatment of chronic constipation. Acta Ther., 1993 ; 19 : 61-712. Goovaerts L, Ravelli GP: Lactitol for the treatment of chronic constipation. Acta Ther., 1993; 19: 61-71
3. Food and Drug Administration, Department of Health and Human Services, Fédéral Register / Vol. 61, No. 44 / March 5, 1996 / Rules and Régulations / 21 CFR Part 332 / Antiflatulent Drug Products for3. Food and Drug Administration, Department of Health and Human Services, Federal Register / Vol. 61, No. 44 / March 5, 1996 / Rules and Régulations / 21 CFR Part 332 / Antiflatulent Drug Products for
Over-the-Counter Human Use ; Final Rule / page 8835-8839.Over-the-Counter Human Use; Final Rule / page 8835-8839.
4. Food and Drug Administration, Department of Health and Human Services, Fédéral Register / April 1, 1999 / Rules and Régulations / 21 CFR Ch. I Part 332 / Antiflatulent Drug Products for Over-the-Counter Human Use / page 228-229. 4. Food and Drug Administration, Department of Health and Human Services, Federal Register / April 1, 1999 / Rules and Régulations / 21 CFR Ch. I Part 332 / Antiflatulent Drug Products for Over-the-Counter Human Use / page 228-229 .

Claims

REVENDICATIONS
1) Composition pharmaceutique ou diététique nouvelle, caractérisée en ce qu'elle associe un saccharide soluble, peu ou pas absorbé par l'organisme et un antiflatulent de la famille chimique des siloxanes, dans des proportions telles que :1) New pharmaceutical or dietetic composition, characterized in that it combines a soluble saccharide, little or not absorbed by the body and an antiflatulent of the chemical family of siloxanes, in proportions such as:
• la concentration finale du saccharide dans la composition nouvelle est supérieure à 80 % (p/p) pour une composition solide ou supérieure à 40 % (p/v) pour une composition liquide ou semi- liquide ;• the final concentration of the saccharide in the new composition is greater than 80% (w / w) for a solid composition or greater than 40% (w / v) for a liquid or semi-liquid composition;
• la quantité d'antiflatulent pour 100 g de saccharide dans la composition nouvelle est comprise entre 0,5 g et 100 g.• the amount of antiflatulent per 100 g of saccharide in the new composition is between 0.5 g and 100 g.
2) Composition pharmaceutique ou diététique selon la revendication 1 dans laquelle le saccharide soluble peu ou pas absorbé est choisi parmi les disaccharides comme le lactulose, le lactitol, le trehalose ... ou les fructo-oligosaccharides, ainsi que leurs dérivés thérapeutiquement acceptables (hydrates, ...) ou encore un mélange de lactulose - trehalose ou un mélange de lactulose - fructo- oligosaccharides.2) Pharmaceutical or dietetic composition according to claim 1 in which the soluble saccharide with little or no absorption is chosen from disaccharides such as lactulose, lactitol, trehalose ... or fructo-oligosaccharides, as well as their therapeutically acceptable derivatives (hydrates , ...) or a mixture of lactulose - trehalose or a mixture of lactulose - fructo-oligosaccharides.
3) Composition pharmaceutique ou diététique selon la revendication 1 dans laquelle l'antiflatulent de la famille des siloxanes est un polydiméthylsiloxane ayant démontré son efficacité antiflatulente et sa sécurité chez l'Homme, comme le simeticone, le dimeticone ou un mélange de ceux-ci.3) Pharmaceutical or dietetic composition according to claim 1 wherein the antiflatulent of the siloxane family is a polydimethylsiloxane having demonstrated its antiflatulent efficacy and its safety in humans, such as simeticone, dimeticone or a mixture thereof.
4) Composition pharmaceutique ou diététique selon la revendication 1 présentée sous forme liquide ou semi-liquide dans laquelle les principes actifs sont mélangés à un ou plusieurs excipient (agents émulsifiants, stabilisants, épaississants -type carbomere 434P, carmellose sodique, gomme xanthane -, eau purifiée ....) lui conférant une forme d'émulsion stabilisée ou de gelée orale.4) Pharmaceutical or dietetic composition according to claim 1 presented in liquid or semi-liquid form in which the active principles are mixed with one or more excipient (emulsifying agents, stabilizers, thickeners - 434P carbomer type, sodium carmellose, xanthan gum -, water purified ....) giving it a form of stabilized emulsion or oral jelly.
5) Composition pharmaceutique ou diététique selon la revendication 1 présentée sous forme solide (poudre pour solution buvable, poudre à disperser, comprimé ...) dans laquelle le saccharide est apporté sous forme cristallisée et l'antiflatulent est apporté sous forme liquide en utilisant le saccharide comme support ou sous forme solide (par exemple, simeticone ou dimeticone préalablement fixé sur un support inerte).5) Pharmaceutical or dietetic composition according to claim 1 presented in solid form (powder for oral solution, dispersing powder, tablet ...) in which the saccharide is provided in crystallized form and the antiflatulent is provided in liquid form using the saccharide as a support or in solid form (for example, simeticone or dimeticone previously fixed on an inert support).
6) Composition pharmaceutique ou diététique selon la revendication 1 contenant en outre un ou plusieurs excipients (conservateur, colorant, arôme ....), lui conférant une bonne acceptabilité.6) Pharmaceutical or dietetic composition according to claim 1 further containing one or more excipients (preservative, color, flavor ....), giving it good acceptability.
7) Composition pharmaceutique ou diététique selon la revendication 1 contenant en outre un ou plusieurs autres principes actifs.7) Pharmaceutical or dietetic composition according to claim 1 further containing one or several other active ingredients.
8) Composition pharmaceutique ou diététique selon la revendication 1 dans laquelle le saccharide soluble peu ou pas absorbé est du lactulose ou un dérivé thérapeutiquement acceptable (hydrate, ...) et l'antiflatulent est du simeticone.8) Pharmaceutical or dietetic composition according to claim 1 in which the soluble saccharide little or not absorbed is lactulose or a therapeutically acceptable derivative (hydrate, ...) and the antiflatulent is simeticone.
9) Composition pharmaceutique ou diététique selon la revendication 8 dans laquelle le ratio des quantités simeticone / lactulose (exprimé en g de simeticone par g de lactulose) est compris entre 0,5:100 et 100:100, préférentiellement entre 0,5:100 et 7:100 pour le traitement de la constipation et entre 7:100 et 100:100 pour le traitement des ballonnements avec constipation.9) Pharmaceutical or dietetic composition according to claim 8 in which the ratio of the simeticone / lactulose amounts (expressed in g of simeticone per g of lactulose) is between 0.5: 100 and 100: 100, preferably between 0.5: 100 and 7: 100 for the treatment of constipation and between 7: 100 and 100: 100 for the treatment of bloating with constipation.
10) Composition pharmaceutique ou diététique selon la revendication 8 dans laquelle la quantité de simeticone est de 2,5 g pour 100 g de lactulose.10) Pharmaceutical or dietetic composition according to claim 8 wherein the amount of simeticone is 2.5 g per 100 g of lactulose.
11) Composition pharmaceutique ou diététique selon la revendication 9 présentée sous deux formulations différentes dans lesquelles la quantité de simeticone est de 2,5 g à 7 g pour 100 g de lactulose pour la formulation destinée au « traitement d'attaque » de la constipation et de 0,5 g à 2,5 g pour 100 g de lactulose pour la formulation destinée au « traitement d'entretien » de la constipation.11) Pharmaceutical or dietetic composition according to claim 9 presented in two different formulations in which the amount of simeticone is from 2.5 g to 7 g per 100 g of lactulose for the formulation intended for the "attack treatment" of constipation and from 0.5 g to 2.5 g per 100 g of lactulose for the formulation intended for the "maintenance treatment" of constipation.
12) Composition pharmaceutique ou diététique selon la revendication 1 dans laquelle le saccharide soluble peu ou pas absorbé est du lactitol ou un dérivé thérapeutiquement acceptable (hydrate, ...) et l'antiflatulent est du simeticone, le ratio des quantités simeticone / lactitol (exprimé en g de simeticone par g de lactitol) étant compris entre 0,5:100 et 100:100, préférentiellement entre 0,5:100 et 7:100 pour le traitement de la constipation et entre 7:100 et 100:100 pour le traitement des ballonnements avec constipation.12) Pharmaceutical or dietetic composition according to claim 1 in which the soluble saccharide with little or no absorption is lactitol or a therapeutically acceptable derivative (hydrate, etc.) and the antiflatulent is simeticone, the ratio of the simeticone / lactitol quantities ( expressed in g of simeticone per g of lactitol) being between 0.5: 100 and 100: 100, preferably between 0.5: 100 and 7: 100 for the treatment of constipation and between 7: 100 and 100: 100 for treatment of bloating with constipation.
13) Composition diététique selon la revendication 1 destinée à être additionnée à un aliment traditionnel (compote de fruits, yoghourt ...) et dans laquelle le saccharide peu ou pas absorbé est choisi parmi le lactulose, le lactitol, le trehalose, les fructo-oligosaccharides ainsi que leurs dérivés acceptables en alimentation humaine (hydrates, ...) ou encore un mélange de lactulose - trehalose ou un mélange de lactulose - fructo-oligosaccharides et l'antiflatulent est du simeticone ou du dimeticone.13) Dietetic composition according to claim 1 intended to be added to a traditional food (fruit compote, yogurt ...) and in which the saccharide little or not absorbed is chosen from lactulose, lactitol, trehalose, fructo- oligosaccharides as well as their acceptable derivatives in human food (hydrates, ...) or a mixture of lactulose - trehalose or a mixture of lactulose - fructo-oligosaccharides and the antiflatulent is simeticone or dimeticone.
14) Utilisation d'une composition pharmaceutique ou diététique selon l'une quelconque des revendications 1 à 13 pour la fabrication de médicaments et/ou d'« alicaments » utiles pour prévenir et/ou traiter les troubles digestifs (à type de constipation et/ou ballonnement) ou pour régénérer la flore intestinale ou encore pour traiter l'encéphalopathie hépatique. 14) Use of a pharmaceutical or dietetic composition according to any one of claims 1 to 13 for the manufacture of medicaments and / or "medicaments" useful for preventing and / or treating digestive disorders (with constipation type and / or bloating) or to regenerate the intestinal flora or to treat hepatic encephalopathy.
EP03717376A 2003-02-05 2003-02-05 Medicament or nutriceutical combining a soluble poorly-absorbed saccharide and an antiflatulent from the siloxane group Withdrawn EP1603574A1 (en)

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DE102006001199A1 (en) * 2006-01-10 2007-07-12 Medicoforum Gmbh Powder, useful e.g. to prepare drinking solution or finished solution, and in colon hydrotherapy, comprises polyethylene glycol, sodium hydrogen carbonate, sodium chloride and potassium chloride
DE102012024434A1 (en) 2012-12-14 2014-06-18 Regalismons S.A. Enhancement of the defoaming action of polysiloxanes, related compositions and solutions
RU2555349C2 (en) * 2013-08-22 2015-07-10 Открытое акционерное общество "АВВА РУС" Method for producing pharmaceutical emulsion of lactulose

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FI73121C (en) * 1985-08-08 1987-09-10 Valio Meijerien FOLLOW-UP FODER OCH TILLSATSAEMNE FOER ANVAENDNING DAERI.
ATE117732T1 (en) * 1990-10-04 1995-02-15 Laevosan Gmbh & Co Kg LACTULOSE PREPARATION AND METHOD FOR THE PRODUCTION THEREOF.
JP3022699B2 (en) * 1993-02-02 2000-03-21 森永乳業株式会社 Production method of lactulose anhydride
US5418220A (en) * 1994-03-08 1995-05-23 Schmidt; Alfred Method for treating constipation using dimethicone
CN1288730A (en) * 1999-09-07 2001-03-28 麦克内尔-Ppc股份有限公司 Slight-purgitive composition

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