Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/695—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)
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• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2003
  • 2003-02-05 EP EP03717376A patent/EP1603574A1/de not_active Withdrawn
  • 2003-02-05 WO PCT/FR2003/000358 patent/WO2004078182A1/fr not_active Application Discontinuation
  • 2003-02-05 AU AU2003222360A patent/AU2003222360A1/en not_active Abandoned

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