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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7016—Disaccharides, e.g. lactose, lactulose
• • 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
  • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/66—Microorganisms or materials therefrom
  • A61K35/74—Bacteria
  • A61K35/741—Probiotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/06—Fungi, e.g. yeasts
  • A61K36/062—Ascomycota
  • A61K36/064—Saccharomycetales, e.g. baker's yeast
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to the use of maltitol in the treatment or prevention of inflammatory bowel disease.
• the present invention also relates to a composition containing at least maltitol and at least one additional active agent for the treatment of Chronic Inflammatory Bowel Diseases, but also for persons suffering from irritable bowel syndrome, persons suffering from or abdominal pain whose etiology is often unknown; in the treatment of gastrointestinal cancers, infections ⁇ gastro intestinal lesions, wounds or bruises at least a portion of the gastrointestinal tract.
• Chronic Inflammatory Bowel Diseases include two distinct conditions: ulcerative hemorrhagic rectocolitis (RCH) and Crohn's disease. These two diseases, both distinct and related, are characterized by more or less diffuse inflammatory lesions of the intestine, notably due to a state of hyperactivation of the immune system of the intestine whose origin is unknown.
• the symptoms are mainly digestive, including diarrhea, abdominal pain, slimming, inflammation of the tissues.
• Polyols are widely used in the replacement of sugar in confectionery because of their low calorie but especially acariogenic nature. More recently, the beneficial effect on the health of polyols has been widely recognized because of their hypoglycaemic and hypo-insulinemic character. Polyols therefore potentially have a beneficial effect in the context of cardiovascular diseases or diabetes, but also in the context of diseases related to obesity.
• the Applicant has investigated the effect of polyols and more particularly maltitol in the health of the colon and more particularly an effect of polyols on inflammation of the colon.
• fructo-oligosaccharides or certain branched maltodextrins have shown an effect on inflammation of the colon.
• the effect of these polysaccharides would be through the induction of growth of lactobacilli, bacteroids and endogenous bifidobacteria of the gut in humans and animals.
• Lactobacilli have the advantage of lowering the pH of the medium by producing lactic acid, which prevents the growth of pathogenic flora such as proteobacteria or enterobacteria, causative agents of pathologies such as Crohn's disease or certain ulcerative colitis.
• Bifidobacteria and bacteroids are particularly described for their production of glucosidase-type enzymatic activities, which promote the release of flavonoids with antimutagenic and antioxidant effects.
• intestinal flora The induction of intestinal flora can be demonstrated by the measurement of these glycolytic activities such as in particular alpha- and beta-glucosidases.
• Inflammatory diseases and their respective treatment are the subject of active research.
• Experimental models for the induction of colitis have been developed, such as the induction of colitis by the administration of an allergen-containing solution (TriNitroBenzene Sulfonate or TNBS) in ethanol in rats or laboratory mice.
• an allergen-containing solution TriNitroBenzene Sulfonate or TNBS
• Ethanol allows the destruction of the barrier constituted by the intestinal mucosa and thus promotes the penetration of TNBS into the intestinal wall, and TNBS causes acute necrosis, often transmural, probably due to oxidative damage.
• This model is considered for localized hypersensitivity studies of the colon, and is particularly appropriate in that the inflammations caused by this model are sensitive to drugs administered in the context of IBD.
• maltitol has a curative and / or preventive effect on inflammation of the colon in animals and therefore, a priori, in humans.
• the present invention thus relates to a composition comprising at least maltitol for use in treating or preventing at least one disorder selected from inflammation of the intestine, gastrointestinal infections, and lesions, wounds or bruises of at least a portion of the gastrointestinal tract in humans or animals.
• the Applicant has also highlighted the fact that maltitol promotes the development of bifidogenic bacteria to the detriment of unwanted bacteria. This has notably been revealed by the very significant increase in alpha- and beta-glucosidase and esterase activities.
• the anti-inflammatory composition of the intestine according to the invention makes it possible to stimulate, by a factor of 1.1 to 10, preferably 1.2 to 6, even more preferably from 1.5 to 5.5, the enzymatic activities.
• alpha-glucosidase and / or fetal beta-glucosidase as will be exemplified hereinafter.
• the maltitol fermentation of the anti-inflammatory composition according to the invention by the microorganisms of the colon induces a lowering of the pH of the caecal, intestinal and faecal contents, which induces a balanced growth of said microorganisms.
• the use of the anti-inflammatory composition according to the invention also makes it possible to increase the production of AGV in the colon and the coecum.
• AGVs are especially chosen from the group consisting of acetic, butyric and propionic acid, preferably propionic and butyric acids.
• the anti-inflammatory composition according to the invention also makes it possible to increase the production of propionic acid by a factor of 1.5 to 3, preferably by a factor of 2 to 2.5.
• the protective effect of the colonic mucosa is demonstrated, particularly in animals, after administration of TNBS and results in remarkable results, as will be exemplified below.
• This effect significantly reflects the protective effect of said compositions against intestinal inflammation, making it possible to envisage the preparation of anti-inflammatory and / or analgesic compositions of the intestine improving the well-being of patients, both in humans. than animals.
• a daily amount of maltitol in the range 1.25 to 2.5 g / our / rat has a curative effect and / or preventive with respect to intestinal inflammation, gastrointestinal infections ⁇ intestinal lesions, lesions, wounds or bruises on at least part of the tissue of the gastrointestinal tract.
• Such a daily quantity corresponds in fact to a 5% and 10% dry mass intake (respectively 50g and 100g of maltitol / kg of food) in the diet of a rat or 5% (weight / volume) in the diet. drinking water from a rat.
• the composition according to the invention is therefore provided, in the animal, at a rate of 0.5 to 10 g / day / animal, preferably 1 to 5 g / day / animal and, in 1 to 50 g / person, preferably 5 to 50 g / individual, more preferably 10 to 50 g / / individual.
• the composition according to the invention also comprises at least one additional active agent, effective in the treatment or prevention of inflammation of the intestine and / or in the treatment or prevention of infections.
• at least one additional active agent effective in the treatment or prevention of inflammation of the intestine and / or in the treatment or prevention of infections.
• said additional active agent is chosen from suifasalazine, corticosteroids, atypical antidepressants, their derivatives and their mixtures.
• the composition also comprises a prebiotic chosen from oligosaccharides, polysaccharides and mixtures thereof.
• said prebiotic is selected from fructans, such as inulin and fructooligosaccharides (FOS); polydextrose; galacto-oligosaccharides (GOS); trans-galacto-oligosaccharides (TOS), xylo-oligosaccharides (XOS), branched maltodextrins, Acacia gum and mixtures thereof.
• fructans such as inulin and fructooligosaccharides (FOS); polydextrose; galacto-oligosaccharides (GOS); trans-galacto-oligosaccharides (TOS), xylo-oligosaccharides (XOS), branched maltodextrins, Acacia gum and mixtures thereof.
• the branched maltodextrins may be prepared according to the process described in patent EP 1 006 128.
• the composition according to the invention also comprises at least one other polyol chosen from lactitol, mannitol, sorbitol, xylitol, erythritol, arabitol and their mixtures.
• the composition according to the invention also comprises a probiotic chosen from yeasts, preferably Saccharomyces cerevisiae, and bacteria, preferably chosen from Lactobacillus, Bifidobacterium, Escherichia coli, Bacillus and Enteroccocus.
• yeasts preferably Saccharomyces cerevisiae
• bacteria preferably chosen from Lactobacillus, Bifidobacterium, Escherichia coli, Bacillus and Enteroccocus.
• the composition is in the form of sublingual, oral or rectal administration.
• the composition according to the invention is in the form of tablets, capsules, powders, granules, solutions or suspensions, emulsions or suppositories.
• the invention also relates to the use of maltitol as a medicament.
• the invention is also directed to a medicament comprising an effective dose of maltitol and a pharmacologically acceptable carrier for use in treating or preventing at least one disorder selected from inflammation of the intestine, gastrointestinal infections, and lesions and wounds. or bruising of at least a portion of the gastrointestinal tract in humans or animals.
• the term "effective dose” is understood to mean an amount of maltitol of 0.5 to 10 g / day / animal, preferably 1 to 5 g / day / animal and 1 to 50 g animal. / / individual, preferably 5 to 50 g / / individual, more preferably 10 to 50 g / / individual, in humans.
• the invention also relates to a kit for the therapeutic or prophylactic treatment of the human or animal body comprising:
• a second composition comprising an additional active agent effective in the treatment or prevention of inflammation of the intestine and / or in the treatment or prevention of gastrointestinal infections ⁇ intestinal lesions, wounds or bruises on the fabric at least a portion of the gastrointestinal tract in humans or animals.
• the invention also provides a method of treatment and / or prevention of inflammation of the intestine and / or treating or preventing infections of the gastro intestinal ⁇ , lesions, wounds or bruises on the fabric at least a portion ⁇ gastro intestinal tract in humans or animals, comprising a step of administering to a patient in need thereof a pharmaceutically effective dose of maltitol, the said maltitol is administered, alone or in mixture with at least one other additional active agent effective for the treatment or prevention of inflammation of the intestine and / or in the treatment or prevention of gastrointestinal infections ⁇ intestinal lesions, wounds or bruises on the fabric at least a portion of the tract gastrointestinal tract in humans or animals.
• Example 1 Example 1
• maltitol The metabolism of maltitol has been compared to that of glucose through a mid-term nutritional supplementation study. Maltitol was administered at a fixed dose of 10% by weight (dry / dry) in the food for 36 days (from day 1 to day 36) in the Sprague-Dawley rat. During this nutritional intervention, several physiological parameters were studied: blood, urine and feces were collected at the beginning and end of the intervention, analyzed and the results compared. At the end of the experiment, the animals were sacrificed and the cocees removed.
• dextrose control is to replace the 10% maltitol added to the standard diet with a 100% absorbed molecule in the small intestine.
• Table 1 Biochemical parameters measured in the caecum after supplementation with 10% maltitol in the food for 36 days.
• Fermentation of maltitol is not only observable in the cecum but also in the colon due to a decrease in the pH of faeces reflecting the colonic environment (Table 2).
• the increase of flora The beneficial effect of the colon is observable through a strong increase in the activity of alpha- and beta-glucosidases (respectively -gluc and ⁇ -gluc) and beta-galactosidase ( ⁇ -gal) in the feces.
• the substrates are as follows: 5 mM nitrophenyl CC-D-glucopyranoside (Sigma); 5mM p-nitrophenyl ⁇ -D-glucopyranoside (Sigma); 5mM p-nitrophenyl ⁇ -D-glucuronide (Sigma) and 10mM p-nitrophenyl ⁇ -D-galactopyranoside (Sigma). They are prepared with phosphate buffer dihydrogenophosphate KH 2 PO 4 and frozen for a period of less than 2 months.
• Samples are frozen after sampling. For the assay, they are thawed and then centrifuged at 14300 rpm for 3 minutes.
• the assay is performed on a microplate.
• Samples and controls are duplicated in the wells of the microplate.
• the controls are as follows: ⁇ -glucosidase (Maltase), activity: 5.8 U / mg (Fluka) at 0.40 g / l; ⁇ -glucosidase (cellobiase), activity: 66.6U / g (Fluka) at 7 g / l; ⁇ -galactosidase (lactase), activity: 11.8 U / mg at 0.50 g / l.
• Control solutions are prepared with osmosis water.
• the microplate is prepared as follows
• the microplate is read on the Spectra Max plus 384 spectrometer using SOFTMAX® software at a wavelength of 405 nm.
• the software is configured according to the following parameters:
• microplate agitated 5 seconds before the first reading, then shaken again for 3 seconds before each reading.
• the results are expressed in units of absorbance at 405 nm / minute / gram of faeces (wet or dry).
• Table 2 Biochemical parameters measured in faeces after supplementation with 10% maltitol in the 29-day diet.
• Table 4 Evolution of the enzymatic activity of the - glucosidase as a function of time and of the supplementation or not with 5% maltitol (Uabs / min / g of feces)
• TNBS Trinitrobenzene Sulfonic Acid
• the administration of maltitol was performed via the drinking water to ensure the continuity of maltitol intake despite the injection of TNBS which was likely to degrade food intake.
• the dose of maltitol ingested by the animal remains the same as in Example 2, namely approximately 1.25 g / day / rat.
• Preventive maltitol supplementation maintained a high level of glucosidase activity (a and ⁇ ) after TNBS injection (Table 7).
• Table 7 Enzymatic activities according to the supplementation or not with 5% maltitol in the faeces collected between D21 and D24 (after the injection of TNBS)
• Table 8 Evaluation of parameters related to the colon after the injection of TNBS or NaCl (size in cm, Wallace's score (SW) weight of the colon full or empty in g)

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• 2011
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