Classifications

• • 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
  • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
  • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
• • 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
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
  • A61K31/728—Hyaluronic acid
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0031—Rectum, anus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • 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
• • 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
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

• the present invention relates to a topical composition containing a probiotic and hyaluronic acid or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of inflammatory bowel disease.
• IBD Inflammatory bowel disease
• Conventional therapies are represented mainly by: 5-aminosalicylic acid (5-ASA), corticosteroids, azathioprine/6-mercaptopurine, methotrexate, cyclosporine, and anti-TNFa agents, which are mainly intended to modulate the immune system [ 1 ].
• 5-ASA 5-aminosalicylic acid
• corticosteroids corticosteroids
• azathioprine/6-mercaptopurine methotrexate
• methotrexate methotrexate
• cyclosporine cyclosporine
• anti-TNFa agents which are mainly intended to modulate the immune system [ 1 ].
• probiotics defined as “live microorganisms which when administered in adequate amounts confer a health benefit on the host” [2] could modulate in a positive way the human microbiota, i.e. the set of symbiotic microorganisms which are found in the digestive tract, allowing to increase the commensal bacteria at the expense of the pathogen ones present in greater quantities in patients with IBD.
• a possible mechanism of action of the association 5-ASA and Lactobacillus casei DG rectally may be related to alterations in the microbial flora that adheres to the mucosa, thus contributing to the manipulation of the mucosal immune response and changing the balance of pro-inflammatory cytokines in favor of the anti-inflammatory ones.
• Hyaluronic acid a glycosaminoglycan
• Hyaluronic acid is known to play an important role in ensuring the hydration of the tissues, at the same time protecting them from excessive stresses and strains [1 1 - 13].
• hyaluronic acid By stimulating the formation of collagen and connective tissue, hyaluronic acid protects the body from viruses and bacteria, increases the plasticity of tissues and ensures optimal skin hydration [1 1 , 14].
• a topical composition containing a probiotic and hyaluronic acid is particularly advantageous in the treatment of inflammatory bowel disease.
• the probiotic and hyaluronic acid show a surprising synergistic effect in the treatment of the abovementioned disease.
• the object of the present invention is a topical composition containing a probiotic and hyaluronic acid or a pharmaceutically acceptable salt thereof, and preferably at least one physiologically acceptable excipient, for use in the treatment of inflammatory bowel disease, such as Crohn's disease and ulcerative colitis.
• a probiotic according to the invention is selected from Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus buchneri, Lactobacillus casei, Lactobacillus paracasei, Lactobacillus catenaforme, Lactobacillus cellobiosus, Lactobacillus crispatus, Lactobacillus curvatus, Lactobacillus delbrueckii, Lactobacillus fermentum, Lactobacillus jensenii, Lactobacillus leichmannii, Lactobacillus minutus, Lactobacillus plantamm, Lactobacillus reuteri, Lactobacillus rogosae, Lactobacillus salivarius, Bifidobacterium adolescentis, Bifidobacterium angulatum, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium catenulatum, Bifido
• Bifidobacterium plantamm Bifidobacterium pseudocatenulatum, Bifidobacterium pseudolongum, Streptococcus lactis, Streptococcus rajfinolactis, Streptococcus thermophilus, or a mixture thereof.
• the probiotic is a Lactobacillus, more preferably is Lactobacillus casei, even more preferably is Lactobacillus casei DG (strain deposited at the Pasteur Institute in Paris with the deposit number I- 1572CNCM).
• Hyaluronic acid or a pharmaceutically acceptable salt thereof according to the invention is a high molecular weight hyaluronic acid, it preferably has a molecular weight comprised between 500,000 and 3,000,000 dalton, more preferably greater than or equal to 1 ,000,000 dalton.
• Physiologically acceptable excipients are those known to the expert in the field, as described in the Handbook of Pharmaceutical Excipients, sixth edition 2009, incorporated herein by reference.
• excipients include, but are not limited to, diluents, binders, surfactants, gelling agents, stabilizers.
• a particularly preferred excipient according to the present invention is xanthan gum.
• the composition contains an amount of Hving probiotic cells of between 200 million and 10 billion, preferably between 500 million and 2 billion.
• the composition contains an amount of living probiotic cells comprised between 0.1 and 3% by weight, preferably less than 1 % by weight, with respect to the total weight of the composition.
• the composition contains an amount of hyaluronic acid or a pharmaceutically acceptable salt thereof comprised between 10 mg and 300 mg, preferably between 50 mg and 150 mg.
• the composition contains an amount of hyaluronic acid or a pharmaceutically acceptable salt thereof comprised between 3 and 15% by weight, preferably of about 5% by weight, with respect to the total weight of the composition.
• the composition contains an amount of living probiotic cells of between 0.1 and 3%, and an amount of hyaluronic acid of between 3 and 15% of the total weight of the composition.
• the composition may be administered orally or rectally, preferably it is administered rectally.
• composition of the present invention acts mainly at a topical level, i.e. it does not enter the circulatory system but exerts its action only at a local level through a combination of bacterial load reduction at the application site, and repair of the intestinal mucosa.
• the probiotic and hyaluronic acid act in synergy on the inflammatory process at the intestinal level, reducing the pro- inflammatory factors and increasing the anti-inflammatory ones.
• the probiotic modulates, directly or indirectly, the so-called “gut microbiota”, exerting an important action on the intestinal permeability and the mucosal immune system; in this way, it allows to keep the potentially pathogenic bacteria, responsible for an excessive immune and inflammatory response, away from the surface of the intestinal mucosa.
• Hyaluronic acid is, however, a compound with significant cicatricial and anti-inflammatory properties, by means of a direct action on TLR (Toll-Like Receptors). Furthermore, by stimulating the formation of collagen and connective tissue, it protects the body from viruses and bacteria, increases the plasticity of tissues and ensures optimal hydration of the skin. This protective action allows to preserve the integrity of the intestinal mucosa and to promote the so-called "mucosal healing".
• the composition of the invention can be formulated in semisolid or liquid form, preferably as a cream, ointment, pomade, solution, suspension, powder to disperse in water or gel; more preferably, the composition is formulated as powder to disperse in water.
• composition of the invention provide a greater consistency and a higher viscosity to the preparation, necessary to ensure that the product may remain in situ for a longer time.
• the composition of the invention is administered in the form of an enema or a rectal foam, preferably in the form of an enema.
• the composition of the invention acts directly on the ongoing inflammatory process, by significantly stimulating the production of collagen and connective tissue, resulting in the repair of the intestinal mucosa injured by the onset of inflammatory bowel disease.
• composition of the invention is able to play an important immunomodulatory role in the modification of the composition of the human microbiota, by increasing the commensal species and reducing the presence of potentially pathogenic species.
• the composition may be administered alone or in combination with a traditional inflammatory bowel disease therapeutic agent selected from 5-ASA, corticosteroids, azathioprine/6-mercaptopurine, methotrexate, cyclosporine, and anti-TNF agents.
• a traditional inflammatory bowel disease therapeutic agent selected from 5-ASA, corticosteroids, azathioprine/6-mercaptopurine, methotrexate, cyclosporine, and anti-TNF agents.
• the composition is administered rectally, one or more times per day, more preferably twice a day.
• composition of the invention is administered for a period of treatment comprised between 2 and 16 weeks, preferably for a period comprised between 4 and 12 weeks, even more preferably for a period of at least 8 weeks.
• the composition is administered as a combined preparation with one of the abovementioned conventional therapeutic agents, for simultaneous, separate or sequential use.
• a further object of the present invention is the composition containing a probiotic and hyaluronic acid or a pharmaceutically acceptable salt thereof, and preferably at least one physiologically acceptable excipient, for use in the prevention of acute radiation proctitis. Such use is particularly directed to patients undergoing radiation therapy for prostate cancer.
• the object of the present invention is a topical composition containing a probiotic and hyaluronic acid or a pharmaceutically acceptable salt thereof, and preferably, at least one physiologically acceptable excipient.
• This formulation will be the object of a clinical study aimed to verify its effectiveness in the treatment of inflammatory bowel disease, such as Crohn's disease and ulcerative colitis.
• the following table summarizes the qualitative and quantitative composition of the above invention:
• the final solution which is to be administered rectally, must be an isosmotic solution, it is necessary to modify in an appropriate manner the qualitative and quantitative composition of the thixotropic agents, in this respect, it is important to consider that also the hyaluronic acid possess a viscosifying power of, and it is, therefore, necessary to dose in an appropriate manner the quantities of excipients which have a similar power.
• the amount of hyaluronic acid may be increased up to a quantity equal to about 200-300 mg, corresponding to about 9-14% with respect to the total weight of the composition, thereby reducing the xanthan gum, in order to avoid too viscous formulations which would lead to the possible formation of lumps.
• the percentage of hyaluronic acid may be left unchanged and the amount of xanthan gum increased by about 0.5-6%.
• the xanthan gum may also optionally be replaced by another viscosifying agent, such as hydroxypropylmethylcellulose (HPMC), which has a viscosity power greater than xanthan gum.
• HPMC hydroxypropylmethylcellulose
• Such an excipient could be increased only up to a 3-4%, compared to what was instead done with xanthan gum.
• the amount of living lactobacilli cells could be increased even up to about 10 billion, corresponding to approximately 2% of the total weight of the composition (or, taking into account the excess of living cells which is normally employed, up to a maximum of 9%), without minimally perturbing the final composition, especially in terms of viscosity
• the following compositions may be obtained:
• Lactobacillus casei DG 5 ( 1 billion) 0.5
• Lactobacillus casei DG 5 ( 1 billion) 0.5
• Lactobacillus casei DG 5 ( 1 billion) 0.5
• Lactobacillus casei DG 5 ( 1 billion) 0.5

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• Health & Medical Sciences (AREA)
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• Oil, Petroleum & Natural Gas (AREA)
• Bioinformatics & Cheminformatics (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2015
  • 2015-04-21 MA MA039710A patent/MA39710A/fr unknown
  • 2015-04-22 JP JP2016564193A patent/JP2017513906A/ja active Pending
  • 2015-04-22 CA CA2944118A patent/CA2944118C/en active Active
  • 2015-04-22 US US15/305,470 patent/US11464814B2/en active Active
  • 2015-04-22 EP EP15726329.4A patent/EP3134072A1/en not_active Withdrawn
  • 2015-04-22 WO PCT/IB2015/052938 patent/WO2015162570A1/en not_active Ceased
• 2022
  • 2022-10-06 US US17/961,478 patent/US20230052820A1/en not_active Abandoned

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