WO2024246701A1 - Nouvelles combinaisons de principes actifs, compositions les contenant et leur utilisation en thérapie - Google Patents

Nouvelles combinaisons de principes actifs, compositions les contenant et leur utilisation en thérapie Download PDF

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Publication number
WO2024246701A1
WO2024246701A1 PCT/IB2024/055080 IB2024055080W WO2024246701A1 WO 2024246701 A1 WO2024246701 A1 WO 2024246701A1 IB 2024055080 W IB2024055080 W IB 2024055080W WO 2024246701 A1 WO2024246701 A1 WO 2024246701A1
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water
pharmaceutically acceptable
hyaluronic acid
soluble hydrolyzed
weight
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Pasqua Oreste
Giorgio Zoppetti
Berardino VAIRA
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Glycores 2000 Srl
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Glycores 2000 Srl
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Priority to EP24733306.5A priority Critical patent/EP4719346A1/fr
Priority to CN202480046466.7A priority patent/CN121604957A/zh
Publication of WO2024246701A1 publication Critical patent/WO2024246701A1/fr
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    • 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
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • the present invention relates to some new combinations of water-soluble hydrolyzed fibroin and hyaluronic acid, or a salt thereof, optionally together with a bioadhesive agent, the oral compositions including such combinations, and their use in therapy, in particular in the prevention and/or treatment of esophagitis and, in general, of the epithelial oesophagus damages.
  • Fibroin is an insoluble protein present in the silk produced by some insects, like Bombyx mori larvae, and other moths such as Antheraea, Cricula, Sarnia and Gonometa.
  • Silk in its original form is constituted by two main proteins, sericin and fibroin, sericin being the sticky interleave between two filaments of fibroin. (Hakimi O et al "Spider and mulberry silkworm silks as compatible biomaterials", Composites Part B: Engineering. 38 (3): 324-37, April 2007).
  • the water-soluble hydrolyzed fibroin derived from silk fibroin contains about 30 % of free amino acids and oligopeptides. This hydrolyzed has a high ability to acquire water thanks to the characteristic aminoacidic composition, and when applied to the skin, forms a protective layer which gives softness and a distinct smoothness sensation; this is the main reason why the water-soluble hydrolyzed fibroin is used in cosmetics.
  • Hyaluronic acid is a natural linear polysaccharide belonging to the glycosaminoglycan family, constituted by the disaccharide repetition formed by glucuronic acid linked to N- acetylglucosamine.
  • Hyaluronic acid is ubiquitarian in the living organisms and in the last decades has taken more attention in the pharmaceutical and cosmetic areas as component of various topical and oral formulations
  • chondr oprotective/relieving compositions especially to be administered as animal feed inside the thoroughbred horses races and comprises hyaluronic acid alone or in the combination with chondroitin sulphate and/or glucosamine, together with a jelly agent like for example a cellulose derivative.
  • a composition which comprises 1 % by weight of sodium hyaluronate, 4 % by weight of chondroitin sulphate and 1 % by weight of carboxymethylcellulose
  • EP2296670 discloses the combination of chondroitin sulphate and hyaluronic acid for the preparation of medicaments against esophagitis.
  • the patent claims a combination of 150- 500 mg of chondroitin sulfate and 80-120 mg of hyaluronic acid and from 300 to 750 mg of a bio- adhesive agent, with a dynamic viscosity from 39 to 100 mPas.s
  • It is another object of the invention to provide for pharmaceutical oral compositions comprising the combinations of the invention, together with one or more pharma or food grade carriers and/or excipients.
  • Figure 1 shows the % AD of the composition of the invention and placebo, in presence of mucin film at pH 3 (A) and pH 7 (B), according to Example 8.
  • Figure 2 shows the physical properties of a composition of the invention (A), a composition comprising only sodium hyaluronate but not water-soluble hydrolyzed fibroin (B), and a composition comprising sodium hyaluronate and chondroitin sulfate in lieu of water-soluble hydrolyzed fibroin (C), according to Example 9.
  • fibroin in its hydrolyzed water-soluble form especially in the presence of hyaluronic acid or one of its salts, shows a high efficacy in the protection of the oesophagus mucosa.
  • combinations of water-soluble hydrolyzed fibroin and hyaluronic acid or one of its pharmaceutically acceptable salts prevent and/or heal the esophagitis onset, for example in case of oesophageal reflux, and allow for the treatment of oesophagitis or of the pathologies where the damage of the oesophageal epithelium of different origins occurs, like for example produced by side effects of drugs.
  • a subject-matter of the invention is a combination for oral use which consists in a water-soluble hydrolyzed fibroin and hyaluronic acid or one of its pharmaceutically acceptable or food grade salt.
  • Water-soluble hydrolyzed fibroin here is used to indicate a hydrolyzed water-soluble protein rich of free amino acids and low molecular weight peptides that is obtained from silk fibroin.
  • Water-soluble hydrolyzed fibroins (herein also named “fibroin according to the invention” or only “fibroin”) are commercially available.
  • a suitable water-soluble hydrolyzed fibroin according to the invention is of food grade, for example the one marketed by Shaanxi Yuantai Biological Technology Co., Ltd (China) under the name Hydrolyzed Silk Fibroin.
  • any type of amino acid or oligopeptide mixture derived from silk is suitable, provided it is water-soluble, i.e. that can be fully solubilized in water without leaving a solid residue.
  • the hyaluronic acid is in salified form, more preferably in its sodium or potassium salified form, even more preferably in its sodium salified form.
  • the hyaluronic acid is in salt form, more preferably in its sodium or potassium salt form and has a weight average molecular weight M w from 0.1 to 2 MDa, more preferably from 0.1 to 1.3 MDa.
  • Hyaluronic acid and its salts are also commercially available.
  • the weight ratio of water-soluble hydrolyzed fibroin and hyaluronic acid or one of its salts as defined above is from 10/1 to 1/1 (w/w), preferably from 6/1 to 2/1 (w/w), more preferably from 5/1 to 4/1 (w/w), for example from 3/1 to 3.5/1 (w/w).
  • a preferred ratio is about 3.3/1 (w/w).
  • a subject-matter of the invention is a combination for oral use constituted by the water-soluble hydrolyzed fibroin and hyaluronic acid or one of its pharmaceutically acceptable salts or food acceptable grade salts, as defined above, together with one or more pharmaceutically acceptable bioadhesive compounds.
  • bioadhesive compounds are known to the art for their ability to make the active ingredients associated thereto to adhere on the action sites for the local administration (topical or oral) of drugs or to cover portions of the body.
  • bioadhesive compounds are pharmaceutically acceptable polymers, preferably selected from: the pol oxamers, like the copolymers of ethylene and propylene oxide, in particular the products known under the name of Lutrol®; polymers of polyvinylpyrrolidone type, like the polyvinylpyrrolidone Kw24-32, that corresponds to a molecular weight of about 40,000 Da; and cellulose derivatives, like for example the hydroxypropyl cellulose and hydroxyethyl cellulose.
  • the pol oxamers like the copolymers of ethylene and propylene oxide, in particular the products known under the name of Lutrol®
  • polymers of polyvinylpyrrolidone type like the polyvinylpyrrolidone Kw24-32, that corresponds to a molecular weight of about 40,000 Da
  • cellulose derivatives like for example the hydroxypropyl cellulose and hydroxyethyl cellulose.
  • bioadhesive compounds can be also utilized, for example mixtures of cellulose derivatives and of the type of polyvinylpyrrolidone.
  • a subject-matter of the invention are oral pharmaceutical compositions comprising the combinations of the invention, together to one or more pharmaceutically acceptable carriers and/or excipients.
  • compositions of the invention comprise the combinations of the water-soluble hydrolyzed fibroin and hyaluronic acid or one of its pharmaceutically acceptable or food grade salts, together with one or more pharmaceutically acceptable carrier and/or excipients.
  • compositions of the invention comprise the combination of the water-soluble hydrolyzed fibroin and hyaluronic acid or one of its pharmaceutically or food grade acceptable salts, and one or more pharmaceutically acceptable bioadhesive compounds, together with pharmaceutically acceptable carriers and/or excipients.
  • compositions of the invention are suitable for the oral administration and can be in tablets form, chewable tablets, gummy oral form, hard capsules, soft capsules, powders, granules, or in liquid form, like solutions or suspensions.
  • the compositions of the invention are in water based, liquid form, and have a dynamic viscosity from 200 to 5,000 mPa.s, measured at 20°C and at atmospheric pressure.
  • the liquid oral compositions of the invention have a dynamic viscosity from 200 to 5,000 mPa.s, measured at 20°C and at atmospheric pressure, for example a dynamic viscosity selected among the following: from 200 to 4,000, from 200 to 1,000, from 200 to 2,000, from 500 to 2,000 or from 2,000 to 5,000.
  • the dynamic viscosities here reported have been measured as described in the Experimental Section below.
  • compositions of the present invention can be in form of single dosage unity or in multidose form, preferably in single dosage unity form.
  • Each dosage unity can, for example, contain from 100 to 1,000 mg of water-soluble hydrolyzed fibroin and from 50 to 200 mg of hyaluronic acid, preferably in one of its pharmaceutically acceptable or food grade salt form, more preferably the sodium salt.
  • each dosage unit preferably contains from 200 to 600 mg of water-soluble hydrolyzed fibroin and from 60 to 150 mg of hyaluronic acid, preferably in one of its pharmaceutically acceptable or food grade salt form, more preferably the sodium salt.
  • dosage units can contain:
  • hyaluronic acid 400 mg of water-soluble hydrolyzed fibroin and 75 mg of sodium hyaluronate; where such hyaluronic acid is preferably is in its pharmaceutically acceptable or food grade salt form, more preferably sodium salt.
  • compositions of the invention in addition to the water- soluble hydrolyzed fibroin according to the invention and to the hyaluronic acid, in the form of pharmaceutically or food grade acceptable salts, more preferably sodium salt, also comprise one or more bioadhesive compounds as defined above, in amounts from 1 to 3,000 mg, more preferably from 100 to 1,000 mg.
  • bioadhesive compounds as defined above, in amounts from 1 to 3,000 mg, more preferably from 100 to 1,000 mg.
  • the amounts of bioadhesive compounds depend on the target viscosity of the composition of the invention.
  • the solid forms can include starches, cellulose and its derivatives; lubricants like talc, stearic acid, polyethylene glycol or magnesium stearate; diluents like talc, cellulose powder, lactose, com starch or wheat starch, mannitol, sorbitol; disaggregating agents like microcrystalline cellulose or crospovidone; ligands like methylcellulose, sodium carboxymethylcellulose, alginic acid, alginates; sweeteners like saccharose, dextrose, mannitol, saccharine, xylitol, sorbitol: or aromas like synthetic or natural oils.
  • lubricants like talc, stearic acid, polyethylene glycol or magnesium stearate
  • diluents like talc, cellulose powder, lactose, com starch or wheat starch, mannitol, sorbitol
  • disaggregating agents like microcrystalline cellulose or crospovidone
  • Carriers and excipients suitable for the chewable oral forms include for example lubricants, binders, sweeteners, aromas, bioadhesives and disintegrating agents.
  • Water is a carrier for the liquid compositions, but not the only one.
  • Other carriers and excipients for liquid formulations usually aqueous ones, suspensions or solutions, include for example antioxidants, like sodium metabisulfite or sodium sulfite, thickening agents like microcrystalline cellulose, hydroxypropyl cellulose, carboxymethylcellulose or polyvinylpyrrolidone.
  • compositions of the invention can also contain preservatives like methyl parabens, ethyl parabens, sodium ethylendiaminotetracetic acid (EDTA), sodium benzoate or a basic salt of sorbic acid.
  • preservatives like methyl parabens, ethyl parabens, sodium ethylendiaminotetracetic acid (EDTA), sodium benzoate or a basic salt of sorbic acid.
  • compositions of the invention can also contain flavourings and/or sweeteners, like for example natural sugars or reduced sugars like saccharose, dextrose, xylitol, mannitol or sorbitol or synthetic products like sodium saccharin or aspartame; synthetic or natural oils, these latter extracted from plants, leaves, flowers, fruits and their combinations, like cinnamon, mint, anise and citrus fruits leaves, bitter almonds, citrus fruits like orange and/or lemon, oils from linden and grape fruit.
  • the preferred flavourings are those giving a taste of mint or fruit, like grape fruit, cherry, or citrus fruits, in particular orange and lemon, aromas and their mixtures.
  • chocolate, vanilla, or eucalyptus aromas and the fruit essence in particular apple, pear, kiwi, peach, strawberry, cherry, apricot, orange, lemon and grape fruit, can be advantageously used.
  • compositions of the invention are pharmaceutical or food grade, preferably pharmaceutical acceptable forms.
  • the preservatives like sodium benzoate, ascorbic acid and its salts, in particular potassium sorbate, EDTA and its salts, can be present in the compositions at a concentration from 0.01 to 0.4% by weight, with respect to the total weight of the composition.
  • the synthetic sweeteners can be present in the compositions at a percentage from 0.1 to 5 % by weight, with respect to the total weight of the composition, while the natural sweeteners, and optionally the reduced sugars can be present from 10 to 20 %, preferably from 15 to 20 % by weight, with respect to the total weight of the composition.
  • the flavouring can be supported in solid matrix and are in general present in an amount of 0.1-0.5% by weight, with respect to the total weight of the composition.
  • liquid compositions are preferred, water based, preferably having a dynamic viscosity from 200 to 5,000 mPa.s, at 20°C at atmospheric pressure.
  • pH of such liquid compositions is from 4.8 to 5.2.
  • the viscosity of the liquid compositions of the invention is important because a product with a very low viscosity (for example 100 mPa.s or lower) could be easily washed out from the target site where the composition performs its action, the oesophagus. A too high viscosity will result in difficulties in the administration of the composition.
  • a preferred liquid composition is a water solution, that comprises: a) water-soluble hydrolyzed fibroin at the concentration of from 2 to 6 % by weight; b) hyaluronic acid, preferably in the form of one of its pharmaceutically or food acceptable salts, preferably as sodium salt, at the concentration of from 0.6 to 1.5 % by weight; c) at least one bioadhesive component as defined above, at the concentration of from 0.01 to 2 % by weight; d) water; e) optionally other pharmaceutically acceptable carriers and/or excipients.
  • compositions disclosed above may have a dynamic viscosity from 200 to 5,000 mPa.s, at 20°C at atmospheric pressure, for example a viscosity selected among the following: from 200 to 4,000, from 200 to 1,000, from 200 to 2,000, from 500 to 2,000 or from 2,000 to 5,000.
  • liquid compositions of the invention can be packaged in multi-dosage unity forms, for example in sealed sachet stick-pack type, or in small plastic or glass bottles, or any other container provided by the current technology, including the multi-dosage containers, preferably equipped with an appropriate device for the needed dosage administration.
  • compositions of the invention can be administered once or more than once a day.
  • the daily dosage depends on the age, sex, and on the healthy state of the subject to be treated and on the severity of the disease or impairment.
  • a daily dosage from 200 to 1,000 mg of water-soluble hydrolyzed fibroin according to the invention, for example from 400 to 600 mg of hyaluronic acid, preferably in form of one of its pharmaceutically or food acceptable salts, more preferably as sodium salt, for example for 100 to 300 mg, such a daily dosage being able to be divided in two or more administrations, for example two daily administrations.
  • a preferred daily dosage includes the administration of 500 mg of water-soluble hydrolyzed fibroin according to the invention, and 150 mg of hyaluronic acid, preferably in one of its pharmaceutically or food acceptable salts form, more preferably as sodium salt, for example divided in two administrations. However other dosages can be considered.
  • the fibroin according to the invention has the ability to adhere to the oesophagus epithelium forming layers over the mucosa.
  • fibroin according to the invention adhere to the epithelial cell layers, including the cells of the oesophagus mucosa.
  • a subject-matter of the invention is a water-soluble hydrolyzed fibroin in the prevention and/or treatment of the damages of the oesophagus epithelium and for the prevention and/or treatment of oesophagitis of various origins, for example from gastroesophageal reflux, or derived from drugs side effects or inappropriate feeding.
  • a subject-matter of the invention is a pharmaceutical composition comprising a water-soluble hydrolyzed fibroin, and its use in the prevention and/or treatment of the damages of the oesophageal epithelium and for the prevention and/or treatment of oesophagitis of various origin, for example from gastroesophageal reflux or derived from drugs side effects or from an inappropriate feeding.
  • a subject-matter of the invention is the use of the combinations and of the compositions of the invention in therapy, preferably the use in the prevention and/or the treatment of the damages of the oesophagus epithelium and in the prevention and/or treatment of oesophagitis of different origins, for example from gastroesophageal reflux or derived from drugs side effects or inappropriate feeding.
  • Applicant carried out experimental assays to compare the behaviour of a representative composition of the invention with respect to a composition containing only sodium hyaluronate and composition containing sodium hyaluronate and condroitin sulfate (in lieu of water-soluble hydrolyzed fibroin) at acidic pH, i.e. at a pH of the stomach and of the oesophagus in the presence of gastroesophageal reflux.
  • the details of the experimentations are given in Example 9 below and the results are shown in Figure 2.
  • the composition of the invention at acidic pH forms a cohesive gel, while no gel is formed with the composition comprising only sodium hyaluronate and a just a weak increase in viscosity was shown by the composition containing sodium hyaluronate and condroitin sulfate.
  • the formation of a cohesive gel showed by the composition of the invention is completely unexpected and particularly advantageous, as it helps the composition to adhere to the oesophagus and stomach epithelium.
  • a subject-matter of the invention is the method for the prevention and/or the treatment of the damages of the oesophagus epithelium and in the prevention and/or the treatment of oesophagitis of different origins, for example from gastroesophageal reflux or from drugs side effects or inappropriate feeding, which comprises to administer an efficacious dose of a combination of the invention to a subject in need thereof.
  • compositions of the invention can be administered to mammals, preferably, but not only to humans, but also, for instance, to cats and dogs.
  • composition of the invention can be prepared by a simple mixing of the active principles of the combinations and optionally of the carriers and excipients.
  • the water base liquid compositions are prepared according to a process that comprises the dissolution of the bioadhesive compounds in water, optionally at reduced pressure and under stirring at a temperature from 40 to 80°C and keeping under stirring for some time, for example 0.5-3 hours; the decrease of the temperature to 25-50°C and the addition of the fibroin of the invention and the hyaluronic acid or one of its pharmaceutically or food acceptable salts; the decrease of the temperature to 25°C and optionally the addition of the preservative, colouring agents and fragrances, previously dissolved in water; the correction of the pH of the solution so obtained to 4.5-5.5, preferably 4.8-5.2.
  • compositions of the invention are provided in the Experimental Section here below.
  • the procedure for the preparation of the water-based compositions of the invention is another subject-matter of the invention.
  • the dynamic viscosity has been measured at 20°C, at atmospheric pressure by a rotational viscosimeter Brookfield DVII with spindle TF and at 15 RPM
  • step (iii) To the solution obtained in step (i) the solution obtained in step (ii) is added and the mixture is kept under mild stirring at 25°C for 15 minutes. The pH is measured and 4 M HC1 is added to bring the pH in a range from 4.8 to 5.2
  • step (ii) 15 gr of sodium benzoate powder, 18 gr of potassium sorbate powder, 30 gr of aroma and 1612 gr of pure water are added in a mixer with magnetic stirring. A mild stirring is maintained until a clear solution has obtained.
  • step (ii) The solution obtained in step (ii) is added to the mixer with the solution obtained in step (i), the mild stirring and the temperature at 25°C are maintained for 15 minutes.
  • the pH of the solution is 6.8, therefore the pH is reduced to below 5.2 with 4 M hydrochloric acid.
  • step (i) 75 gr of sodium hyaluronate with weight average molecular weight 0.5 Md, about 10 kg of solution to fill 1,000 dosage units are obtained with the following dosage unit composition:
  • step (i) 75 gr of sodium hyaluronate with weight average molecular weight 0,1 Md, about 10 kg of solution to fill 1,000 dosage units are obtained with the following dosage unit composition:
  • the relief of symptoms has been defined as the reduction of pain or of the retrosternal burning, the reduction of the epigastric pain or burning, the reduction of the regurgitation or the sensation of acid in the mouth. All the patients filled a questionnaire at start and at the end of the trial and the data have been evaluated. The results obtained as statistically valid with p ⁇ 0.05. The treatment was fully safe, nobody retired during the trial and the product compliance was very favourable. The effectiveness was very satisfactory. All patients have shown intensity and frequency reduction after 4 weeks of treatment, in particular 14 patients had an 85 % reduction of all studied symptoms, 2 patients the 60 % and 2 of 15 %. The decrease of the acidic sensation in the mouth resulted statistically significative (p ⁇ 0.05).
  • the fibroin solution according to Example 6 was compared in the inclined plane test with a placebo solution prepared according to Example
  • Mucoadhesion is a function of pH, ionic strength, and mucin concentration, therefore, given the intended use of the medical device, mucoadhesive properties were evaluated both at pH 7 and pH 3. This analysis was performed at a controlled temperature, specifically at 37°C which is the expected temperature of the site of application of the test item.
  • Citrate and phosphate buffer solutions characterized by pH values equal to 3 and 7 respectively, were prepared according to the European Pharmacopoeia.
  • pH 3 citrate buffer sodium citrate dihydrate and citric acid were dissolved in MilliQ water, while, for pH
  • Two different mucin suspensions were prepared by dispersing porcine gastric mucin in citrate buffer solution (MUC pH 3) or phosphate buffer solution (MUC pH 7) under magnetic stirring at room temperature.
  • the final mucin concentration was 8% w/w.
  • the inclined plane apparatus consists of a plexiglass support coated with a biological substrate and can be inclined at different angles in a close chamber to maintain the set temperature. Underneath an electronic balance capable of registering weight at pre-set time points is placed, to maintain a constant pre-set temperature.
  • the biological substrate consisted of a mucin film, which was prepared by casting 2.5 ml of a 8% w/w mucin suspension in pH 3 citrate buffer and pH 7 buffer, at 45°C for 45 minutes. The test items Example 6 and placebo were analysed as such, and all the measurements were carried out at 37°C.
  • % AD % DROPPED without mucin film - % DROPPED with mucin film wherein:
  • % DROPPED without mucin film % amount of formulation dropped on the microbalance in absence of the biological substrate
  • % DROPPED with mucin film % amount of formulation dropped on the microbalance in presence of artificial mucus.
  • Inclined plane method measurements indicate that for both pH values considered, stronger interactions are established between the composition of the invention and mucins, even stronger at lower pH values, i.e. at pH similar to the one of the stomach and of the oesophagus in the presence of gastroesophageal reflux.
  • the fibroin composition according to Example 6 was compared with a composition prepared according to Example 6 containing no water-soluble hydrolyzed fibroin (only sodium hyaluronate) (Reference 1), and with a composition prepared according to Example 6 containing chondroitin sulfate in place of water-soluble hydrolysed fibroin (Reference 2).
  • the three samples had a final pH of 4, 8-5, 2 and a dynamic viscosity of 1000- 2000 cP.
  • the three solutions have been brought to pH 1 with 2 M hydrochloric acid.

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Abstract

La présente invention concerne certaines nouvelles combinaisons de fibroïne hydrolysée soluble dans l'eau et d'acide hyaluronique, ou un sel de celles-ci, éventuellement conjointement avec un agent bioadhésif, des compositions à administrer par voie orale comprenant de telles combinaisons, et leur utilisation en thérapie, en particulier dans la prévention et/ou le traitement de l'oesophagite et, de manière générale, des dommages de l'oesophage épithélial.
PCT/IB2024/055080 2023-05-26 2024-05-24 Nouvelles combinaisons de principes actifs, compositions les contenant et leur utilisation en thérapie Ceased WO2024246701A1 (fr)

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EP24733306.5A EP4719346A1 (fr) 2023-05-26 2024-05-24 Nouvelles combinaisons de principes actifs, compositions les contenant et leur utilisation en thérapie
CN202480046466.7A CN121604957A (zh) 2023-05-26 2024-05-24 活性成分的新组合、含有它们的组合物及它们在疗法中的用途

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US6924273B2 (en) 2000-10-03 2005-08-02 Scott W. Pierce Chondroprotective/restorative compositions and methods of use thereof
WO2009138843A1 (fr) * 2008-05-13 2009-11-19 Hertek S.A. Utilisation orale de glycosaminoglycanes et compositions correspondantes
CN106727099A (zh) * 2016-11-25 2017-05-31 江苏爱西施科技服务咨询股份有限公司 一种去油保湿洁面乳及其制备方法
WO2020205774A1 (fr) * 2019-03-29 2020-10-08 Trustees Of Tufts College Compositions à base de fibroïnes de soie, ses procédés de préparation et ses méthodes d'utilisation
CN112546289A (zh) * 2020-12-11 2021-03-26 北京中卫医正科技有限公司 一种复合生物水凝胶敷料及其制备方法

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