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
  • A61K31/7024—Esters of saccharides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

• the present invention relates to a synthetic polysulfated oligosaccharide having 1 to 4 monosaccharides, its salts, or its complexes, at a concentration greater than or equal to 70 mg / ml, for its use for the healing of wounds, in particular for activating the wound. angiogenesis during wound healing.
• Wound healing is a natural biological phenomenon, with mammalian tissue capable of repairing localized lesions through their own repair and regeneration processes.
• the speed and quality of wound healing depend on the general condition of the affected organism, the etiology of the wound, the condition and location of the wound, and whether or not it occurs. infection, as well as genetic factors that may or may not predispose to healing disorders.
• the natural healing of a wound occurs mainly in three successive phases, each of these phases being characterized by specific cellular activities that advance the repair process according to precise chronological sequences: the inflammatory phase, the granulation phase (or phase proliferative), and the ripening phase.
• the first phase begins with the rupture of the blood vessels, which triggers the formation of a clot (blood coagulation) mainly composed of fibrin and fibronectin, and which will constitute a temporary matrix.
• a clot blood coagulation
• fibrin and fibronectin mainly composed of fibrin and fibronectin
• This matrix partially fills the lesion and will allow the migration within the injured area of the inflammatory cells recruited to ensure the debridement of the wound.
• the platelets present will also release factors (for example cytokine, growth factors) allowing the recruitment of cicatrization cells such as inflammatory cells (neutrophils and macrophages), fibroblasts and endothelial cells.
• the second phase corresponds to the development of the granulation tissue.
• the fibroblasts are activated and will differentiate into myo-fibroblasts with major contractiles, generated by actin micro filaments, allowing the contraction of the wound.
• the third phase of the repair process, maturation, is accompanied by a remodeling of the granulation tissue.
• Part of the extracellular matrix is digested by proteases (essentially matrix metalloproteinases (MMPs) and elastases), and progressive reorganization of the extracellular matrix is observed.
• MMPs matrix metalloproteinases
• type III collagen predominant in the granulation tissue, is replaced by type I collagen, the main matrix component of the dermis.
• the fibroblasts, myofibroblasts and vascular cells have their proliferation and / or their activity reduced. Then the excess cells die by apoptosis.
• the inflammatory state gradually decreases.
• This phase is the longest: after about a year, the scar reshapes, it is no longer red or rigid, no longer causes pain and is flattened.
• wounds include chronic wounds such as venous ulcers, sores or wounds characteristic of diabetic subjects.
• Chronic wounds are defined by a lack of healing after a delay of 6 weeks from the onset of the wound regardless of the treatment applied. To treat this type of wound, it may be crucial to speed up the healing process.
• the present invention is more particularly concerned with the activation of angiogenesis, in particular during the healing of wounds, in particular to allow an acceleration of cicatrization.
• the invention relates to a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, at a concentration greater than or equal to 70 mg / ml, for its use to activate angiogenesis. , in particular to activate angiogenesis during wound healing.
• the subject of the invention is also, according to a second aspect, a pharmaceutical composition
• a pharmaceutical composition comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, at a concentration greater than or equal to 70 mg / ml, for its use. to activate angiogenesis, in particular to activate angiogenesis during wound healing.
• activate angiogenesis any positive stimulation of revascularization by means of any action aimed at promoting circulation and blood flow, and more particularly by increasing the generation or length of the capillaries or blood vessels, but also through any modification of the structure of said capillaries or blood vessels on any part of the human or animal body and preferably during the healing of wounds.
• Figure 1 illustrates the effect of treatment with PBS, VEGF-A or KSOS (potassium salt of sucrose octasulfate) on chicken embryo chorioallantoic (CAM) membranes.
• FIGS. 2A, 2B and 2C respectively illustrate the parameters of total length of the tubes, number of segments and number of points of connection of the blood vessels, and more particularly their level of induction relative to a negative control (PBS), observed on chorioallantoic membranes (CAM) of chicken embryos treated with VEGF-A or KSOS at different concentrations.
• PBS negative control
• CAM chorioallantoic membranes
• the oligosaccharides used in the context of the present invention are synthetic oligomers formed from 1 to 4 units of osteos, preferably from 1 to 3 units of osteos, and more preferably from 1 or 2 units of osteos, generally related. between them by glycosidic linkage alpha or beta. In other words, it is mono, di, tri or tetrasaccharides, and preferably mono or disaccharides.
• ose units of these polysaccharides there is no particular limitation on the nature of the ose units of these polysaccharides. Preferably, it will be pentoses or hexoses.
• a monosaccharide mention may be made of glucose, galactose or mannose.
• a disaccharide mention may be made of maltose, lactose, sucrose or trehalose.
• a trisaccharide mention may be made of melezitose.
• tetrasaccharide mention may be made of stachyose.
• the oligosaccharide is a disaccharide, and more preferably sucrose.
• polysulfated oligosaccharide is understood to mean an oligosaccharide of which at least two, and preferably all, hydroxyl groups of each monosaccharide have been substituted with a sulphate group.
• the polysulfated oligosaccharide used in the context of the present application is sucrose octasulfate.
• polysulfated oligosaccharides used in the context of the present invention may be in the form of salts or complexes.
• alkali metal salts such as sodium, calcium or potassium salts; silver salts; or the amino acid salts.
• sucrose octasulfate commonly known as sucralfate.
• the polysulfated oligosaccharides used are preferably the potassium salts rather than the aluminum salts of sucrose octasulfate.
• polysulfated oligosaccharides used in the context of the present invention may be in the form of a micronized powder or in solubilized form.
• polysulfated oligosaccharide used in the context of the present invention is the potassium salt of sucrose octasulfate (known by the abbreviation KSOS), marketed in the Urgotul® Start product by Laboratoires URGO.
• KSOS sucrose octasulfate
• the polysulfated synthetic oligosaccharide according to the invention is used at a concentration greater than or equal to 70 mg / ml, preferably greater than or equal to 100 mg / ml. According to a preferred embodiment, the synthetic polysulfated oligosaccharide according to the invention is used at a concentration of between 100 mg / ml and 1000 mg / ml.
• compositions comprising the synthetic polysulfated oligosaccharide described above, at a concentration greater than or equal to 70 mg / ml, for its use for activating angiogenesis, in particular for activating wound angiogenesis. .
• the oligosaccharide compounds according to the invention may be used alone or as a mixture of two or more of them, or in combination with one (or more) other active substance (s). ).
• the active ingredients are chosen from anti-bacterials, antiseptics, anti-pain agents, anti-inflammatory agents, healing promoting agents, depigmenting agents, antipruriginous agents, UV screening agents, soothing agents and agents. moisturizers, antioxidants, and mixtures thereof.
• the assets are chosen from:
• anti-bacterials such as polymyxin B, penicillins (amoxycillin), clavulanic acid, tetracyclines, minocycline, chlorotetracycline, aminoglycosides, Amikacin, Gentamicin, Neomycin, silver and its salts (silver sulfadiazine), probiotics, silver salts;
• antiseptics such as sodium mercurothiolate, eosin, chlorhexidine, phenylmercury borate, hydrogen peroxide, Dakin liquor, triclosan, biguanide, hexamidine, thymol, Lugol, Povidone iodine, Merbromine, Benzalkonium and Benzethonium Chloride, ethanol, isopropanol;
• anti-pain agents such as paracetamol, codeine, dextropropoxyphene, tramadol, morphine and its derivatives, corticosteroids and derivatives;
• anti-inflammatories such as glucocorticoids, nonsteroidal anti-inflammatory drugs, aspirin, ibuprofen, ketoprofen, flurbiprofen, diclofenac, aceclofenac, ketorolac, meloxicam, piroxicam, tenoxicam, Naproxen, Indomethacin, Naproxcinod, Nimesulide, Celecoxib, Etoricoxib, Parecoxib, Rofecoxib, Valdecoxib, Phenylbutazone, Niflumic acid, Mefenamic acid;
• the active agents promoting healing such as retinol, vitamin A, vitamin E, N-acetyl-hydroxyproline, extracts of Centella Asiatica, papain, silicones, essential oils of thyme, niaouli, rosemary and of sage, hyaluronic acid, Allantoin, - Hema'tite (gattefossé), Vitamin C, TEGO Pep 4-17 (evonik), Toniskin (silab), Collagen (Expanscience), Timecode (Seppic), Gatuline skin repair (Gattefossé), Panthenol, PhytoCellTec Rose Alp (Mibelle Biochemistry), Erasyal (libragen), Serilesine (Lipotec), Talapetraka Heterosides (beyer), Stoechiol (codif), Macarose (Sensient), Dermaveil (Ichimaru Pharcos), Phycosaccaride AI ( Codif);
• depigmenting agents such as kojic acid (Kojic Acid SL ® - Quimasso (Sino Lion)), Arbutin (Olevatin ® - Quimasso (Sino Lion)), the mixture of palmitoylpropyl of sodium and white water lily extract (Sepicalm ® - Seppic), undecylenoyl phenylalanine (Sepiwhite ® - Seppic),
• - moisturizing active ingredients such as xpermoist (lipotec), hyaluronic acid, urea, fatty acids, glycerin, waxes, exossin (unipex) - UV filters such as Parsol MCX, Parsol 1789 soothing agents such as chamomile, bisabolol, xanthalene, glycyrrhébuzenique acid, tanactine (CPN), Calmiskin (Silab),
• antioxidants such as vitamin E.
• the oligosaccharide compounds according to the invention can be used in combination with an antioxidant.
• the synthetic polysulfated oligosaccharides used in the context of the present invention may be administered topically, and in particular implemented in a pharmaceutical formulation, for example a gel, a solution, an emulsion, a cream, granules or granules. capsules of variable size ranging from nano or micrometer to millimeter, which will allow their application directly at the level of the wound.
• a pharmaceutical formulation for example a gel, a solution, an emulsion, a cream, granules or granules. capsules of variable size ranging from nano or micrometer to millimeter, which will allow their application directly at the level of the wound.
• the compounds used in the context of the present invention may be used in a solution for subcutaneous injection.
• these compounds may be incorporated in the same pharmaceutical formulation or in separate galenic formulations.
• the amount of synthetic polysulfated oligosaccharides according to the invention used in the galenic formulation is adapted according to the desired kinetics as well as specific constraints related to its nature, solubility, heat resistance, etc.
• the synthetic polysulfated oligosaccharide compounds used in the context of the present invention, or a galenic formulation containing them, will be incorporated into a dressing.
• polysulfated oligosaccharide synthetic compounds and in particular the potassium salt of sucrose octasulfate or a galenic formulation containing it, may be incorporated into any element of the structure of a dressing provided that this compound can enter directly or indirectly into contact with the surface. of the wound.
• this compound or a galenic formulation containing it
• this compound will be incorporated into the layer of the dressing that comes into contact with the wound or deposited on the surface of the dressing that comes into contact with the wound.
• the potassium salt of the sucrose octasulfate may thus be deposited, continuously or discontinuously, on the surface intended to come into contact with the wound:
• liquid form for example by spraying a solution or suspension containing it;
• the layer or surface coming into contact with the wound may consist for example of an absorbent material such as a hydrophilic absorbent foam polyurethane; a textile material such as a compress, such as a nonwoven, a film, a fiber web; an absorbent adhesive material or not; an adherent interface structure or not.
• an absorbent material such as a hydrophilic absorbent foam polyurethane
• a textile material such as a compress, such as a nonwoven, a film, a fiber web
• an absorbent adhesive material or not an adherent interface structure or not.
• sucrose octasulfate potassium salt used in the galenic formulation or in the dressing will be adapted according to the desired kinetics as well as specific constraints related to its nature, solubility, heat resistance, etc.
• dressing refers to all types of dressings used for the treatment of wounds.
• a dressing comprises at least one layer or matrix, adhesive or not.
• the synthetic polysulfated oligosaccharide compounds according to the invention, or a galenic formulation containing them, can be incorporated in any element of the structure of a dressing, for example in the matrix.
• this compound may be incorporated into the layer of the dressing that comes into contact with the wound or deposited on the surface of the layer of the dressing that comes into contact with the wound.
• deposition techniques are well known to those skilled in the art and some are for example described in the patent application WO 2006/007814.
• the synthetic polysulfated oligosaccharide compound according to the invention may be incorporated in an absorbent dressing based on gelling fibers, for example the product AQUACEL® marketed by CONVATEC.
• the nursing staff keeps them in place with a band or covers them with a secondary element such as a second absorbent dressing or a band of contention. It is therefore useful that the dressing remains attached to the wound so that the caregiver keeps their hands free to position these secondary elements.
• a secondary element such as a second absorbent dressing or a band of contention.
• an adhesive having the property of adhering to the skin without adhering to the wound.
• an adhesive mention may be made of adhesives based on silicone or polyurethane elastomers, such as silicone or polyurethane gels, and hydrocolloid adhesives.
• hydrocolloid adhesives consist in particular of an elastomeric matrix based on one or more elastomers chosen from poly (styrene-olefin-styrene) block polymers in combination with one or more compounds chosen from plasticizers, such as mineral oils. , tackifying resins and, if necessary, antioxidants, in which is incorporated a quantity, preferably a small amount, of hydrocolloids (from 3 to 20% by weight), for example sodium carboxymethylcellulose or superabsorbent polymers such as the products sold under the name LUQUASORB® by BASF.
• the synthetic polysulfated oligosaccharide compounds used in the context of the present invention, or a galenic formulation containing them will be incorporated in a dressing comprising a hydrocolloid adhesive, said polysulfated oligosaccharide being incorporated in said adhesive preferably in a amount of between 1 and 15% by weight, more preferably between 5 and 10% by weight, relative to the weight of the adhesive
• a hydrocolloid adhesive preferably in a amount of between 1 and 15% by weight, more preferably between 5 and 10% by weight, relative to the weight of the adhesive
• an adhesive net on the nonwoven makes it particularly advantageous to reduce or avoid the risk of small fibrils of the textile material coming into contact with the wound and clinging to the tissues. thus causing a painful sensation of withdrawal, or even an obstacle to the healing process of the wound.
• the synthetic polysulfated oligosaccharide compound according to the invention is incorporated in such an adhesive at a concentration compatible with its solubility and its resistance to heat.
• the synthetic polysulfated oligosaccharide compound according to the invention is preferably used in an amount of between 1 and 15% by weight, and more preferably between 5 and 10% by weight, relative to the total weight of adhesive
• this nonwoven dressing we can associate the latter with an additional absorbent layer, and preferably an absorbent layer that does not gel, such as in particular a compress such as that used in the product URGOTUL ® Duo or URGOTUL® Trio, an absorbent hydrophilic foam, preferably a hydrophilic polyurethane foam having a higher absorption capacity than the nonwoven such as that used in the CELLOSORB® product.
• an absorbent hydrophilic foam preferably a hydrophilic polyurethane foam having a higher absorption capacity than the nonwoven such as that used in the CELLOSORB® product.
• the synthetic polysulfated oligosaccharide compound according to the invention is incorporated in a nonwoven dressing, associated with an additional absorbent layer, and preferably an absorbent layer which does not gel, such as in particular a compress.
• the synthetic polysulfated oligosaccharide compound according to the invention is incorporated in a non-woven dressing, associated with an additional absorbent layer, and preferably an absorbent layer which does not gel, such as in particular an absorbent hydrophilic foam. , preferably a hydrophilic polyurethane foam having a higher absorption capacity than the nonwoven.
• the nonwoven and the foam may be combined by techniques well known to those skilled in the art, for example by hot calendering with a heat fusible powder based on TPU / polycaprolactone polymers. This technique is commonly used for bonding nonwovens for the medical market.
• this foam or the nonwoven can be covered with a support to protect the wound from the outside.
• This support may be of greater size than that of the other layers and made adhesive continuously or discontinuously on its face coming into contact with the wound to optimize the maintenance of the dressing during its use, particularly if the wound is located on non-planar body areas.
• This support and its adhesive are preferably impervious to fluids but very permeable to water vapor to allow optimal management of the exudates absorbed by the dressing and avoid maceration problems.
• Such supports are well known to those skilled in the art and consist for example of breathable and impermeable films such as polyurethane films, foam / film or nonwoven / film complexes. additives
• the oligosaccharide compounds according to the invention may be used in combination with one (or more) additives commonly used in the preparation of dressings. These additives may especially be chosen from perfumes, preservatives, vitamins, glycerine, citric acid, etc.
• additives may especially be chosen from perfumes, preservatives, vitamins, glycerine, citric acid, etc.
• the activity of the synthetic polysulfated oligosaccharides according to the invention has been demonstrated in the following nonlimiting examples.
• VEGF-A was used as a positive control.
• the potassium salt of sucrose octasulfate (KSOS) is in the form of a solution at different concentrations, buffered with PB S.
• PB S buffer solution was used as a negative control.
• the eggs are broken in a weighing dish in order to get rid of the shell, thus making the embryo and all structures accessible for future treatment. Ex ovo embryos are then returned to the hatcher, where they will continue to grow in vitro.
• Embryos will be treated with vehicle (PBS alone), VEGF or different concentrations of KSOS.
• the treatment zone is delimited by a silicone ring 1 cm in diameter and 0.2 mm thick.
• the treatment volume is 25 ⁇ .
• the treated embryos are returned to the hatcher for 48 hours.
• Figure 1 illustrates the observations of the embryos as a function of the treatment: the photos are taken at the level of the treatment area.
• VEGF induces anarchic neovascularization of CAM, as expected.
• KSOS showed a slight vascular change of 30mg / mL, compared to the negative control (PBS alone) with an accentuation of this effect at the higher doses shown in the photos by the arrows.
• Small vessels are found accompanied by a reaction that is similar to a hyperemic reaction (Vasodilation, increased blood flow).
• Vasodilation increased blood flow.
• 100 mg / mL a well-developed vascular network is observed, with the appearance of hemorrhagic zones or spots (top arrow).
• the results are therefore considered convincing, as demonstrating an angiogenesis activation equivalent to that observed with VEGF-A used as a positive control.
• b and c are representative of the formation of new vessels characteristic of angiogenesis.
• FIG. 2 illustrates these different parameters for each group tested.
• VEGF induces a significant increase in the 3 parameters measured.
• KSOS also induces a significant increase in the 3 parameters measured from 100 mg / mL. At lower doses, ie at 30 and 50 mg / mL, an underdeveloped vascular network is nevertheless visible, but the activation of angiogenesis is not considered significant compared to activation. observed for treatment with VEGF-A or 100 mg / mL KSOS.
• KSOS undeniably induces increased CAM vascularization at the treatment area.
• the development of a network of blood vessels increasingly pronounced according to the inoculated dose is clearly quantifiable with image analysis.
• Activation of angiogenesis demonstrated for KSOS can accelerate the healing of wounds.

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• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
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• Dermatology (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
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• 2015
  • 2015-11-17 FR FR1561056A patent/FR3043556B1/fr active Active
• 2016
  • 2016-11-15 US US15/776,643 patent/US20180325930A1/en not_active Abandoned
  • 2016-11-15 EP EP16812984.9A patent/EP3377072A1/de not_active Withdrawn
  • 2016-11-15 WO PCT/FR2016/052964 patent/WO2017085397A1/fr active Application Filing

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