Use of oligosaccharide compounds for preventing the recurrence of neuro-ischemic wounds in diabetic patients

Abstract

The invention relates to a synthetic polysulfated oligosaccharide having 1 to 4 monosaccharide units, the salts thereof, or the complexes thereof, for use in preventing the recurrence of a neuro-ischemic wound.

Description

Description Title: USE OF OLIGOSACCHARIDE COMPOUNDS TO PREVENT THE RECURRENCE OF NEURO-ISCHEMIC WOUNDS IN DIABETIC PATIENTS

[0001] The present invention relates to a synthetic polysulfated oligosaccharide having 1 to 4 monosaccharide units, its salts, or its complexes, for use in treating a neuroischemic wound, in particular in preventing the recurrence of a neuroischemic wound, such as a neuroischemic diabetic foot ulcer. Background to the invention

[0002] Wound healing is a natural biological phenomenon, with mammalian tissues capable of repairing localized lesions through their own repair and regeneration processes.

[0003] 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 the occurrence or absence of infection, as well as genetic factors predisposing or not to healing disorders.

[0004] Natural wound healing occurs mainly in three successive phases, each of which is characterized by specific cellular activities that advance the repair process according to precise chronological sequences: the inflammatory phase, the granulation phase (or proliferative phase) which continues with the epidermization phase, then the maturation phase.

[0005] The first phase, the inflammatory phase, begins as soon as the blood vessels rupture, which triggers the formation of a clot (blood coagulation) mainly composed of fibrin and fibronectin, and which will constitute a temporary matrix. This matrix partially fills the lesion and will allow the migration within the injured area of ​​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 healing cells such as inflammatory cells (neutrophils and macrophages), fibroblasts and endothelial cells.

[0006] The second phase corresponds to the development of granulation tissue. First, colonization of the wound by a proliferation of fibroblasts is observed. Then, the migration of endothelial cells from healthy vessels will allow the formation of new blood vessels (neovascularization), or angiogenesis, of the injured tissue. This stage of angiogenesis is fundamental to initiate healing. In the granulation tissue, fibroblasts are activated and will differentiate into myofibroblasts with significant contractile properties, generated by actin microfilaments, allowing contraction of the wound.

[0007] The third phase of the repair process, maturation, is accompanied by remodeling of the granulation tissue. Part of the extracellular matrix is ​​digested by proteases (mainly matrix metalloproteases (MMPs) and elastases), and a progressive reorganization of the extracellular matrix is ​​observed. Gradually, type III collagen, the majority in granulation tissue, is replaced by type I collagen, the main matrix component of the dermis. At the end of the maturation phase, fibroblasts, myofibroblasts, and vascular cells experience reduced proliferation and / or activity. Then, excess cells die by apoptosis. In parallel with the remodeling of the extracellular matrix and the apoptosis of excess cells, the inflammatory state gradually decreases.This phase is the longest: after about a year, the scar remodels itself, it is no longer red or rigid, no longer causes pain and it flattens out.

[0008] However, some types of wounds do not heal properly, with the three key stages of the process occurring abnormally, despite the best possible physicochemical and biological conditions being in place. Indeed, the speed and quality of wound healing depend on intrinsic and extrinsic factors. This repair process can therefore be abnormally prolonged depending on: - the etiology of the wound; - its condition and location; - the occurrence of an infection caused by the presence of certain infectious agents such as Staphylococcus aureus or Pseudomonas aeruginosa, the germs most frequently encountered during a wound infection; - the existence of a pre-existing pathology (such as diabetes, immune deficiency, venous insufficiency, etc.); - the external environment; or - genetic factors predisposing or not to healing disorders.

[0009] These wounds include chronic wounds such as venous ulcers, pressure sores, or wounds characteristic of diabetic patients, located on the foot. Chronic wounds are defined by a lack of healing after a period of 4 to 6 weeks from the onset of the wound, regardless of the treatment applied. To treat this type of wound, it can be crucial to accelerate the healing process.

[0010] Wounds in diabetic patients are characterized as a very particular type of chronic wound, with their own specificities.

[0011] Diabetes is an increasingly widespread disease. According to recent estimates, approximately 537 million people worldwide suffer from it, a figure expected to reach 643 million individuals by 2030. Diabetic patients are exposed to various complications related to their disease. These include the increased incidence of cardiovascular events such as myocardial infarction, stroke (Cerebrovascular Accidents), and complications microvascular diseases such as retinopathy (which can lead to blindness - diabetes is the leading cause of blindness worldwide) and nephropathy (which can lead to kidney failure requiring dialysis). One of the most dramatic complications of diabetes is amputation. It is estimated that worldwide, a person has a lower limb amputated due to diabetes every 30 seconds and that 85% of these amputations are preceded by a foot ulcer (International Diabetes Federation, IDF 2005) and is a leading cause of amputation worldwide. Approximately 19 to 34% of people with diabetes will develop a foot ulcer during their lifetime and 20% of diabetic patients with a foot ulcer will have an amputation. The 5-year mortality rate after amputation is 50 to 70%, much higher than some cancers.

[0012] A diabetic foot ulcer (DFU) is defined as "a deep wound located below the ankle in a diabetic patient, regardless of its duration" (IDF, 2005). Indeed, the primary cause of the lack of healing of these diabetic wounds is linked to exacerbated glucose bioavailability. This induces numerous physiological and metabolic changes, such as skin thickening and significant oxidative stress that can lead to neuropathy and arteriopathy. Arteriopathy and neuropathy are therefore two distinct major risk factors for delayed wound healing in diabetic patients, and more specifically for diabetic foot wounds.

[0013] Diabetic foot ulcers are classified into different categories. On the one hand, there are diabetic foot ulcers in neuropathic patients and on the other hand, diabetic foot ulcers in arteriopathic patients, which are clearly distinguished from diabetic foot ulcers in neuropathic patients by the presence of ischemic damage, i.e. arterial damage (characterized in particular by the reduction of arterial blood supply to an organ). Thus, the diabetic foot of the neuropathic patient is generally characterized by a warm, well-perfused foot and a palpable pedal pulse. In addition, the neuropathic patient presents a very clear, or even total, loss of sensitivity in the area of ​​the lesion (and of the foot, or even the leg). The ulceration is often located on the sole of the foot, under a neglected callus subjected to strong plantar pressure.Conversely, the diabetic foot of the arteriopathic patient is cold with a pedal pulse that is not palpable. In general, it is painful, because the patient's sensitivity is little or not altered. However, this type of patient presents a more or less pronounced alteration at the level of the vessels of the wound, ranging from a simple reduction in the blood supply to an irreversible necrosis of the various vascular tissues that can lead to amputation at the level of the altered area or even beyond. For this type of patient, the ulcers are located partly at the level of the sole of the foot, but also frequently on the toes or in areas located behind the heel.Neuroischemic diabetic foot ulcers have the same characteristics as arteriopathic wounds (same locations, the foot is cold with a pedal pulse that is not palpable), except that they are generally not painful, because this arterial damage is associated with neurological damage (hence the term "neuroischemic"). These two. Different types of ulcers (neuropathic and neuroischemic / ischemic) have different healing prognoses. Indeed, patients with neuropathic ulcers heal more quickly than patients with ischemic or neuroischemic ulcers, with ischemia significantly hampering the healing process and increasing the risk of infection, as shown, for example, in the study “Comparison of characteristics and healing course of diabetic foot ulcers by etiological classification: neuropathic, ischemic and neuroischemic,” Totsu RR et al., J Diabetes Complications, 2014 Jul_Aug; 28(4):528-35.

[0014] Neuroischemic diabetic foot ulcers are estimated to be present in more than 50% of patients in high-income countries (Prompers L, Huijberts M, Apelqvist J, Jude E, Piaggesi A, Bakker K, et al. High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia. 2007;50(1):18-25 and Schaper NC, Van Netten JJ, Apelqvist J, Lipsky BA, Bakker K. Prevention and management of foot problems in diabetes: a summary guidance for daily practice 2015 based on the IWGDF Guidance Documents. Diabetes Metab Res Rev 2016;32(suppl 1):7-15).

[0015] These neuroischemic diabetic foot ulcers pose a challenge to the management of diabetic foot disease and are associated with more serious outcomes, including infection, which often leads to amputation or even death in cases of systemic infection (Armstrong DG, Cohen K, Courric S, Bharara M, Marston W. Diabetic foot ulcers and vascular insufficiency: our population has changed, but our methods have not. J Diabetes Sci Technol 2011; 5: 1591-95.): lower probability of healing longer healing times higher probability of ulcer recurrence increased risk of major amputations potentially higher mortality.

[0016] Unfortunately, even after a foot ulcer has healed, the development of a new ulcer (recurrence) is a real public health problem. Approximately 40% of patients experience a new ulcer (recurrence) within 1 year of ulcer healing, nearly 60% within 3 years, and 65% within 5 years (Armstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. N Engl J Med. 2017;376(24):2367-75.).

[0017] Recurrence rates within the first year after ulcer healing are significantly higher, especially in the first few weeks after ulcer healing, because the neoepithelium is fragile in the weeks and months after ulcer healing (Bus SA, Lavery LA, Monteiro-Soares M, Rasmussen A, Raspovic A, Sacco ICN, et al. Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36 Suppl 1:e3269).

[0018] Uncontrolled diabetes, diabetic polyneuropathy, peripheral arterial disease, the presence of foot deformities likely to generate wounds, a history of ulceration, and previous surgical interventions are well recognized as significant risk factors for the repeated development of diabetic foot ulcers, with high rupture rates at healed wound sites and are widely described in the literature (Lâzaro-Martinez, JL; Aragôn-Sânchez, J.; Âlvaro-Afonso, FJ; Garcia-Morales, E.; Garcia-Âlvarez, Y.; Molines-Barroso, RJ The best way to reduce reulcerations: If you understand biomechanics of the diabetic foot, you can do it. Int. J. Low Extrem. Wounds 2014, 13, 294-319).

[0019] Some of these risk factors, such as foot structure or blood supply, can be improved by surgical interventions when possible, but these interventions do not address concomitant factors that appear to be important predictors for the development of new ulcers (Dubsky M, Jirkovska A, Bern R, Fejfarova V, Skibova J, Schaper NC, et al. Risk factors for recurrence of diabetic foot ulcers: prospective followup analysis in the Eurodiale subgroup. Int Wound J. 2013;10(5):555-61 ).

[0020] One of these factors, impaired microcirculation, has been shown to play a significant role in the pathogenesis of tissue breakdown and is generally not resolved after wound healing (Chao, CYL; Cheing, GLY Microvascular dysfunction in diabetic foot disease and ulceration. Diabetes Metab. Res. Rev. 2009, 25, 604-614.).

[0021] The treatment of ischemic wounds has been previously described, including the treatment of diabetic foot. For example, patent FR3066390 describes the use of oligosaccharide compounds to treat arteriopathic diabetic foot ulcers. Edmonds et al. also describe the use of sucrose octasulfate (TLC-NOSF) for the treatment of neuroischemic diabetic foot ulcers (Lancet Diabetes Endocrinol 2017), and Lazaro-Martinez et al. describe the use of a TLC-NOSF dressing for the treatment of neuroischemic diabetic foot ulcers (Journal of Wound Care, Volume 28, June 2019). Application FR3113583 also describes the use of oligosaccharide compounds to increase skin oxygenation during the treatment of ischemic wounds.

[0022] International guidelines also recommend the use of a TLC-NOSF (Technology Lipido-Colloid - Nano-OligoSaccharide Factor) dressing for the treatment of neuroischemic diabetic foot ulcers (Rayman G, et al., Guidelines on use of interventions to enhance healing of chronic foot ulcers in diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36 Suppl 1:e3283, or National Institute for Health and Care Excellence. UrgoStart for treating leg ulcers and diabetic foot ulcers. April 2023, https: / / www.nice.org.uk / guidance / mtg42).

[0023] Oligosaccharide compounds have also already been described for their use in activating angiogenesis, for example in patent FR3043556.

[0024] Oligosaccharide compounds have also been described for the treatment of neuropathic diabetic foot ulcers (Richard et al., Journal of Wound Care, Vol 21, No. 3, March 2012).

[0025] However, the recurrence of neuroischemic wounds, particularly neuroischemic diabetic foot ulcers, is one of the major unsolved problems, requiring a new therapeutic approach for patients in remission. Indeed, by preventing the recurrence of neuroischemic diabetic foot ulcers, we avoid hospitalizations, care, medical and nursing visits, but also amputations related to the appearance of this type of wound. This can reduce the costs of such care and interventions, but also, and above all, improve the patient's quality of life.

[0026] New treatments for these wounds are always desired, as is a better understanding of the phenomenon of recurrence of these wounds. Statement of the invention

[0027] The present invention is based on the inventors' results demonstrating that - unexpectedly - it is possible to significantly reduce the recurrence of neuroischemic wounds.

[0028] The invention thus relates to a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, for its use in preventing the recurrence of a neuroischemic wound, preferably of the foot ulcer of neuroischemic diabetics.

[0029] According to a second aspect, the invention also relates to a pharmaceutical composition comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, for its use in preventing the recurrence of a neuroischemic wound, preferably of the neuroischemic diabetic foot ulcer.

[0030] According to a third aspect, the invention finally relates to a dressing comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, in particular a potassium salt of sucrose octasulfate for preventing the recurrence of a neuroischemic wound, preferably of the neuroischemic diabetic foot ulcer.

[0031] Detailed description of the invention

[0032] The invention relates to the use of a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, or a pharmaceutical composition or a dressing containing said oligosaccharide.

[0033] According to one embodiment, the invention relates to a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, for its use in preventing the recurrence of neuroischemic diabetic foot ulcer.

[0034] According to one embodiment, the invention relates to a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, for its use in preventing the recurrence of a neuroischemic wound for at least 12 months, preferably 12 months after healing of said wound.

[0035] According to one embodiment, the invention relates to a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, for its use in preventing the recurrence of neuroischemic diabetic foot ulcer for at least 12 months, preferably 12 months after healing of said ulcer.

[0036] According to one embodiment, the invention relates to a synthetic polysulfated oligosaccharide having 1 to 4 monosaccharide units, its salts, or its complexes, for use in preventing the recurrence of a neuroischemic wound in a patient with unbalanced diabetes, diabetic polyneuropathy, peripheral arterial disease, having deformities in the foot, having a history of ulceration and / or having had previous surgery in the foot. According to the invention, "deformities in the foot" means any deformities likely to generate wounds, for example hallux valgus, hallux rigidus, quintus varus, osteoarthritis or Charco-Marie-Tooth disease.

[0037] In one embodiment, the invention relates to a synthetic polysulfated oligosaccharide having 1 to 4 monosaccharide units, its salts, or its complexes, for use in preventing recurrence of neuroischemic diabetic foot ulcer in a patient with unbalanced diabetes, diabetic polyneuropathy, peripheral arterial disease, having deformities in the foot, having a history of ulceration or having had previous surgery in the foot.

[0038] Synthetic polysulfated oligosaccharides with 1 to 4 sugar units

[0039] The oligosaccharides used in the context of the present invention are synthetic oligomers formed from 1 to 4 ose units, preferably from 1 to 3 ose units, and more preferably from 1 or 2 ose units, generally linked together by alpha or beta glycosidic bond. In other words, they are mono, di, tri or tetrasaccharides, and preferably mono or disaccharides.

[0040] There is no particular limitation regarding the nature of the ose units of these polysaccharides. Preferably, they will be pentoses or hexoses. Examples of monosaccharides include glucose, galactose or mannose. Examples of disaccharides include maltose, lactose, sucrose or trehalose. Examples of trisaccharides include melezitose. Examples of tetrasaccharides include stachyose.

[0041] According to one embodiment, the oligosaccharide for its use according to the invention is characterized in that it comprises 1 to 3 ose units, more particularly 1 or 2 ose units preferably chosen from pentoses and hexoses, as well as the salts and complexes of these compounds.

[0042] Preferably, the oligosaccharide is a disaccharide, and more preferably sucrose.

[0043] For the purposes of the present invention, the term “polysulfated oligosaccharide” means an oligosaccharide of which at least two, and preferably all, of the hydroxyl groups of each ose have been substituted by a sulfate group.

[0044] Preferably, the polysulfated oligosaccharide used in the context of the present invention is sucrose octasulfate.

[0045] The polysulfated oligosaccharides used in the context of the present invention may be in the form of salts or complexes.

[0046] Examples of salts include alkali metal salts such as sodium, calcium or potassium salts; silver salts; or amino acid salts.

[0047] Examples of complexes include hydroxyaluminum complexes.

[0048] Within the scope of the present invention, particularly preferred compounds are the following: - the potassium salt of sucrose octasulfate; - the silver salt of sucrose octasulfate; and - the hydroxyaluminum complex of sucrose octasulfate, commonly called sucralfate.

[0049] In particular, in the context of the present invention, the polysulfated oligosaccharides used are preferably the potassium salts rather than the aluminum salts of sucrose octasulfate.

[0050] The polysulfated oligosaccharides used in the context of the present invention may be in the form of micronized powder or in solubilized form.

[0051] An example of a 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 product Urgotul® Start by URGO Laboratories.

[0052] According to a preferred embodiment, the invention relates to sucrose octasulfate potassium salt (KSOS) for use in preventing recurrence of neuroischemic diabetic foot ulcer.

[0053] According to one embodiment, the oligosaccharide for its use according to the invention is characterized in that its concentration is greater than or equal to 70 mg / mL, preferably 100 mg / mL, and more preferably between 100 and 1000 mg / mL.

[0054] In the context of the present invention, the polysulfated oligosaccharides used can be associated with phosphate buffered saline (PBS).

[0055] Composition

[0056] The invention also relates to a pharmaceutical composition comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, for its use in preventing the recurrence of a neuroischemic wound.

[0057] According to one embodiment, the invention relates to a pharmaceutical composition comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, for its use in preventing the recurrence of neuroischemic diabetic foot ulcer.

[0058] According to a particular embodiment, said pharmaceutical composition comprises 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, preferably 100 mg / mL, and more preferably between 100 and 1000 mg / mL, in particular to prevent the recurrence of neuroischemic diabetic foot ulcer.

[0059] The synthetic polysulfated oligosaccharide used in the pharmaceutical composition according to the invention is preferably sucrose octasulfate, more particularly the potassium salt of sucrose octasulfate.

[0060] Additional active substance

[0061] Generally speaking, the synthetic polysulfated 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), for example in compositions such as those mentioned above.

[0062] Generally, the active ingredients are chosen from antibacterials, antiseptics, painkillers, anti-inflammatories, active ingredients promoting healing, depigmenting agents, antipruritics, UV filters, soothing agents, moisturizing agents, antioxidant agents, and their mixtures.

[0063] Generally, assets are chosen from: - antibacterials such as Polymyxin B, penicillins (Amoxycillin), clavulanic acid, tetracyclines, Minocycline, chlortetracycline, 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's solution, triclosan, biguanide, hexamidine, thymol, Lugol's, Povidone iodine, Merbromine, Benzalkonium and Benzethonium Chloride, ethanol, isopropanol; - painkillers such as Paracetamol, Codeine, Dextropropoxyphene, Tramadol, Morphine and its derivatives, Corticosteroids and derivatives; - anti-inflammatory drugs such as glucocorticoids, non-steroidal 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; - active ingredients that promote healing such as Retinol, Vitamin A, Vitamin E, N-acetyl-hydroxyproline, Centella Asiatica extracts, papain, silicones, essential oils of thyme, niaouli, rosemary and sage, hyaluronic acid, Allantoin, -Hema'tîte (gattefossé), Vitamin C, TEGO Pep 4-17 (evonik), Toniskin (silab), Collageneer (Expanscience), Timecode (Seppic), Gatuline skin repair (gattefossé), Panthenol, PhytoCellTec Alp Rose (Mibelle Biochemistry), Erasyal (libragen), Serilesine (Lipotec), Talapetraka Heterosides (beyer), Stoechiol (codif), macarose (Sensient), Dermaveil (Ichimaru) Pharcos), Phycosaccaride Al (Codif); - depigmenting agents such as kojic acid (Kojic Acid SL® - Quimasso (Sino Lion)), Arbutin (Olevatin® - Quimasso (Sino Lion)), sodium palmitoylpropyl and white water lily extract mixture (Sepicalm® - Seppic), undecylenoyl phenylalanine (Sepiwhite® - Seppic), antipruritics: hydrocotisone, enoxolone, diphenyhydramine, antihistamine for local application anti H1; - 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, glycyrrhebenic acid, tanactin (CPN), Calmiskin (Silab); - antioxidant agents, such as vitamin E.

[0064] According to a preferred embodiment, the oligosaccharide compounds according to the invention can be used in combination with an antioxidant agent.

[0065] Galenic

[0066] The synthetic polysulfated oligosaccharides used in the context of the present invention can be administered topically, and in particular implemented within a galenic formulation, in the form of a composition, such as for example a gel, a solution, an emulsion, a cream, granules, capsules (of variable sizes ranging from nano or micrometer to millimeter), which will allow their application directly to the wound. Alternatively, the compounds used in the context of the present invention can be implemented within a solution for subcutaneous injection.

[0067] If they are used as a mixture of two or more of them or in combination with one or more other active substances, these compounds may be incorporated into the same galenic formulation or into separate galenic formulations.

[0068] Of course, the quantity of synthetic polysulfated oligosaccharides according to the invention used in the galenic formulation is adapted according to the desired kinetics as well as the specific constraints linked to its nature, solubility, heat resistance, etc.

[0069] Bandage

[0070] Preferably, the synthetic polysulfated oligosaccharide compounds used in the context of the present invention, or a galenic formulation containing them, will be integrated into a dressing.

[0071] For the purposes of this application, dressing means all types of dressings used for the prevention of recurrence of wounds and / or the treatment of wounds.

[0072] The invention thus relates to a dressing comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, in particular a potassium salt of sucrose octasulfate, for preventing the recurrence of a neuroischemic wound.

[0073] According to one embodiment, the invention relates to a dressing comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, for use in preventing recurrence of neuroischemic diabetic foot ulcer.

[0074] The synthetic polysulfated oligosaccharide compound according to the invention, 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 come directly or indirectly into contact with the surface of the wound.

[0075] Preferably and in order to promote rapid action, this compound (or a galenic formulation containing it) can be incorporated into the layer of the dressing which comes into contact with the wound or deposited on the surface of the dressing which comes into contact with the wound.

[0076] Such deposition techniques are well known to those skilled in the art and some are for example described in patent application WO 2006 / 007814.

[0077] Advantageously, the potassium salt of sucrose octasulfate (or a galenic formulation containing it) can thus be deposited, continuously or discontinuously, on the surface intended to come into contact with the wound: - either in liquid form, for example by vaporization of a solution or suspension containing it; - either in solid form, for example by sieving a powder containing it.

[0078] The layer or surface coming into contact with the wound may consist, for example, of an absorbent material such as a hydrophilic absorbent polyurethane foam; a textile material such as a compress, such as a non-woven fabric, a film, a fibre veil; an absorbent or non-adhesive adhesive material; an adherent or non-adherent interface structure.

[0079] Typically, a dressing comprises at least one layer or matrix, whether adhesive or not.

[0080] Alternatively, the layer or surface coming into contact with the wound may consist, for example, of a textile weave, preferably made of polyester as described in patent application WO 01 / 70285 or in patent application WO2013 / 093298 on which an elastomeric matrix comprising a polysulfated oligosaccharide will be coated. synthetic having 1 to 4 ose units, its salts, or its complexes, in particular a potassium salt of sucrose octasulfate, as described in patent application WO2008 / 149035 or in application WO2014 / 009488.

[0081] The synthetic polysulfated oligosaccharide compounds according to the invention, or a galenic formulation containing them, may be incorporated into any element of the structure of a dressing, for example in the matrix.

[0082] The invention thus relates to a dressing comprising a textile frame coated with an elastomeric matrix comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, in particular a potassium salt of sucrose octasulfate, for its use in preventing the recurrence of a neuroischemic wound.

[0083] According to a preferred embodiment, the invention thus relates to a dressing comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, in particular a potassium salt of sucrose octasulfate for preventing the recurrence of a neuroischemic wound, said dressing comprising a textile weave coated with an elastomeric matrix, and said matrix comprising said synthetic polysulfated oligosaccharide.

[0084] Generally speaking, the galenic or the structure of the dressing can be adjusted to obtain a specific release profile of the potassium salt of sucrose octasulfate, rapid or delayed, depending on the needs.

[0085] Of course, the quantity of sucrose octasulfate potassium salt used in the galenic formulation or in the dressing will be adapted according to the desired kinetics as well as the specific constraints linked to its nature, solubility, heat resistance, etc.

[0086] According to a variant of the invention, the synthetic polysulfated oligosaccharide compound according to the invention can be incorporated into an absorbent dressing based on gelling fibers, such as for example the AQUACEL® product marketed by the company CONVATEC.

[0087] Very often, when applying these dressings, the caregiver holds them in place with a bandage or covers them with a secondary element such as a second absorbent dressing or a support bandage. It is therefore useful to keep the dressing fixed to the wound so that the caregiver has their hands free to position these secondary elements. Generally speaking, any type of adhesive commonly used in dressings can be used for this purpose.

[0088] In order not to damage healthy tissue or the edges of the wound, particularly when removing the dressing, an adhesive is preferred which has the property of adhering to the skin without adhering to the wound.

[0089] Examples of such an adhesive include adhesives based on silicone or polyurethane elastomers, such as silicone or polyurethane gels, and hydrocolloid adhesives.

[0090] Such hydrocolloid adhesives are in particular made up of an elastomeric matrix based on one or more elastomers chosen from poly(styrene-olefin-styrene) block polymers in association with one or more compounds chosen from plasticizers, such as mineral oils, tackifying resins and, if necessary, antioxidants, into which is incorporated a quantity, preferably small, of hydrocolloids (from 3 to 20% by weight) such as for example sodium carboxymethylcellulose or superabsorbent polymers such as the products marketed under the name LUQUASORB® by the company BASF.

[0091] According to a preferred embodiment, the synthetic polysulfated oligosaccharide compounds used in the context of the present invention, or a galenic formulation containing them, will be integrated into a dressing comprising a hydrocolloid adhesive, said polysulfated oligosaccharide being incorporated into said adhesive preferably in an amount of between 1 and 15% by weight, more preferably between 5 and 10% by weight, relative to the weight of the adhesive.

[0092] The formulation of such hydrocolloid adhesives is well known to those skilled in the art and described for example in patent applications FR2783412, FR2392076 and FR2495473.

[0093] The use of an adhesive mesh on the non-woven fabric makes it possible in a particularly advantageous way to reduce or avoid the risk of small fibrils of the textile material coming into contact with the wound and sticking to the tissues, thus causing a painful sensation upon removal, or even an obstacle to the wound healing process.

[0094] According to a preferred embodiment of the present invention, the synthetic polysulfated oligosaccharide compound according to the invention is incorporated into such an adhesive at a concentration compatible with its solubility and its heat resistance.

[0095] Based on these criteria, 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 the adhesive.

[0096] If the absorption of this non-woven dressing is to be increased, it may be combined with an additional absorbent layer, preferably an absorbent layer that does not gel, such as in particular a compress such as that used in the URGOTUL® Duo or URGOTUL® Trio product, an absorbent hydrophilic foam, preferably a hydrophilic polyurethane foam with an absorption capacity greater than that of the non-woven material such as that used in the URGOTUL ABSORB® product.

[0097] According to a preferred embodiment, the synthetic polysulfated oligosaccharide compound according to the invention is incorporated into a non-woven dressing, associated with an additional absorbent layer, and preferably an absorbent layer which does not gel, such as in particular a compress.

[0098] According to another preferred embodiment, the synthetic polysulfated oligosaccharide compound according to the invention is incorporated into 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 an absorption capacity greater than that of the non-woven fabric.

[0099] The nonwoven and the foam can be combined by techniques well known to those skilled in the art, for example by hot calendering using a hot-melt powder based on TPU / polycaprolactone polymers.

[0100] This technique is commonly used for bonding non-woven fabrics intended for the medical market.

[0101] Finally, this foam or non-woven fabric (when used alone) can be covered with a support to protect the wound from the outside.

[0102] This support can be larger than the other layers and made adhesive continuously or discontinuously on its side coming into contact with the wound in order to optimize the support of the dressing during use, in particular if the wound is located on non-flat areas of the body.

[0103] This support and its adhesive are preferably impermeable to fluids but very permeable to water vapor in order to allow optimal management of exudates absorbed by the dressing and avoid maceration problems.

[0104] Such supports are well known to those skilled in the art and consist, for example, of breathable and waterproof films such as polyurethane films, foam / film or non-woven / film complexes.

[0105] Additives

[0106] In addition to the active agents, the synthetic polysulfated 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 in particular be chosen from perfumes, preservatives, vitamins, glycerin, citric acid, etc.

[0107] Therapeutic application

[0108] The synthetic polysulfated oligosaccharide compound according to the invention is used to prevent the recurrence of a neuroischemic wound.

[0109] According to a preferred embodiment, the synthetic polysulfated oligosaccharide compound according to the invention is used to prevent the recurrence of neuroischemic diabetic foot ulcer.

[0110] The invention also relates to a method for preventing the recurrence of a neuroischemic wound, preferably a neuroischemic diabetic foot ulcer, comprising applying a synthetic polysulfated oligosaccharide compound according to the invention, as defined above, to the skin of a patient.

[0111] The invention also relates to the use of a synthetic polysulfated oligosaccharide compound according to the invention, as defined above, for the preparation of a medicament for preventing the recurrence of a neuroischemic wound, preferably a neuroischemic diabetic foot ulcer.

[0112] According to the invention, "recurrence of diabetic foot ulcer" means any new episode of ulcer, regardless of the location and time elapsed since the previous foot ulcer.

[0113] According to the invention, the term "neuroischemic wound(s)" means the wound(s) resulting from a reduction in arterial blood supply and peripheral neurological damage. Neuroischemic wounds are classified into 3 categories: wounds with low ischemia (grade 1), wounds with moderate ischemia (grade 2), and finally wounds with critical ischemia (grade 3). The distinction between these different grades is established by the following classification, described in the publication "The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System: Risk stratification based on Wound, Ischemia, and foot Infection (Wlfl)", Joseph L. Mills Sr.MD, Michael S. Conte MD et al., Journal of Vascular Surgery.

[0114] [Table 1] IPSC grade (TcPO2 Pressure Index Ankle Systolic) 1 0.6 - 0.79 40 - 59 mm Hg 3 < 0.39 < 30 mm Hg

[0115] Table 1. Different classifications of ischemic wounds

[0116] According to a preferred embodiment, the present invention relates to grade 1, 2 or 3 neuroischemic wounds. The present invention consists here of preventing the recurrence of these wounds which often recur after their healing, in particular in a patient at high risk of recurrence, such as a patient with unbalanced diabetes, diabetic polyneuropathy, peripheral arterial disease, with deformities in the foot, with a history of ulceration or having had previous surgery in the foot.

[0117] The activity of the synthetic polysulfated oligosaccharides according to the invention has been demonstrated in the following non-limiting examples.

[0118] Examples

[0119] Example 1: Prevention of recurrence of neuroischemic diabetic foot ulcer

[0120] The aim of this study was to evaluate the preventive effect of using a sucrose octasulfate-based dressing in the recurrence of neuroischemic diabetic foot ulcers. 50 patients treated and healed after treatment with a dressing containing sucrose octasulfate (the "treatment" group) were followed for one year (after ulcer healing) to assess the level of recurrence. This "treatment" group was compared with that of a study of 42 patients (the "control" group) who were followed for one year after ulcer healing with a neutral dressing (not containing sucrose octasulfate), in exactly the same way as the patients in the "treatment" group, with the same protocol and for the same period. This is therefore a prospective comparative study comprising two arms, one arm of 50 patients and one arm of 42 patients.The 92 patients in this study were treated and monitored in the same way, in the same department, with the same care protocol, during the same calendar period, the only difference being that one group had healed after treatment with dressings containing sucrose octasulfate, while the second group had healed after treatment with dressings not containing sucrose octasulfate, such as neutral interface, hydrocellular or alginate dressings. In this study, Mepitel, Exufiber or Mepilex dressings marketed by Molnlycke were used.

[0121] Patient characteristics are presented in Table 2 below.

[0122] [Table 2]

[0123] Table 2. Patient characteristics

[0124] 1. Materials & Methods

[0125] Patients

[0126] The study was conducted on 92 patients. The inclusion criteria for patients in the study were as follows: - patients over 18 years of age diagnosed with type 1 or 2 diabetes, with a non-infected neuroischemic diabetic foot ulcer of grade IC or I IC, as defined by the University of Texas Diabetic Wound Classification System (Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound classification system. The contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care. 1998;21(5):855-9). These patients were selected to start treatment with a potassium sucrose octasulfate dressing for the "treatment" group or to start treatment with another type of dressing not containing potassium sucrose octasulfate (excluding any therapy likely to have an influence on wound oxygenation) for the "control" group.

[0127] Patients with critical limb ischemia, end-stage renal disease or dialysis, edema due to vascular, renal or cardiac disease, patients with chronic obstructive pulmonary disease (COPD) that may alter systemic oxygen saturation, patients with a stroke within the last three months, acute Charcot foot, and those with surgical revascularization within the three months prior to study entry were excluded.

[0128] Patient assessment

[0129] Neuropathy was confirmed for all patients using a 10 g Semmes-Weinstein Monofilament Test and / or a biothesiometer (Me.Te.Da. srl, Via Silvio Pellico, 4, 63074 San Benedetto del Tronto, Italy) (Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound classification system. The contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care. 1998;21(5):855-9, or Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36 Suppl 1:e3266).

[0130] TcPO2 values ​​were measured using the TCM400 measuring device (Radiometer, Copenhagen, Denmark), placing the electrode on the angiosome of the posterior tibial artery or dorsalis pedis depending on the ulcer location (Izzo V, et al., Rearfoot Transcutaneous Oximetry is a Useful Tool to Highlight Ischemia of the Heel. Cardiovasc Intervent Radiol. 2017;40(1):120-4). Patients were placed in a supine position during the 10-minute examination and asked not to move or talk. After calibration, the electrode was placed at the dorsalis pedis artery in all diabetic foot ulcers located in the toes or forefoot and at the posterior tibial artery in patients who had diabetic foot ulcers in the midfoot or hindfoot. TcPO2 values ​​were assessed on day 0, then only in patients with a new ulcer on a monthly basis and on the day of wound closure / healing.

[0131] Wound Assessment

[0132] Wound healing was assessed based on improvements in the Wollina scoring system (Wollina U, et al., Some effects of a topical collagen-based matrix on the microcirculation and wound healing in patients with chronic venous leg ulcers: preliminary observations. Int J Low Extrem Wounds. 2005;4(4):214-24), and wound area surface area at day 0 and monthly until healing. Healing was defined as complete epithelialization without any drainage, confirmed at least 10 days after wound closure was first noted (Edmonds M, et al., Sucrose octasulfate dressing versus control dressing in patients with neuroischaemic diabetic foot ulcers (Explorer): an international, multicenter, double-blind, randomized, controlled trial. Lancet Diabetes Endocrinol. 2018;6(3): 186-96)).

[0133] All patients received standard care consisting of ulcer debridement and proper offloading following the recommendations of the IWGDF guidelines (Bus SA, et al., Guidelines on offloading foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36 Suppl 1:e3274.). Diabetic foot ulcers in the treatment group were treated with a dressing containing sucrose octasulfate (UrgoStart Contact, 10 x 10 cm, Laboratoires Urgo Medical, Chenôve, France). This is a non-adherent, non-occlusive dressing with a soft contact layer composed of a polyester mesh impregnated with a lipidocolloid matrix containing sucrose octasulfate potassium salt (NOSF: nanooligosaccharide factor).Diabetic foot ulcers in the control group were treated with a dressing traditionally used in the treatment of diabetic foot ulcers, other than a dressing containing sucrose octasulfate. A senior healthcare provider followed all patients for their care on the ward by applying the dressing twice a week until wound healing and / or until the end of the study. In addition, the same clinician followed up on a monthly basis to record study variables.

[0134] Statistical analysis

[0135] The assumption of normality of all continuous variables was checked using the Shapiro-Wilk test. Normally distributed variables (Shapiro-Wilk test with p > 0.05) were reported as mean and standard deviation.

[0136] Student's t-test for paired samples was used to explore differences in TCPO2 values, Wollina score, and wound area within the octasulfate dressing treatment due to the normal distribution of the variables.

[0137] All statistical analyses were performed using SPSS Statistics for Mac OS version 25.0 (SPSS, Chicago, IL, USA). P values ​​<0.05 were considered statistically significant, with 95% confidence intervals.

[0138] 2. Results

[0139] A total of 92 patients were included in this pilot study and followed for one year. The results on ulcer recurrence are presented in Table 3.

[0140] [Table 3] 141] Table 3. Recurrence of ulcers in the 92 patients in the study

[0142] In the "treatment" group, the recurrence rate of neuroischemic diabetic foot ulcer at one year, with patients reviewed every month, is 28% while it is 66.7% in similar patients in the "control" group, followed with the same protocol but having healed with dressings other than dressings containing sucrose octasulfate. These results therefore show that a synthetic polysulfated oligosaccharide having 1 to 4 sugar units, its salts, or its complexes, more particularly sucrose octasulfate, very significantly reduces the recurrence of neuroischemic wounds.

Claims

Claims

1. Synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, for use in preventing recurrence of a neuroischemic wound.

2. Oligosaccharide for use according to claim 1 wherein said neuroischemic wound is a neuroischemic diabetic foot ulcer.

3. Oligosaccharide for use according to any one of the preceding claims, in a patient with unbalanced diabetes, diabetic polyneuropathy, peripheral arterial disease, with deformities in the foot, with a history of ulceration and / or having had previous surgery on the foot.

4. Oligosaccharide for its use according to any one of the preceding claims, characterized in that its concentration is greater than or equal to 70 mg / mL, preferably 100 mg / mL, and more preferably between 100 and 1000 mg / mL.

5. Oligosaccharide for its use according to any one of the preceding claims, characterized in that it comprises 1 to 3 ose units, more particularly 1 or 2 ose units preferably chosen from pentoses and hexoses, as well as the salts and complexes of these compounds.

6. Oligosaccharide for its use according to any one of the preceding claims, characterized in that it is chosen from: - the potassium salt of sucrose octasulfate; - the silver salt of sucrose octasulfate; and - the hydroxyaluminum complex of sucrose octasulfate, preferably the potassium salt of sucrose octasulfate.

7. Oligosaccharide for its use according to any one of the preceding claims, characterized in that it is implemented in the form of a composition such as a gel, a solution, an emulsion, a cream, granules or capsules allowing application directly to the wound.

8. A pharmaceutical composition comprising a synthetic polysulfated oligosaccharide having 1 to 4 monosaccharide units, its salts, or its complexes, for use in preventing recurrence of a neuroischemic wound, preferably a neuroischemic diabetic foot ulcer.

9. A dressing comprising a synthetic polysulfated oligosaccharide having 1 to 4 sugar units, its salts, or its complexes, in particular a potassium salt of sucrose octasulfate for preventing recurrence of a neuroischemic wound, preferably a neuroischemic diabetic foot ulcer.

10. A dressing according to claim 9, comprising a textile weave coated with an elastomeric matrix, said matrix comprising said synthetic polysulfated oligosaccharide.

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