Composition comprising a vasoconstrictor for preventing peripheral neuropathies

Abstract

The invention relates to a composition in a form suitable for topical administration, comprising, in a physiologically acceptable medium, a vasoconstrictor. The invention is characterized in that the composition comprises a vasoconstrictor selected from adrenergic agonists, for use in the prevention and / or treatment of peripheral neuropathies regardless of their cause, and more particularly those induced by chemotherapy during the treatment of cancer.

Description

COMPOSITION INCLUDING A VASOCONSTRICTOR TO PREVENT PERIPHERAL NEUROPATHIES TECHNICAL FIELD The invention relates to the field of pharmaceutical compositions in a form suitable for topical administration. More particularly, it relates to a composition comprising a vasoconstrictor for use in the prevention of chemotherapy-induced peripheral neuropathies during cancer treatment. Neurotoxicity from cancer treatments is the most frequent limiting factor after hematological toxicity. Peripheral nerve damage accounts for the majority of neurological complications related to chemotherapy toxicity. These complications result from direct toxic damage to the axon or nerve endings, or from demyelination. All nerve fibers are susceptible to damage, including sensory, motor, and autonomic nerve fibers. Symptoms present as a predominantly sensory or sensorimotor distal polyneuritis which is generally dose-dependent and regressive upon cessation of treatment. However, persistent neuropathy several years after stopping chemotherapy is common. To this end, as an illustrative example, a population-based cohort study (n=884 survivors of early-stage breast cancer without recurrence and who were treated with taxanes, versus 1768 control women with no history of cancer) conducted in Sweden shows the persistence of neurological signs in nearly half of the cancer patients more than 3 years after stopping chemotherapy (Engvall et al., “Persistent neuropathy among early-stage breast cancer survivors in a population-based cohort”, Br J Cancer, 2021 Aug; 125(3):445-457). The medications responsible for this toxicity include: - spindle poisons which are periwinkle alkaloids and their derivatives (vincristine, vinblastine, vindesine, vinorelbine), taxanes such as paclitaxel and, to a lesser extent, docetaxel, and epothilones; - platinum salts such as cisplatin and especially oxaliplatin; - certain targeted therapies such as bortezomib, thalidomide and other "imides". Symptoms vary and can take the form of: - tingling or a feeling of paralysis (paresthesia), affecting the hands, feet and sometimes the face; - unusual sensations, independent of a painful stimulus, spontaneous or provoked (friction, pressure...). They resemble burning, electric shocks or shooting pains; - sensation of numbness or decreased sensitivity, such as, for example, the perception of the temperature of a bath; - balance problems, particularly when walking, accompanied or not by a feeling of dizziness; or - tremors, cramps or muscle weakness. Some patients are more particularly exposed to these peripheral effects, such as alcoholics, diabetics, or those with liver function abnormalities or who have already received neurotoxic chemotherapies. The occurrence of severe peripheral neurotoxicity requires a dose reduction and if it persists, discontinuation of anticancer treatment should be considered. PREVIOUS TECHNIQUE No therapeutic prevention to date can avoid the development of these toxic neuropathies, non-innocent side effects which sometimes justify a change in therapeutic strategy when other molecules are available or a reduction in dosage, thus limiting the survival gain of these patients. Since neuropathies induced by anticancer drugs are often dose-dependent and cumulative, reducing the administered doses or even interrupting treatment often remains the best option to reduce symptoms. Numerous therapies, both preventive and curative, have been tested without much success, and there currently appears to be no drug approved by health authorities for this indication. Among the treatments tested, the following compounds can be mentioned for example. Acetyl-L-carnitine (ALC) has shown a neuroprotective role in animals, but two clinical studies (Hershman et al., "Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy", J Clin Oncol Off J Am Soc Clin Oncol. 10 Jul 2013, 31 (20):2627-33; Hershman et al. "Two-Year Trends of Taxane-induced Neuropathy in Women Enrolled in a Randomized Trial of Acetyl-L-Carnitine (SWOG S0715)", J Natl Cancer Inst. 18 Jan 2018) evaluating the impact of ALC supplementation in breast cancer patients treated with taxanes for 24 weeks showed no benefit. Worse still, a worsening of symptoms was even shown compared to the placebo. Glutathione is a tripeptide involved in numerous detoxification reactions, notably by eliminating reactive oxygen species, including free radicals that form under oxidative stress. Initial trials However, encouraging results were contradicted by a large study (Leal et al., "North Central Cancer Treatment Group / Alliance trial N08CA-the use of glutathione for prevention of paclitaxel / carboplatin-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled study. Cancer. June 15, 2014, 120(12): 1890-7) involving 185 patients treated with the paclitaxel / carboplatin combination. N-acetylcysteine ​​(NAC) is a non-essential amino acid that, in animals, blocks neuronal apoptosis by activating the p53 signaling pathway and reduces cisplatin-induced sensory neuropathy. However, electrophysiological tests (Lin et al., "N-acetylcysteine ​​has neuroprotective effects against oxaliplatin-based adjuvant chemotherapy in colon cancer patients: preliminary data," Support Care Cancer Off J Multinatl Assoc Support Care Cancer, May 2006, 14(5):484-7) demonstrate no benefit of NAC supplementation in preventing oxaliplatin-induced neuropathy in humans. Vitamin E (or alpha-tocopherol) is a fat-soluble vitamin believed to protect neuronal cell bodies from DNA damage and the accumulation of toxins. However, a large study (Huang et al., "Vitamin E does not decrease the incidence of chemotherapy-induced peripheral neuropathy: a meta-analysis," Contemp Oncol Poznan Pol. 2016, 20(3):237-41) conducted on 207 patients treated with taxanes, platinum salts, or a combination of these two classes of antineoplastic agents, showed no difference between the vitamin E-treated arm and the placebo arm in terms of incidence, time to onset, or improvement of neuropathy symptoms. Org 2766 is a small peptide derived from the corticotropic hormone ACTH (Adrenocorticotropic Hormone, also known as adrenocorticotropic hormone or adrenocorticotropin) but lacking adrenocorticotropic and melanotropic effects. Initial encouraging results were refuted by a larger study (Koeppen et al., "Lack of neuroprotection by an ACTH (4-9) analogue" ("A randomized trial in patients treated with vincristine for Hodgkin's or non-Hodgkin's lymphoma," J Cancer Res Clin Oncol, March 2004, 130(3): 153-60)) evaluating the efficacy of this compound in preventing vincristine-induced neuropathy in 150 patients with lymphoma (Hodgkin's and non-Hodgkin's). This study showed no difference compared to the placebo group. Glutamate and glutamine have been proposed as neuroprotective agents, but clinical studies (Loven et al., "Long-term glutamate supplementation failed to protect against peripheral neurotoxicity of paclitaxel", Eur J Cancer Care (Engl), Jan 2009, 18(l):78-83; Amara S., "Oral glutamine for the prevention of chemotherapy-induced peripheral neuropathy", Ann Pharmacother. Oct 2008, 42(10): 1481-5) do not show any benefit. Omega-3 fatty acids are polyunsaturated fatty acids found in cell membrane phospholipids, including those of the central and peripheral nervous systems. Promising results were shown in a study (Ghoreishi et al., "Omega-3 fatty acids are protective against paclitaxel-induced peripheral neuropathy: a randomized double-blind placebo controlled trial," BMC Cancer. August 15, 2012, 12:355) of 57 patients treated with paclitaxel, as well as in a second study (Esfahani et al., "The effect of n-3 polyunsaturated fatty acids on incidence and severity of oxaliplatin-induced peripheral neuropathy: a randomized controlled trial," Biomark Res. 2016, 4:13) of 71 patients treated with oxaliplatin. These results, however, still need to be confirmed in larger studies. All-trans retinoic acid (ATRA), or tretinoin, is the acidic form of vitamin A. Retinoids play an important role in several biological functions, including epithelial and neuronal differentiation. By binding to the RAR-J32 receptor, ATRA appears to stimulate neurite growth and nerve regeneration in rats with peripheral nerve damage. However, in a study (Arrieta et al., "Retinoic acid reduces chemotherapy-induced neuropathy in an animal model and patients with lung cancer," Neurology. 6 Sept 2011, 77(10):987-95) conducted on 95 lung cancer patients treated with cisplatin and paclitaxel, no statistically significant difference was found between the ATRA group and the placebo group. Goshajinkigan (GJG) is a Japanese mixture of 10 herbs used to relieve various symptoms such as numbness, pain associated with diabetic neuropathy, paresthesia, or dysesthesia. A study (Oki E et al., "Preventive effect of Goshajinkigan on peripheral neurotoxicity of FOLFOX therapy (GENIUS trial): a placebo-controlled, double-blind, randomized phase III study," Int J Clin Oncol. August 2015, 20(4):767-75) conducted on 182 patients treated with oxaliplatin for colorectal cancer showed no benefit from this treatment. Intravenous calcium and magnesium infusions have been proposed for the prevention of oxaliplatin-induced neuropathies. However, their development was halted due to a lack of benefit and a risk of reduced antitumor efficacy of oxaliplatin (Loprinzi et al., "Phase III randomized, placebo-controlled, double-blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB / Alliance)", J Clin Oncol Off J Am Soc Clin Oncol. 1 Apr 2014, 32(10):997-1005; Jordan et al., "Calcium and Magnesium Infusions for the Prevention of Oxaliplatin-Induced Peripheral Neurotoxicity: A Systematic Review", Oncology. 2016, 90(6):299-306). Amifostine is an organic thiophosphate used as a cytoprotective adjuvant that potentially blocks the hematological, nephrological, and neurological toxicity of alkylating agents. Clinical trial results (Spâthe et al., "Neuroprotection with amifostine in the first-line treatment of advanced ovarian cancer") support this finding. with carboplatin / paclitaxel-based chemotherapy--a double-blind, placebo-controlled, randomized phase II study from the Arbeitsgemeinschaft Gynâkologische Onkologoie (AGO) Ovarian Cancer Study Group », Support Care Cancer Off J Multinatl Assoc Support Care Cancer, Oct 2005, 13( 10):797-805) do not show sufficient benefit and its use is therefore not recommended in this indication. Carbamazepine is an anticonvulsant that antagonizes voltage-gated sodium channels. Its efficacy in treating neuropathic pain (particularly of diabetic origin) led to its marketing authorization for this indication. However, only one study (von Delius et al., "Carbamazepine for prevention of oxaliplatin-related neurotoxicity in patients with advanced colorectal cancer: final results of a randomised, controlled, multicenter phase II study," Invest New Drugs, April 2007, 25(2):173-80) evaluates the efficacy of this anticonvulsant in humans in preventing oxaliplatin-induced neuropathy in patients with advanced colorectal cancer: it shows no benefit compared to the placebo group. Gabapentin and pregabalin are two GABA (gamma-aminobutyric acid) analogs that have received marketing authorization for the treatment of neuropathic pain. These two molecules have notably demonstrated their efficacy in reducing the incidence of chronic post-surgical pain. However, only one study (Mitchell et al., "Addition of gabapentin to a modified FOLFOX regimen does not reduce oxaliplatin-induced neurotoxicity," Clin Colorectal Cancer, July 2006, 6(2):146-51) evaluates the preventive efficacy of gabapentin in oxaliplatin treatments: it shows no benefit, either in terms of the severity of neuropathies or in terms of symptom reversibility. Similarly, a phase 3 study (de Andrade et al.), “Pregabalin for the Prevention of Oxaliplatin-Induced Painful Neuropathy: A Randomized, Double-Blind Trial”, The Oncologist, Oct 2017, 22(10):1154-1105) double-blind, conducted with pregabalin in 199 patients treated with oxaliplatin for colorectal cancer, did not show efficacy. Amitriptyline is a tricyclic antidepressant of the imipramine type, inhibiting the presynaptic reuptake of serotonin, dopamine, and norepinephrine. It is a standard treatment for refractory pain such as neuropathic pain and neuralgia. Its analgesic effects, the mechanism of action of which is independent of its antidepressant effects, appear to result from increased availability of the synoptic monoamines serotonin and norepinephrine within the pain-modulating systems of the central nervous system. However, amitriptyline has not demonstrated any beneficial effect in the prevention of neuropathies in one study (Kautio et al., "Amitriptyline in the prevention of chemotherapy-induced neuropathic symptoms", Anticancer Res. July 2009, 29(7):2601-6) including 99 patients treated with vinca alkaloids, platinum salts or taxanes. Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant. It increases serotonin and norepinephrine levels within the synoptic cleft of descending inhibitory pathways in the spinal and supraspinal regions. Its efficacy has been demonstrated in the treatment of neuropathic pain. Despite several studies (Durand et al., "Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial," Ann Oncol Off J Eur Soc Med Oncol, Jan 2012;23(l):200-5; Zimmerman et al.),, “MCI 104: a pilot randomized, placebo-controlled, double-blind study of venlafaxine to prevent oxaliplatin-induced neuropathy”, Support Care Cancer Off J Multinatl Assoc Support Care Cancer, March 2016, 24(3): 1071-8), its benefit in chemotherapy-induced neuropathies is not considered sufficient to be recommended, particularly by the American Cancer Society. We also know of patent document WC03 / 099289, which discloses a composition including an adrenergic agonist such as brimonidine and its use in treating neuropathic pain, including neuropathic pain following cancer treatment, targeting the nerve itself. The results obtained indicate that a variety of α-adrenergic agonists with different activity profiles and bioavailability of α-1 and α-2 receptors can be effective peripheral analgesic agents when α-2A receptor activation is prevented. We can also cite patent document W02006 / 01 1915 which relates to a composition which can be used in the form of a cream or a gel comprising (a) a first component which may be an adrenergic agonist such as brimonidine and (b) a second component, for the treatment of neuropathic pain, as well as patent document WO2018 / 129313 which describes a topical formulation comprising detomidine (0.001-3 wt%), in which detomidine can be replaced by brimonidine, and its use for the treatment of neuropathic pain. Furthermore, among existing treatments, the use of chilled gloves and socks is sometimes recommended. Its effectiveness, albeit limited, has been demonstrated in a Dutch study involving 180 patients divided into two equal groups: one group wore gloves and socks, and the other wore nothing (Beijers et al., "Multicenter randomized controlled trial to evaluate the efficacy and tolerability of frozen gloves for the prevention of chemotherapy-induced peripheral neuropathy," Ann Oncol. 2020 Jan; 31(1): 131-136). A statistically significant difference was shown in neuropathy symptoms and patient quality of life. The main drawback of this approach is poor tolerance of the gloves and socks, with one-third (1 / 3) of patients unable to tolerate the cold and prematurely withdrawing from the study for this reason. Currently, there is no drug treatment that effectively prevents chemotherapy-induced peripheral neuropathy during cancer treatment. Cooling gloves and socks appear to offer some benefit but are too poorly tolerated to be considered a standard treatment. The challenge is therefore to identify a new pharmacological mechanism, excluding those already tested, and capable of preventing (and treating) neurological toxicity, particularly in the case of chemotherapy. TECHNICAL PROBLEM Considering the above, one problem that the present invention aims to solve is to develop an optimized topical formulation based on an active ingredient never before proposed for such use for the prevention of peripheral neuropathies, whatever their cause and more particularly those induced by chemotherapy. This product would therefore make it possible to respond more specifically to a significant unmet need for both oncologists and cancer patients. TECHNICAL SOLUTION The solution to this problem posed has as its first objective a composition in a form suitable for topical administration comprising, in a physiologically acceptable medium, a vasoconstrictor, characterized in that said vasoconstrictor is chosen from among the adrenergic agonists, for its use in the prevention of chemotherapy-induced peripheral neuropathies during the treatment of cancer. BENEFITS PROVIDED The mechanism of action of the composition implemented within the framework of the invention in the prevention of peripheral neuropathy advantageously consists of a vasoconstriction of the cutaneous capillaries resulting in a decrease in cutaneous blood flow in the treated area and therefore a reduction in the dose of chemotherapy arriving at that place (pharmacokinetic exclusion). The topical composition developed according to the invention, comprising a vasoconstrictor and in particular brimonidine or its salts, is preferably in the form of a hydrogel. While this active ingredient, thus formulated, is already known, for example, for skin protection, an unexpected effect has been demonstrated by the Applicant regarding the use of such a product in the context of chemotherapy for the prevention of neuropathies, as illustrated in Example 3. On the contrary, there are published tests (Fuchs et al., "Heat, but not mechanical hyperalgesia, following adrenergic injections in normal human skin," Pain 90 (2001) 15-23) that show that the use of a vasoconstrictor lowers the threshold of Heat sensitivity means that pain is felt at a lower temperature. Since heat and pain are transmitted by the same fibers, it seems surprising that a vasoconstrictor could reduce neuropathy, as one would expect a worsening of symptoms due to the lowering of the pain threshold. A pilot clinical trial was also conducted on patients (6) beginning taxane chemotherapy as part of cancer treatment. This study confirmed the potential of such a vasoconstrictor composition according to the invention in the prevention and treatment of chemotherapy-induced peripheral neuropathies, as illustrated in Example 4. Compared to refrigerated gloves or socks, the solution thus proposed according to the invention solves the major problem of cold intolerance which excludes access to this treatment for one third (1 / 3) of patients. The vasoconstrictor composition developed according to the invention has also demonstrated its safety in two other clinical trials: it does not expose to problems of local intolerance and its passage into the general circulation is insignificant, reducing the risk of adverse effects or drug interaction to virtually zero, as illustrated in example 5. For this purpose, and unlike refrigerated gloves and socks which can only be used during chemotherapy infusion, the use of such a topical product allows for multiple administrations outside the hospital setting to cover the entire period during which the chemotherapy will be present in the bloodstream. DESCRIPTION OF IMPLEMENTATION METHODS The invention relates to a composition in a form suitable for topical administration comprising, in a physiologically acceptable medium, a vasoconstrictor. A physiologically acceptable medium is defined as a medium that is compatible and suitable for use in contact with human and animal cells, particularly with skin, mucous membranes and / or hair, without toxicity, irritation, undue allergic response and the like, and proportionate to a reasonable benefit / risk ratio. A physiologically acceptable medium according to the invention may include any excipient known and used in the pharmaceutical field, compatible with a vasoconstrictor used in the composition according to the invention. Of course, a person skilled in the art will take care to choose any compound(s) to be added to the composition used according to the invention in such a way that the advantageous properties intrinsic to the present invention are not, or are not substantially, altered by the proposed addition. Their concentration is also chosen so that it does not impair the advantageous properties of the compositions used according to the invention. The composition according to the invention is characterized in that it comprises a vasoconstrictor selected from adrenergic agonists, for its use in the prevention of chemotherapy-induced peripheral neuropathies during the treatment of cancer, or whatever the cause. The term "prevention" refers to the administration of the composition with the aim of avoiding or delaying the onset of chemotherapy-induced peripheral neuropathy during cancer treatment in a healthy subject (in terms of peripheral neuropathies) or one at known risk, for example, having already experienced peripheral neuropathies. The composition according to the invention is preferably administered to patients undergoing anti-cancer treatment by chemotherapy who have experienced or are likely to experience chemotherapy-induced peripheral neuropathies during cancer treatment, more preferably human beings. Adrenergic agonists are active ingredients whose effects are similar to stimulation of the sympathetic nervous system. The adrenergic agonists preferentially used in the composition according to the invention are alpha-1 and / or alpha-2 adrenergic agonists, more preferentially targeting essentially alpha-2 receptors. By adrenergic agonist targeting essentially alpha-2 receptors, we mean, in addition to "pure" alpha-2 agonists, also mixed molecules (which are therefore not "pure" alpha-2s) whose activity is mainly alpha-2 but also exhibiting activity at the level of alpha-1 receptors. The adrenergic agonists most preferably used in the composition according to the invention are chosen from brimonidine or its salts. Pharmaceutically acceptable salts are defined as salts of a compound of interest that are safe and effective for topical use in mammals and possess a desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the specified compounds. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodine, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, ptoluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)).Some compounds used in the present invention can form pharmaceutically acceptable salts with different. Amino acids. Suitable base salts include, but are not limited to, salts of aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine. For a review of pharmaceutically acceptable salts, see BERGE et al., 66 J. PHARM. SCI. 1-19 (1-77). In this context, the term "hydrate" refers to a compound of interest, or a pharmaceutically acceptable salt thereof, that further comprises a stoichiometric or non-stoichiometric amount of water bound to it by non-covalent intermolecular forces. Preferably, the brimonidine used in the composition according to the invention is brimonidine tartrate. The composition used according to the invention comprises the adrenergic agonist, more preferably the alpha-2 adrenergic agonist, and even more preferably brimonidine or its salts, more preferably still brimonidine tartrate, at a concentration preferably between 0.15% and 3.00% by weight of the total weight of the composition (w / w), more preferably between 0.50% and 2.50% w / w, even more preferably between 0.75% and 1.50% w / w, more preferably still 1.00% or 1.50% w / w. For your information, regarding brimonidine, for example, the concentration can be expressed as a base and as a salt. Most often, the concentration is expressed as a salt; for a brimonidine tartrate concentration of 0.5% or 1.5%, the concentration expressed as brimonidine base is 0.33% and 1%, respectively. The concentration of vasoconstrictor, preferably brimonidine, more preferably brimonidine tartrate, and the dose thus applied is advantageously adapted according to the application site. The composition suitable for topical administration used according to the invention is preferably in the form of ointments, emulsions, creams, milks, ointments, powders, soaked swabs, syndets, solutions, gels, sprays, foams, suspensions, sticks. Preferably, the composition used according to the invention is in the form of a hydrogel, oil-in-water emulsion or water-in-oil emulsion, more preferably hydrogel and oil-in-water emulsion. Preferably, the composition used according to the invention is in the form of a hydrogel in a solvent-based phase comprising: - polyethylene glycol in combination with propylene glycol and / or dimethyl sulfoxide (DMSO); - a hydrophilic film-forming agent selected from a Polyvinylpyrrolidone / Vinyl Acetate copolymer, polyvinylpyrrolidone in a non-crosslinked form or acetate, taken alone or in combination; and - glycerin. The hydrogel composition preferably used according to the invention comprises a Polyvinylpyrrolidone / Vinyl Acetate copolymer as a hydrophilic film-forming agent. The hydrogel composition preferably used according to the invention comprises polyethylene glycol at a concentration of between 5-20%, more preferably 10%, by weight of the total weight of the composition in combination with propylene glycol at a concentration of between 10-30%, more preferably 20%, by weight of the total weight of the composition. The hydrogel composition preferably used according to the invention further comprises a gelling agent selected from xanthan gum and hydroxyethylcellulose (HEC), taken alone or in combination. The composition according to the invention is thus characterized by its use in the prevention and / or treatment of peripheral neuropathies, whatever their cause and in particular those induced by chemotherapy during the treatment of cancer. Neuropathies prevented by the use of the composition according to the invention preferentially present themselves in the form of tingling or paresthesia, electric shocks or shooting pains independent of a stimulus, numbness or decreased sensitivity, balance disorder, particularly when walking, accompanied or not by a feeling of dizziness, tremors, cramps or muscle weakness, or even sensations of heat and burning, particularly in the extremities. The composition is preferably used according to the invention to prevent or treat chemotherapy-induced peripheral neuropathies resulting more particularly from treatment with: - platinum derivatives chosen from cisplatin and oxaliplatin, preferably oxaliplatin; - spindle poisons: a) periwinkle alkaloids and their derivatives chosen from vincristine, vinblastine, vindesine and vinorelbine, or b) taxanes chosen from paclitaxel and docetaxel; - targeted therapies chosen from among bortezomib and imides, preferably thalidomide. EXAMPLES The present invention will now be illustrated by means of the following examples: Example 1: Hydrogel formulations with different concentrations of brimonidine tartrate (*) 0.5, 0.75, 1.0 and 1.5% Brimonidine Tartrate correspond respectively to 0.33, 0.50, 0.67 and 1% Brimonidine base. Example 2: Emulsion formulations Example 3: A 58-year-old patient is being treated for breast cancer with a combination of IV paclitaxel at 80 mg / m² 2 every week and cyclophosphamide IV at 600 mg / m² 2 every three weeks. To reduce the risk of neuropathy, this treatment is accompanied by the use of refrigerated socks and gloves, worn for 1 hour 30 minutes during each chemotherapy session. After two chemotherapy sessions, the patient experienced tingling in the fingers of both hands. From the third chemotherapy session onwards, she applies to her hands, in particular to the back of the hand and the palms, in addition to the refrigerated gloves, a hydrogel composition according to the invention (see example 1) comprising 1% brimonidine tartrate at a rate of two applications per day on the day of chemotherapy and the two following days. Surprisingly, the tingling not only did not worsen but disappeared completely and did not reappear during subsequent sessions until the end of the 12 planned sessions.

[0001] Example 4: A phase 2a, single-center, open-label, subindividual study with approximately 30 patients included was conducted to confirm the good tolerance of a hydrogel composition according to the invention when applied to the hands and feet and its ability to prevent peripheral neuropathy in breast cancer patients treated with taxanes, a chemotherapy that frequently leads to this type of neurological disorder. For information purposes, neuropathies are present in 80% of patients treated with taxanes (by infusion of either Docetaxel administered every 3 weeks for a total of 4 cycles, or Paclitaxel administered weekly for 12 cycles). Patients were included at the start of treatment with taxanes and followed up during the 12 treatment cycles, as well as 3 months after stopping treatment. Each patient received the study product, namely the hydrogel composition containing 1.5% brimonidine tartrate (see Example 1), applied to one hand and one foot twice daily for three days, starting on the first day of each taxane treatment cycle and continuing for the following two days (the elimination half-life of paclitaxel being approximately 24 hours) throughout the duration of taxane treatment (usually 12 weekly cycles). The patients themselves applied the composition (wearing a glove on their dominant hand) to the areas dorsal and palmoplantar of the foot and hand on one side of the body, including the fingers, toes and around the nails. Assessments of taxane-induced peripheral neuropathy include clinical evaluations by an oncologist, an examination by a neurologist, patient questionnaires completed by a nurse, and instrumental and objective neurophysiological measurements conducted by trained personnel. More specifically, the following parameters were analyzed: - Clinical scores of motor and sensory peripheral neuropathy using the CTCAE v5.0 nomenclature: distribution of the different severities at each visit, by side (treated / untreated), and by location (hand / foot); proportion of patients with a grade 2 and above during the study, all visits combined, by side (treated / untreated), and by location (hand / foot); - Modified total neuropathy score (TNS score): average total score at each visit, by side (treated / untreated), and by location (hand / foot); - Patient questionnaire for peripheral neuropathy (CIPN PRO questionnaire, derived from the validated CIPN-20 questionnaire): distribution of positive responses at each visit, by side (treated / untreated), and by location (hand / foot); - Reduction in the dose of taxane chemotherapy: Proportion of patients requiring a dose reduction of taxanes during the 12-cycle treatment period; and - Instrumental measurements of heat sensitivity (hot / cold) (QST), pressure sensitivity (Von Frey filaments), vibration sensitivity (Sensiometer), electrochemical conductance test (Sudoscan): mean values, median values ​​per visit, per side (treated / untreated), and per location (hand / foot), variation from Baseline. Based on the results obtained, this study confirms the benefit of using a composition according to the invention based on an adrenergic agonist vasoconstrictor in the prevention of chemotherapy-induced neuropathies. In particular, this study confirmed the potential for preventing neuropathy through applications of the hydrogel composition according to the invention, notably through instrumental measurements highlighting a significant difference in the measured parameters. Example 5: A phase 1 study was conducted in 36 healthy volunteers with a hydrogel composition according to the invention based on brimonidine tartrate at different concentrations (see example 1) to study the local and systemic tolerance as well as the pharmacokinetics of the product. In a first group of 20 volunteers, 4 increasing concentrations of the gel (between 0.5 and 1.5% brimonidine tartrate) were applied daily to mini areas of 4 cm2 located on the chest of the volunteers. The treatment was administered for three weeks and the investigator scored any effects observed on the treatment areas. Based on the results obtained, no local reaction was observed and the score therefore remained zero for all volunteers throughout the duration of the study. In a second group of 8 healthy volunteers, 2 g of the 1% gel according to the invention were applied daily for 5 consecutive days to a surface area of ​​1000 cm² 2 corresponding to the entire face, chest and upper back. Blood samples were taken to characterize the pharmacokinetic profile of the active ingredient on day 1, after the first application, on day 3 and on day 5 after the last application. Based on the results obtained, no local reactions were observed, confirming the good skin tolerance of the tested product. Furthermore, blood tests showed low, often unquantifiable, levels of the active ingredient, confirming negligible systemic exposure and the absence of risk of systemic side effects or drug interactions. In a final group of 8 volunteers, the 1.5% gel according to the invention was applied twice daily for 5 days to both hands at a concentration of 2 mg / cm². 2 , dose usually recommended for topical application. Initially, the product was applied and the hands remained free. In a second step, both hands were treated and then covered with occlusive gloves for a period of 2 hours after application of the product according to the invention. According to the results thus obtained, no local intolerance reaction was observed in the two experiments, confirming the good tolerance of the product according to the invention.

Claims

DEMANDS 1. Composition in a form adapted for topical administration comprising, in a physiologically acceptable medium, a vasoconstrictor, characterized in that said vasoconstrictor is selected from adrenergic agonists, for its use in the prevention of chemotherapy-induced peripheral neuropathies during the treatment of cancer.

2. Composition for its use according to claim 1, characterized in that the chemotherapy results from treatment by: - platinum derivatives chosen from cisplatin and oxaliplatin, preferably oxaliplatin; - spindle poisons: a) periwinkle alkaloids and their derivatives chosen from vincristine, vinblastine, vindesine and vinorelbine, or b) taxanes chosen from paclitaxel and docetaxel; - targeted therapies chosen from among bortezomib and imides, preferably thalidomide.

3. Composition for its use according to any one of the preceding claims, characterized in that the neuropathies prevented present themselves in the form of tingling, or paresthesia, electric shocks or shooting pains independent of a stimulus, numbness or decreased sensitivity, balance disorder, particularly when walking, with or without a feeling of dizziness, tremors, cramps or muscle weakness, sensations of heat and burning, particularly in the extremities.

4. Composition for its use according to any one of the preceding claims, characterized in that the adrenergic agonists are adrenergic agonists essentially targeting alpha-2 receptors.

5. Composition for its use according to claim 4, characterized in that the adrenergic agonists are selected from brimonidine or its salts, preferably brimonidine tartrate.

6. Composition for its use according to any one of the preceding claims, characterized in that the composition is in the form of a hydrogel, oil-in-water emulsion or water-in-oil emulsion, preferably hydrogel and oil-in-water emulsion.

7. Composition for its use according to claim 6, characterized in that it is in the form of a hydrogel in a solvent-based phase comprising: - polyethylene glycol in combination with propylene glycol and / or dimethyl sulfoxide (DMSO); a hydrophilic film-forming agent selected from a polyvinylpyrrolidone / vinyl acetate copolymer, polyvinylpyrrolidone in non-crosslinked or acetate form, taken alone or in combination; and - glycerin.

8. Composition for its use according to claim 7, characterized in that it comprises a Polyvinylpyrrolidone / Vinyl Acetate copolymer as a hydrophilic film-forming agent.

9. Composition for its use according to any one of claims 7 or 8, characterized in that it comprises polyethylene glycol at a concentration of between 5-20%, preferably 10%, by weight of the total weight of the composition in combination with propylene glycol at a concentration of between 10-30%, preferably 20%, by weight of the total weight of the composition.

10. Composition for its use according to any one of claims 7 to 9, characterized in that it further comprises a gelling agent selected from xanthan gum and hydroxyethylcellulose (HEC), taken alone or in combination. 1 1. Composition for its use according to any one of the preceding claims, characterized in that it comprises the adrenergic agonist at a concentration of between 0.15% and 3.00% by weight of the total weight of the composition, preferably between 0.50% and 2.50% w / w, more preferably between 0.75% and 1.50% w / w, even more preferably 1.00% or 1.50% w / w.

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