COMPOSITION INCLUDING A VASOCONSTRICTOR TO PREVENT AND / OR TREAT PERIPHERAL NEUROPATHIES AND / OR NEUROPATHIC PAIN

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 and / or neuropathic pain, whatever their cause, and in particular those induced by chemotherapy during cancer treatment.

Description

Title of the invention: Composition comprising a vasoconstrictor for preventing and / or treating peripheral neuropathies and / or neuropathic pain technical field

[0001] 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 and / or treatment of peripheral neuropathies and / or neuropathic pain, particularly induced by chemotherapy during cancer treatment.

[0002] Neurotoxicity from anticancer treatments is the most frequent limiting factor after hematological toxicity. Peripheral nerve damage accounts for the majority of neurological damage related to chemotherapy toxicity. This damage results 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 fibers.

[0003] The symptoms present themselves in the form of a distal polyneuritis with predominantly sensory or sensorimotor symptoms which is generally dose-dependent and regressive upon cessation of treatment.

[0004] Nevertheless, persistent neuropathy several years after stopping chemotherapy is common.

[0005] To this end, by way of illustrative example, a population-based cohort study (n = 884 survivors of early-stage breast cancer without recurrence and who were treated with taxanes, against 1768 control women with no history of cancer) conducted in Sweden shows the persistence of neurological signs in almost 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).

[0006] The drugs responsible for this toxicity include, in particular:

[0007] - 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;

[0008] - platinum salts such as cisplatin and especially oxaliplatin;

[0009] - certain targeted therapies such as bortezomib, thalidomide and other "imides".

[0010] The symptoms are variable and may take the form of:

[0011] - tingling or a feeling of paralysis (paresthesia), affecting the hands, the feet and sometimes the face;

[0012] - unusual pains, independent of a painful stimulus, spontaneous or caused (friction, pressure...). They resemble burns, electric shocks or shooting pains;

[0013] - sensation of numbness or decreased sensitivity, such as, by example, the perception of the temperature of a bath;

[0014] - balance disorder, particularly when walking, whether accompanied or not by a a dizzying impression; or even

[0015] - tremors, cramps or muscle weakness.

[0016] Some patients are more particularly exposed to these peripheral damages such as alcoholic patients, diabetics, or those with liver function abnormalities or who have already received neurotoxic chemotherapies.

[0017] The occurrence of severe peripheral neurotoxicity requires a dose reduction and if it persists, discontinuation of anticancer treatment should be considered. Previous technique

[0018] No therapeutic prevention to date makes it possible to 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.

[0019] 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.

[0020] Many therapies, both preventive and curative, have been tested without much success and there does not appear to be any drug approved by health authorities for this indication today.

[0021] Among the treatments tested, the following compounds can be mentioned for example.

[0022] 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 taken for 24 weeks showed no benefit. Worse, a worsening of symptoms was even observed compared to the placebo.

[0023] Glutathione is a tripeptide involved in numerous detoxification reactions, notably by eliminating reactive oxygen species, including free radicals that form under oxidative stress. However, initial encouraging trials 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.

[0024] 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) do not demonstrate any benefit of NAC supplementation in preventing oxaliplatin-induced neuropathy in humans.

[0025] Vitamin E (or alpha-tocopherol) is a fat-soluble vitamin that is thought to protect neuronal cell bodies against 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 arm treated with Vitamin E and the arm treated with placebo in terms of incidence, time to onset, or improvement of neuropathy symptoms.

[0026] Org 2766 is a small peptide derived from the corticotropic hormone ACTH (Adrenocorticotropic Hormone) 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.

[0027] 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(1):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.

[0028] Omega-3 fatty acids are polyunsaturated fatty acids present 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, and 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.

[0029] 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-

[32] 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 in 95 lung cancer patients treated with cisplatin and paclitaxel, no statistically significant difference was shown between the ATRA group and the placebo group.

[0030] 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 in 182 patients treated with oxaliplatin for colorectal cancer showed no benefit from this treatment.

[0031] Intravenous calcium and magnesium have been proposed for the prevention of oxaliplatin-induced neuropathy. However, their development was halted due to a lack of benefit and the 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 neuropathy”). 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).

[0032] 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 (Spathe et al., "Neuroprotection with amifostine in the first-line treatment of advanced ovarian cancer 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 for this indication.

[0033] Carbamazepine is an anticonvulsant that is an antagonist of voltage-gated sodium channels. Its efficacy in the treatment of neuropathic pain (particularly of diabetic origin) led to its obtaining Marketing Authorization (MA) 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 the prevention of oxaliplatin-induced neuropathies in patients with advanced colorectal cancer: it shows no benefit compared to the placebo group.

[0034] Gabapentin and pregabalin are two GABA (gamma-aminobutyric acid) analogues 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, (by Andrade et al., “Pregabalin for the Prevention of Oxaliplatin-Induced Painful Neuropathy: A Randomized, Double-Blind Trial”, The Oncologist.A double-blind trial conducted with pregabalin in 199 patients treated with oxaliplatin for colorectal cancer (Oct 2017, 22(10):1154-el05) showed no efficacy.

[0035] Amitriptyline is a tricyclic antidepressant of the imipramine type, inhibiting the presynaptic reuptake of serotonin, dopamine, and norepinephrine. It is Amitriptyline 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 synaptic monoamines serotonin and norepinephrine within the pain-modulating systems of the central nervous system. However, amitriptyline has not demonstrated any beneficial effect in preventing neuropathy in a study (Kautio et al., "Amitriptyline in the prevention of chemotherapy-induced neuropathy symptoms," Anticancer Res. July 2009, 29(7):2601-6) including 99 patients treated with vinca alkaloids, platinum salts, or taxanes.

[0036] Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant. It increases serotonin and norepinephrine levels within the synaptic 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 1C4: 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. .

[0037] Furthermore, among existing treatments, the wearing of chilled gloves and socks is sometimes suggested. Its effectiveness, albeit limited, has been demonstrated in a Dutch study including 180 patients divided into two equal groups, one where patients wore gloves and socks and the other where they 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 the symptoms of neuropathy and in the patients' quality of life. The main drawback of this approach is the 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.

[0038] Thus, there is currently no drug treatment available to effectively prevent and treat peripheral neuropathies, particularly those induced by chemotherapy during cancer treatment. Cooling gloves and socks appear to offer some benefit but are too poorly tolerated to be considered a standard treatment.

[0039] 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.

[0040] Technical problem

[0041] Considering the above, one problem that the present invention proposes to solve is to develop an optimized topical formulation based on an active ingredient never before proposed for such use for the prevention and / or treatment of peripheral neuropathies and / or neuropathic pain, whatever their cause and in particular those induced by chemotherapy.

[0042] This product would thus make it possible to respond more specifically to an important unmet need for both oncologists and cancer patients.

[0043] Technical solution

[0044] The solution to this problem posed has as its first object 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 and / or treatment of peripheral neuropathies and / or neuropathic pain, in particular induced by chemotherapy during the treatment of cancer.

[0045] Advantages provided

[0046] 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.

[0047] On the contrary, published tests (Fuchs et al., “Heat, but not mechanical hyperalgesia, following adrenergic injections in normal human skin,” Pain 90 (2001) 15–23) show that the use of a vasoconstrictor lowers the heat sensitivity threshold, meaning that pain is felt at a lower temperature. Since heat and pain are transmitted by the same fibers, it is therefore surprising that a vasoconstrictor could reduce neuropathy, as one would expect a worsening of symptoms due to the lowering of the threshold.

[0048] 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.

[0049] 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.

[0050] 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 practically zero, as illustrated in example 5.

[0051] For this purpose, and unlike refrigerated gloves and socks which can only be used during chemotherapy infusion, the use of such a product for topical use allows multiple administrations outside the hospital structure to cover the entire period during which the chemotherapy will be present in the bloodstream. Description of the implementation methods

[0052] The invention relates to a composition in a form suitable for topical administration comprising, in a physiologically acceptable medium, a vasoconstrictor.

[0053] A physiologically acceptable medium means a medium that is compatible and suitable for use in contact with human and animal cells, in particular with skin, mucous membranes and / or hair, without toxicity, irritation, undue allergic response and the like, and proportionate to a reasonable benefit / risk ratio.

[0054] 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.

[0055] Naturally, a person skilled in the art will take care to choose the 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 as not to impair the advantageous properties of the compositions used according to the invention.

[0056] The composition according to the invention is characterized in that it comprises a vasoconstrictor selected from adrenergic agonists, for its use in the prevention and / or treatment of peripheral neuropathies and / or neuropathic pain, whatever their cause and in particular those induced by chemotherapy during the treatment of cancer.

[0057] The composition according to the invention is preferably administered to patients with or likely to develop peripheral neuropathies and / or neuropathic pain, whatever the cause and especially that induced by chemotherapy during the treatment of cancer, more preferentially in human beings.

[0058] Adrenergic agonists are active ingredients whose effects are similar to the stimulation of the sympathetic nervous system.

[0059] The adrenergic agonists preferentially used in the composition according to the invention are adrenergic agonists essentially targeting alpha-2 receptors.

[0060] 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.

[0061] The adrenergic agonists most preferably used in the composition according to the invention are chosen from brimonidine or its salts.

[0062] Pharmaceutically acceptable salts or salts are defined as salts of a compound of interest that are safe and effective for topical use in mammals and that 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., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)).Some compounds used in the present invention can form pharmaceutically acceptable salts with various 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 (1977). In this context, the term "hydrate" refers to a compound of interest, or a pharmaceutically acceptable salt thereof, which further comprises a stoichiometric or non-stoichiometric amount of water bound thereto by non-covalent intermolecular forces.

[0063] Preferably, the brimonidine used in the composition according to the invention is brimonidine tartrate.

[0064] 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 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, more preferably between 0.75% and 1.50% w / w, more preferably still 1.00% or 1.50% w / w.

[0065] For information purposes, 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.

[0066] The concentration of vasoconstrictor, preferably brimonidine, more preferably brimonidine tartrate, and the dose thus applied is advantageously adapted according to the application site.

[0067] 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.

[0068] Preferably, the composition used according to the invention is under hydrogel form, oil-in-water emulsion or water-in-oil emulsion, more preferably hydrogel and oil-in-water emulsion.

[0069] In a particularly preferred manner, the composition used according to the invention is in the form of a hydrogel in a solvent-based phase comprising:

[0070] - polyethylene glycol in combination with propylene glycol and / or dimethyl sulfoxide (DMSO);

[0071] - a hydrophilic film-forming agent selected from a Polyvinylpyrrolidone / copolymer Vinyl Acetate, polyvinylpyrrolidone in non-crosslinked or acetate form, taken alone or in combination; and

[0072] - glycerin.

[0073] The hydrogel composition preferably used according to the invention comprises a Polyvinylpyrrolidone / Vinyl Acetate copolymer as a hydrophilic film-forming agent.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] Neuropathies and / or neuropathic pain prevented or treated 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 pain, sensations of heat and burning, particularly in the extremities.

[0078] The composition is preferably used according to the invention to prevent or treat chemotherapy-induced peripheral neuropathies resulting more particularly from treatment with:

[0079] - platinum derivatives selected from cisplatin and oxaliplatin, preferably oxaliplatin;

[0080] - the poisons of the spindle:

[0081] a) periwinkle alkaloids and their derivatives selected from vincristine, vinblastine, vindesine and vinorelbine, or

[0082] b) taxanes selected from paclitaxel and docetaxel;

[0083] - targeted therapies chosen from bortezomib and imides preferentially thalidomide. Examples

[0084] The present invention will now be illustrated by means of the following examples:

[0085] Example 1: Hydrogel formulations with different concentrations of brimonidine tartrate Ingredients Gel Formula# 220 336.0006 Gel Formula# 220 336.0011 Gel Formula# 220 336.0002 Gel Formula# 220 336.0007 Brimonidine Tartrate* 0.50 0.75 1.0 1.5 Propylene Glycol 20 20 20 20 Macrogol 400 Super Refined 10 10 10 10 Poly(1-vinylpyrrolidone-co-vinylacetate) 1 1 1 1 Glycerol 4 4 4 4 Xanthan Gum 0.2-0.75 0.2-0.75 0.2-0.75 0.2-0.75 Preservative System 0.4-1 0.4-1 0.4-1 0.4-1 Citric Acid qs pH 4.5 qs pH 4.5 qs pH 4.5 qs pH 4.5 Sodium Hydroxide qs pH 4.5 qs pH 4.5 qs pH 4.5 qs pH 4.5 Purified Water qs 100 qs 100 qs 100 qs 100 (*) 0.5, 0.75, 1.0 and 1.5% Brimonidine Tartrate correspond respectively to 0.33, 0.50, 0.67 and 1% Brimonidine base.

[0086] Example 2: Emulsion formulations Composition / Formula No. 19.0155-0102 / F4 19.0155-0102 / F5 GELOT Concept GELOT Formula Rationale Formula 0090 + 1% BHA Formula 0090 + 1% BHA Ingredient % w / w Brimonidine Tartrate 0.15-3 0.15-3 Purified Water qs qs Propylene Glycol 20 20 Vegetable Glycerin 48 10 5 5 PEG-400 SR 10 10 Kollidon VA 64 1 1 Xanthan Gum 0.2 0.2 Methyl Paraben 0.2 0.2 Phenoxyethanol 1 1 Gelot 64 3 3 Kolliwax SA 3 3 Miglyol812N 2.5 2.5 Arlamol PS11E-LQ-(RB) 5 5 Kollicream OA 2.5 2.5 Kolliwax CA 4 4 B HA 1 1 Propyl Paraben 0.1 0.1 DL Tocopherol NaOH 10% 0.18 0.2 Total 100.00 100.00 Composition / Formula No. 19.0155-0132 / F2 19.0155-0133 / F1 Concept POLAWAX POLAWAX Formula Justification 19-0155.0091 / F1 + 0.1% Tocopherol 19-0155.0091 / F1 + 1% Tocopherol Ingredient % w / w Vegetable Glycerin 4810 4 4 Propylene Glycol 20 20 PEG-400 SR 10 10 Purified water qs qs Brimonidine Tartrate 0.15-3 0.15-3 Kollidon VA 64 1 1 Xanthan Gum 0.2 0.2 Polawax NF 10 10 Arlamol PSllE-LQ-(RB) 2.35 2.35 Dimethicone (Xiameter P MX-200) 1 1 Kollicream OA 2.5 2.5 Marcol 82 0.65 0.65 BHA DL TOCOPHEROL 0.1 1 IP Paraben s 1 1 NaOH 10% 0.2 0.2 Total 100.00 100.00

[0087] Example 3:

[0088] A 58-year-old female patient is being treated for breast cancer with a combination of IV paclitaxel at 80 mg / m2 every week and IV cyclophosphamide at 600 mg / m2 every three weeks.

[0089] In order to reduce the risk of neuropathy, this treatment is accompanied by the use of refrigerated socks and gloves, worn for 1.5 hours during each chemotherapy session.

[0090] After two chemotherapy sessions, the patient experienced tingling in the fingers of both hands.

[0091] 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.

[0092] Surprisingly, the tingling not only does not worsen but disappears completely and does not reappear during subsequent sessions until the end of the 12 planned sessions.

[0093] Example 4:

[0094] An open-label pilot study recruited patients treated with taxanes as part of their cancer treatment (regardless of cancer type). For information purposes, neuropathies were 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).

[0095] A hydrogel composition comprising 1.5% brimonidine tartrate (see example 1) was applied to both hands, in the morning after washing and in the evening before bedtime, on the day of the chemotherapy session and for the following 2 days (i.e. 3 days of treatment with brimonidine tartrate), for 12 weeks, which is the usual duration of taxane treatment in cancer.

[0096] A neurological examination to screen for neuropathy(ies) was conducted every 3 weeks. In addition, patients completed a validated questionnaire for the detection of motor, sensory or functional neurological disorders (FACT-18 Taxanes) on a weekly basis.

[0097] Based on the results thus obtained, this study confirms the interest of using a composition according to the invention based on an adrenergic agonist vasoconstrictor in the prevention and treatment of chemotherapy-induced neuropathies.

[0098] Example 5:

[0099] 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.

[0100] 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.

[0101] The treatment was administered for three weeks and the investigator scored any effects observed on the treatment areas.

[0102] According to the results thus obtained, no local reaction was observed and the score therefore remained zero for all volunteers throughout the duration of the study.

[0103] 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 an area of ​​1000 cm2 corresponding to the entire face, chest and upper back.

[0104] Blood samples were taken to characterize the pharmacokinetic profile of the active ingredient at J1, after the first application, at J3 and at J5 after the last application.

[0105] Based on the results thus obtained, no local reaction was observed, confirming the good skin tolerance of the tested product. Furthermore, the results of blood tests show low, often non-quantifiable, levels of the active ingredient, confirming insignificant systemic exposure and the absence of risk of systemic side effects or drug interactions.

[0106] In a final group of 8 volunteers, the 1.5% gel according to the invention was applied twice a day for 5 days to both hands at a rate of 2 mg / cm2, the dose usually recommended for topical application.

[0107] Initially, the product was applied and the hands remained free.

[0108] 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.

[0109] 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 suitable 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 and / or treatment of peripheral neuropathies and / or neuropathic pain.

2. Composition for its use according to claim 1 in the prevention and / or treatment of chemotherapy-induced peripheral neuropathies during cancer treatment.

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

4. Composition for use according to any one of the preceding claims, characterized in that the neuropathies and / or neuropathic pains prevented or treated are presented 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, or pain, sensations of heat and burning, particularly in the extremities.

5. 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.

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

7. Composition for 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.

8. 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 a non-crosslinked or acetate form, taken alone or in combination; and - glycerin.

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

10. Composition for 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.

11. 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.

12. 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.