Nanoparticle compositions for treatment of neuropathic pain

Abstract

The present invention relates to novel and innovative compositions for the treatment of neuropathic pain (NP). In particular, the present invention relates to nanoparticles and / or aggregates of nanoparticles, compositions comprising said nanoparticles and / or aggregates of nanoparticles and their use in the treatment of NP.

Description

Technical Field

[0001] The present invention relates to novel and innovative compositions for treating neuropathic pain (NP). Specifically, the present invention relates to nanoparticles and / or aggregates of nanoparticles, compositions comprising the nanoparticles and / or aggregates of nanoparticles, and their use in treating NP.

[0002] Preface

[0003] Neuropathic pain (NP) is characterized by abnormal hypersensitivity to stimulation (hyperalgesia) and nociceptive response to non-noxious stimulation (allodynia). These patients with hyperalgesia experience an increase in the perception of pain caused by painful stimulation, while patients with allodynia experience an increase in the perception of pain due to stimulation that does not usually cause pain. NP patients may also suffer from paresthesia (abnormal sensations comparable to pinprick bites, tingling, itching), or even lose sensitivity. NP has persistent and / or sporadic (paroxysmal) components. The latter is similar to a stab wound or electric shock.

[0004] Many different conditions can lead to NP, such as metabolic disorders, such as diabetes, viral infections (e.g., post-herpetic neuralgia), and autoimmune diseases that affect the central nervous system (CNS) and peripheral nervous system (PNS), such as multiple sclerosis and Guillain-Barré syndrome, respectively. Neuropathic pain is common in cancer patients, which is a direct result of cancer on peripheral nerves (e.g., tumor compression), radiation damage or surgery, or as a side effect of chemotherapy (chemotherapy-induced peripheral neuropathy (CIPN)). For example, oxaliplatin (a platinum-based chemotherapy drug) is commonly used to treat various types of cancer. Oxaliplatin is currently approved as an initial therapy for the treatment of colorectal cancer in many countries. However, the clinical value of oxaliplatin is reduced by acute and chronic forms of peripheral neuropathy (including mechanical hyperalgesia) that appear as side effects in humans and rodents. Oxaliplatin-induced peripheral neuropathy is the most common dose-limiting toxicity associated with therapy, and there is currently no available treatment.

[0005] Other causes of neuropathic pain include trauma-based damage to the nervous system, such as spinal cord injury (SCI), peripheral nerve damage including post-traumatic NP, or post-surgical NP. Complications such as neuromas following trauma and / or surgery can also cause NP.

[0006] There are also certain inflammatory disorders, hereditary neuropathies, and channelopathies [Colloca L, Ludman T,Bouhassira D, et al. (2017) Neuropathic pain. Nature Reviews Disease Primers 3:17002]. The prevalence of neuropathic pain in the general population is estimated to range between 3% and 17% [Cavalli, E., et al., (2019) The neuropathic pain: An overview of the current treatment and future therapeutic approaches, Int. J. Immunopathology & Pharmacology, Vol.33: 1–10].

[0007] Neuropathic pain can be associated with ectopic afferent discharges that result from a higher excitability and repetitive firing capacity of the affected neuron / nerve, which may be due to changes in membrane potential thresholds during illness / disease [Amir, R. et al., (1999) Membrane Potential Oscillations in Dorsal Root Ganglion Neurons: Role in Normal Electrogenesis and Neuropathic Pain, The Journal of Neuroscience, 19 (19):8589–8596]. + Changes in vectorial transport of channels and / or Na + Na+ channel upregulation + Increased electrical conductance, a factor involved in the production of neuropathic (ectopic) afferent discharges in animals and humans.

[0008] Therefore, we believe that NP may be caused by disorders of the peripheral nervous system or the central nervous system (brain and spinal cord). Therefore, NP can be divided into peripheral NP, central NP or mixed (peripheral and central) NP.

[0009] Trigeminal neuralgia, painful radiculopathy, postherpetic neuralgia, painful polyneuropathies (including chemotherapy-induced peripheral neuropathy (CIPN, also known as chemotherapy-induced neuropathic pain or CINP) and diabetic polyneuropathy), and pain from peripheral nerve injury are all classified as peripheral NP. In contrast, central NP includes painful conditions such as spinal cord injury (SCI) neuropathic pain, central pain in multiple sclerosis, and central post-stroke pain (see Finnerup, NB, et al. (2021) Neuropathic Pain: From Mechanisms To Treatment, Physiol Rev 101: 259–301). Figure 4 ).

[0010] Current clinical solutions for treating NP include systemic and local therapies, such as gabapentinoid drugs, tricyclic antidepressants (TCAs), and selective serotonin-norepinephrine reuptake inhibitors (SNRIs), which are systemic therapies and are generally considered first-line treatments.

[0011] Gabapentinoids (gabapentin and pregabalin) and Ca² + Voltage-dependent channel binding, thereby reducing Ca² + Both gabapentin and pregabalin are used to treat diabetic pain, postherpetic neuralgia, SCI, and phantom limb syndrome. However, both gabapentin and pregabalin are associated with side effects including drowsiness, vertigo, peripheral nerve swelling, and blurred vision.

[0012] TCA is used to treat nerve injury pain, postherpetic neuralgia, central postpartum pain and for the treatment of pain after SCI. However, TCA and SNRI are contraindicated for patients with cardiac problems. They are also associated with several side effects, including nausea and drowsiness. Opioids, including tramadol and tapentadol, have been proposed as second-line treatments for NP, but are associated with side effects such as nausea / vomiting, constipation and drowsiness. Drug habituation / addiction and drug abuse also constitute major problems in opioid therapy.

[0013] Topical treatments (lidocaine and capsaicin) are used for the local treatment of neuropathic pain and are usually applied as a patch. Capsaicin (which makes peppers spicy) is a capsaicin receptor 1 agonist. Application of patches containing capsaicin is performed by a physician and can be painful, with a burning sensation on the skin often reported. https: / / www.vidal.fr / medicaments / qutenza-179-mg-patch-cutane-gel-nettoyant-93564.html ]. A single application is designed to produce pain relief for up to approximately three months.

[0014] Third-line treatment for NP includes systemic therapy - tramadol, strong opioids (morphine and oxycodone), and topically applied botulinum toxin-A (BTX-A). Intradermal injections of BTX-A are currently used to treat chronic focal painful neuropathies. Botulinum toxin-A can be administered via multiple intradermal injections, with the affected painful area divided into multiple sites in a checkerboard pattern, typically with 5 U of BTX-A injected into each site [Park, JH., et al. (2017) Botulinum toxin for the treatmentof neuropathic pain, Toxins, 9, 260]. However, botulinum toxin-A causes muscle paralysis and may therefore affect quality of life [Mittal, SO et al. (2016) Botulinum Toxin Treatment of Neuropathic Pain, Seminars in Neurology. 36 (1): 73–83].

[0015] Overall, despite the treatment options listed above, neuropathic pain is difficult to treat, with only approximately 40–60% of patients achieving partial relief [Dworkin, RH, et al. (2007) Pharmacologic management of neuropathic pain: evidence-based recommendations, Pain, 132 (3): 237–51].

[0016] Several physics-based methods have been evaluated clinically for patients with refractory neuropathic pain. These methods include non-invasive transcranial brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS), in which electrical currents are generated in the cortex by transient magnetic fields. In transcranial direct current stimulation (tDCS), low-voltage currents (1-2 mA) are applied transcranially. TENS and PENS are peripheral electrical stimulation methods that have some use in the treatment of NP. Repetitive spinal cord magnetic stimulation (SMS) and frequency-modulated electromagnetic stimulation (FREMS) are two magnetic-based techniques that have been tested in the treatment of NP. The general disadvantage of the latter external stimulation techniques is that their efficacy is limited in time (a few days or weeks) and re-stimulation is usually required to obtain a sustained effect. Spinal stimulation (spinal cord stimulation, SCS) is an invasive technique for inhibiting central neuronal hyperexcitability. The dorsal columns of the spinal cord are electrically stimulated by 50Hz pulses from a generator implanted in the spine. Patients receiving this treatment are usually those who have been unable to obtain pain relief with other non-invasive methods. Zeng, H. et al. recently reviewed the effects of non-invasive neuromodulation (NINM) on peripheral diabetic neuropathy (PDN, or diabetic neuropathic pain, DNP) and found that NINM effects were higher in intensive regimens and in groups with resistant symptoms or intolerance to analgesics [Zeng, H. et al. (2020) Non-invasive neuromodulation effects on painful diabetic peripheralneuropathy: a systematic review and meta-analysis. Scientific Reports 10.]

[0017] In light of the above, there is a need for new treatments for patients suffering from NP, and researchers continue to explore new treatments. For example, patent application US20210402004A1 describes the use of targeted cerium-containing nanoparticles for treating NP by protecting microglia from oxidative activation. The authors note that Ce 3+ / Ce 4+ The conversion of the oxidation state enables the particles to scavenge reactive oxygen species (ROS) and downregulate overactivated microglia. However, a disadvantage of the latter system may be the well-known cytotoxicity associated with the ROS activity of cerium oxide nanoparticles [Kumari, M, et al. (2014) Toxicity study of cerium oxide nanoparticles in human neuroblastoma cells. Int J Toxicol. 33(2):86-97.].

[0018] Therefore, as described above, there is a continuing need for new NP treatments that have reduced side effects compared to those associated with currently available treatments. In addition, there is a need for treatments that have relatively long-lasting efficacy so that patients can experience reduced pain for as long as possible, such as more than three months (which is the average time that current topical treatments are effective).

[0019] In particular, there is a need to treat peripheral neuropathic pain conditions. There is a need to treat patients with peripheral diabetic neuropathy (PDN or DNP). There is a need to treat patients with postherpetic neuralgia. There is a need to treat patients with chemotherapy-induced NP, or CIPN or CINP. There is a need to treat patients with peripheral nerve injury NP, which is post-traumatic and / or post-operative and / or neuroma-induced NP.

[0020] Treatment of focal neuropathic pain is needed. Treatment of refractory and / or chronic neuropathic pain is needed.

[0021] There is a need for treatment of patients with peripheral neuropathic pain. There is a need for treatment of patients with NP caused by autoimmune diseases affecting the peripheral nervous system (PNS), such as Guillain-Barré syndrome. There is a need for treatment of patients with ectopic afferent discharges associated with NP. In general, the above patients need treatment to reduce the pain they perceive.

[0022] The present invention advantageously provides a solution for treating patients with NP (particularly peripheral NP) using non-toxic (chemically inert) and non-biodegradable nanoparticles, unlike those described in the prior art. The treatment is topically applied, has minimal discomfort, is minimally invasive, has a lasting effect, and does not have any side effects associated with currently available systemic treatments. Therefore, the present invention provides an advantageous solution to each of the above-mentioned needs herein. Summary of the invention

[0023] In one aspect, the present invention relates to nanoparticles or aggregates thereof for use in treating neuropathic pain ("NP").

[0024] In one aspect, the invention is directed to a method of treating a patient suffering from neuropathic pain.

[0025] In one aspect of the invention, the nanoparticles can be used to treat patients suffering from trigeminal neuralgia, neuropathic pain following peripheral nerve injury including post-traumatic neuropathic pain, postoperative neuropathic pain or neuropathic pain caused by neuroma, painful polyneuropathy associated with diabetes, human immunodeficiency virus (HIV), Fabry disease, sodium channel gene mutations, autoimmune diseases such as Guillain-Barré syndrome, vasculitis, chronic inflammatory demyelinating polyneuropathy, amyloidosis, non-freezing frostbite, paraneoplastic syndrome or leprosy, chemotherapy-induced peripheral neuropathy (CIPN), postherpetic neuralgia or painful radiculopathy.

[0026] In one particular aspect, the nanoparticles can be used to treat patients suffering from peripheral nerve damage, including post-traumatic neuropathic pain, post-operative neuropathic pain or neuropathic pain caused by neuromas, post-herpetic neuralgia, painful polyneuropathies associated with diabetes, CIPN or HIV.

[0027] In a preferred aspect of the invention, the nanoparticles may be used to treat patients suffering from chemotherapy-induced peripheral neuropathy (CIPN).

[0028] In another preferred aspect of the present invention, the nanoparticles can be used to treat patients suffering from diabetic induced polyneuropathy (also referred to herein as "painful polyneuropathy associated with diabetes" or "peripheral diabetic neuropathy").

[0029] In another aspect of the present invention, the nanoparticles can be used to treat patients suffering from neuropathic pain following peripheral nerve injury, including post-traumatic neuropathic pain, postoperative neuropathic pain, or neuropathic pain caused by a neuroma.

[0030] In another aspect of the invention, the nanoparticles can be used to treat patients suffering from neuropathic pain associated with ectopic afferent discharges.

[0031] There is a need for treatment of patients suffering from peripheral neuropathic pain.

[0032] In another aspect of the invention, the nanoparticles can be used to treat patients suffering from focal neuropathic pain.

[0033] In another aspect of the invention, the nanoparticles can be used to treat patients suffering from refractory and / or chronic neuropathic pain.

[0034] In one aspect of the specification, the nanoparticle or nanoparticle aggregate material can be selected from materials having a dielectric constant ε equal to or lower than 100. ijkInsulator material, the insulator material is selected from metal oxides and mixed metal oxides, wherein the metal is selected from Zr, Hf and / or Re, such as HfO2 and / or ZrO2. In a specific aspect, the material of the nanoparticles or nanoparticle aggregates is a metal oxide or a mixed metal oxide, wherein the metal is Zr and / or Re.

[0035] In one aspect of the present invention, the nanoparticle or nanoparticle aggregate material may be a metal conductor selected from the group consisting of Ir, Pd, Pt, Au, and any mixture thereof.

[0036] In another aspect, the nanoparticle or nanoparticle aggregate material may be a nanoparticle or nanoparticle aggregate material having continuous sp in its structure. 2 Organic materials having a hybridized carbon center (i.e., a carbon double bond or an aromatic ring containing a heteroatom (usually N or S) inside or outside the aromatic ring). Preferred organic materials are selected from polyaniline, polypyrrole, polyacetylene, polythiophene, polycarbazole, polystyrene and / or polypyrene. More preferred organic materials are poly(3,4-ethylenedioxythiophene) (PEDOT), poly(styrene sulfonate) (PSS) or mixtures thereof.

[0037] In one aspect of the invention, when the nanoparticle material is a metallic conductor, the median population core size of the nanoparticles or nanoparticle aggregates is at least 45 nm.

[0038] In one aspect of the invention, the core of the nanoparticle or nanoparticle aggregate is coated with a biocompatible coating that provides a neutral or negative surface charge when measured in an aqueous solution having an electrolyte concentration between 0.001 and 0.2 M, a nanoparticle or nanoparticle aggregate material concentration between 0.01 and 10 g / L, and a pH between 6 and 8.

[0039] In another aspect, the nanoparticles or aggregates thereof can be administered by intradermal and / or intraepidermal injection.The nanoparticles or aggregates thereof can be administered using a dissolvable microneedle patch.

[0040] In another aspect of the present invention, the dose of nanoparticles or aggregates thereof administered is preferably at least 60 μg per square centimeter of skin surface to be injected.

[0041] In another aspect of the present invention, when the patient suffers from painful polyneuropathy associated with diabetes, the dose of nanoparticles or aggregates thereof administered is preferably at least 60 μg per square centimeter of skin surface to be injected.

[0042] In one aspect of the specification, when the patient suffers from CIPN and when the material of the nanoparticles or their aggregates is selected from metal oxides or mixed metal oxides, such as HfO2 and / or ZrO2, the dose of the nanoparticles or their aggregates administered is preferably at least 250 μg per square centimeter of skin surface to be injected, more preferably at least 390 μg.

[0043] In another aspect, when the patient suffers from CIPN and when the nanoparticles or aggregates thereof are selected from a metal conductor selected from Ir, Pd, Pt, Au and any mixture thereof, the dose of the nanoparticles or aggregates thereof administered is preferably at least 70 μg, for example 78 μg, per square centimeter of skin surface to be injected. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 : CIPN model (Example 5): Mechanical allodynia. PWT (g) using von Frey filaments in the test groups at different time points. *, **, ***, and **** indicate statistically significant differences with P < 0.05, P < 0.01, P < 0.001, and P < 0.0001, respectively, when each group was compared with its own value at the 'NP' time point (neuropathic baseline) using Dunnett's multiple comparison test after mixed effects analysis. Values ​​are mean ± SEM.

[0045] Figure 2 : CIPN model (Example 5): Pictures of rat hind paws after intraplantar injection of nanoparticles from Example 1 (gold nanoparticles) show diffusion of the nanoparticles into the skin with no progression between D7 and D26.

[0046] Figure 3 : CIPN model (Example 6): Mechanical allodynia. Paw withdrawal threshold (g) using von Frey filaments in the vehicle group (animals not receiving treatment) at different time points. Values ​​are mean ± SEM.

[0047] Figure 4 : CIPN model (Example 6): Mechanical allodynia. Paw withdrawal threshold (g) using von Frey filaments in the nanoparticle 61 g / L / 20 µL group at different time points. Left paw (white bar): injection of 20 µL of nanoparticle 61 g / L; right paw (grey bar): injection of 20 µL of vehicle (normal saline). Values ​​are mean ± SEM.

[0048] Figure 5: CIPN model (Example 6): Mechanical allodynia. Paw withdrawal threshold (g) using von Frey filaments in the nanoparticle 18g / L / 20µL groups at different time points. Left paw (white bar): injected with 20 µL of nanoparticles 18g / L; right paw (grey bar): injected with 20 µL of vehicle (normal saline). Values ​​are mean ± SEM.

[0049] Figure 6 : CIPN model (Example 6): Mechanical allodynia. Paw withdrawal threshold (g) using von Frey filaments in the nanoparticle 18g / L / 10µL groups at different time points. Left paw (white bar): 10 µL of nanoparticle 18g / L injected; right paw (grey bar): 10 µL of vehicle (normal saline) injected. Values ​​are mean ± SEM.

[0050] Figure 7 : CIPN model (Example 6): Mechanical allodynia. Paw withdrawal threshold (g) using von Frey filaments in pregabalin groups at different time points. Pregabalin was administered systemically (oral); no difference between left and right paws. Values ​​are mean ± SEM.

[0051] Figure 8 : STZ-induced diabetic NP study (Example 7): Mechanical allodynia. Paw withdrawal threshold (g) using von Frey filaments at different time points. Values ​​are mean ± SEM. *, **, ***, and **** indicate statistically significant differences with p < 0.05, p < 0.01, p < 0.001, and p < 0.0001, respectively, when compared to the 'STZ / vehicle' group at each time point. Values ​​are mean ± SEM. DETAILED DESCRIPTION OF THE INVENTION

[0053] definition :

[0054] The terms "treat" or "treatment" refer to both therapeutic and prophylactic or preventive treatments or measures that can significantly slow the progression of a disease or treat symptoms (eg, reduce pain).

[0055] Such treatment or therapy is intended for use in a subject in need thereof, typically a human (also identified herein as a human patient or patient).

[0056] Focal neuropathic pain refers to pain that is limited to a surface area less than 15 cm 2 of neuropathic pain.

[0057] "Refractory neuropathic pain" refers to long-term neuropathic pain that cannot be relieved by standard drug interventions (such as standard antidepressants, anticonvulsants, analgesics, etc.). Experts agree that the definition of "refractory neuropathic pain" is a minimum duration of one year; at least four known effective drugs have been tried for three months or the maximum tolerance time [Smith BH, et al. (2012) Towards a definition of refractory neuropathic painfor epidemiological research. An international Delphi survey of experts, BMC Neurology, 12:29].

[0058] “Chronic neuropathic pain” is defined as neuropathic pain that occurs regularly over a period of several months [J. Smith et al. (2018) J. Neurol. 265, pp231–238].

[0059] "At least partial thermal sensation" refers to the preservation of afferent fibers that allow the patient to feel "evoked" pain, more specifically, cold or warm allodynia / hyperalgesia.

[0060] Thermal sensation, more specifically cold and / or heat allodynia and / or hyperalgesia can be measured according to methods known to those skilled in the art and include protocols for quantitative sensory testing such as the DFNS (German Neuropathic Pain Research Network) protocol [Vollert, J., et al. (2015) Quantitative Sensory Testing using DFNS protocol in Europe: an evaluation of heterogeneity across multiple centers inpatients with peripheral neuropathic pain and healthy subjects, Pain, 157(3)] and the NPSI (Neuropathic Pain Symptom Inventory) protocol [Bouhassira, D., et al. (2004) Development and validation of the Neuropathic Pain Symptom Inventory, Pain, 108:248-257].

[0061] "Thermal sensation" or "at least partial thermal sensation" means that the patient still has (partially) preserved (epidermal) afferent fibers.

[0062] "Level of neuropathic pain" refers to the level of pain measurable using standard questionnaires known to those skilled in the art, including the Numerical Rating Scale (NRS) for pain, the Leeds Assessment of Neuropathic Signs and Symptoms (LANSS), the Neuropathic Pain Questionnaire, DN4, the Pain DETECT Questionnaire, ID Pain, the Neuropathic Pain Scale (NPS), the DFNS protocol and the Neuropathic Pain Symptom Inventory (NPSI) [Haanpää, M., et al. (2011) NeuPSIG guidelines on neuropathic pain assessment, Pain 152 14–27]. Preferably, the NRS for pain and / or the DFNS protocol and / or the NPSI are used.

[0063] Nanoparticles and / or aggregates of nanoparticles

[0064] size

[0065] In the context of the present invention, the term "nanoparticles" refers to products, especially synthetic products, with a size in the nanometer range, typically between about 1 nm and about 1000 nm, preferably between about 1 nm and about 500 nm, even more preferably between about 1 nm and about 100 nm.

[0066] According to one aspect of the invention, the median maximum dimension of the core of a population of nanoparticles or nanoparticle aggregates is between about 10 nm and about 200 nm. The term "aggregate of nanoparticles" refers to a collection of nanoparticles.

[0067] The size of nanoparticles and / or the aggregate of nanoparticles can be measured by electron microscope (EM) technology usually, such as transmission electron microscope (TEM) or cryo-TEM, as well-known to those skilled in the art. Usually measure the size of at least 100 nanoparticles and / or the aggregate of nanoparticles, and the median size of the population of nanoparticles and / or the aggregate of nanoparticles is reported as the size of nanoparticles and / or the aggregate of nanoparticles.

[0068] shape

[0069] Since the shape of nanoparticles and / or aggregates of nanoparticles can affect their "biocompatibility", nanoparticles and / or aggregates of nanoparticles with a fairly uniform shape are preferred. Due to pharmacokinetic reasons, nanoparticles and / or aggregates of nanoparticles that are substantially spherical, circular or oval are preferred. This shape also helps nanoparticles and / or aggregates of nanoparticles to interact with cells or be absorbed by cells.

[0070] Composition / Structure

[0071] The nanoparticles are made of an insulator material with a low relative permittivity, i.e., equal to or less than 100.

[0072] Nanoparticles made of (e.g., including) or consisting of an insulator material having a low relative dielectric constant are typically made from a material that typically has a band gap Eg equal to or higher than 3.0 eV when measured at room temperature (about 25°C) and a relative dielectric constant ε ijk Equal to or lower than 100, preferably lower than 50 or lower than 20, the relative dielectric constant is usually between 20°C and 30°C and at 10 2 Hz to infrared frequencies (see, e.g., Table 12-45 "Permittivity (dielectric constant) of inorganic solid"; Handbook of chemistry and physics; David R. Lide; 88th edition; Compilation of the static dielectric constant of inorganic solid. KF Youngand HPR Frederikse. J. Phys. Chem. Ref. Data, Vol. 2, No. 2, 1973).

[0073] Such nanoparticles are usually prepared with dielectric materials selected from metal oxides, mixed metal oxides (whose metal elements are from the 3rd, 5th or 6th period of the Mendeleev periodic table or lanthanides) and carbon materials. The dielectric material is preferably selected from La2O3, SnO2, Ta2O5, ReO2, ZrO2, HfO2 and carbon diamond. More preferably, the dielectric material is a metal oxide selected from ZrO2, HfO2 and any mixture thereof. Particularly preferred are dielectric materials selected from ZrO2 and HfO2.

[0074] In a specific and preferred aspect, the metal oxide is not CeO2 (cerium oxide). Cerium oxide is also known as "ceria". As mentioned in the introduction, ceria is known to have cytotoxic effects. In fact, Pulido-Reyes et al. (2015) demonstrated that the main driver of the toxicity of ceria nanoparticles is Ce 3+ The surface content percentage of the sites, the higher the Ce 3+ / Ce 4 +ratio leads to higher toxicity [“Untangling the biological effects of cerium oxide nanoparticles: the role of surface valence states,” Scientific reports DOi:10.1038 / srep15613]. It is also known from Soh et al. 2017 [Angew. Chem. Int. Ed. 10.1002 / anie.201704904]. 4+ into the cerium oxide lattice, which is beneficial to the Ce 4+ Convert to Ce 3+ , leading to greater nanoparticle toxicity. Therefore, compared to the known surface inertness of zirconia nanobiomaterials, ceria / zirconia nanoparticles are expected to be more toxic than ceria nanoparticles and zirconia nanoparticles due to the redox reactions that occur on their surfaces [Shtansky et al., (2015): Multifunctional bioactive nanostructured films in “Hydroxyapatite (HAp) for Biomedical Applications” Elsevier, pp 162].

[0075] In another specific and preferred aspect, the metal oxide or mixed metal oxide does not contain cerium (Ce).

[0076] In a particular aspect, when the material is selected from ReO2, ZrO2 and HfO2, preferably selected from ZrO2 and HfO2 (e.g., ReO2 or ZrO2), the median maximum dimension of the core of a population of nanoparticles or nanoparticle aggregates is at least 10 nm and less than 500 nm, preferably between about 10 nm and about 200 nm, even more preferably between about 20 and 100 nm.

[0077] Nanoparticles made from conductive materials

[0078] The nanoparticles prepared from the conductive material are organic nanoparticles or inorganic nanoparticles.

[0079] Inorganic nanoparticles prepared from conductive materials are usually prepared from metal elements having a standard reduction potential E° value equal to or higher than about 0.01 when measured relative to a standard hydrogen electrode at 25°C and 1 atm pressure (see Table 2 "reduction reactions having E° values ​​more positive than that of the standard hydrogen electrode", 8-25, Handbook of chemistry and physics; David R. Lide; 88th edition), more preferably equal to or higher than about 0.1, 0.2, 0.3, 0.4 or 0.5. Typical metal elements used to prepare nanoparticles can be selected from Pd, Ir, Pt, Au and any mixture thereof. Preferably, the metal elements that can be used as conductive materials to prepare nanoparticles are selected from Ir, Pd, Pt, Au and any mixture thereof, and even more preferably selected from Au, Pt, Pd and any mixture thereof. Particularly preferred materials are Au and Pt.

[0080] Typically, when the size of gold nanoparticles is reduced to a few nm, they exhibit catalytic activity (Auffan, M., et al. (2009) Towards a definition of inorganic nanoparticles from an environmental, health and safety perspective, Nature Nanotechnology, 4(10), 634-641). In order to reduce the surface / volume ratio and thus minimize the contribution of the gold nanoparticle surface to the catalytic activity, it is preferred that the core of the nanoparticles of the population or the core of the nanoparticle aggregates have a median maximum size of at least 30 nanometers, typically at least 40 nanometers or at least 45 nanometers.

[0081] In a particular aspect, when the material is a metallic material, typically a metal having a standard reduction potential E° higher than 0.2, in particular any one of Ir, Au, Pt, Pd and any mixture thereof, the median maximum dimension of the core of a population of nanoparticles or nanoparticle aggregates is at least 30 nm, or at least 40 nm, and preferably, as described above, is lower than 500 nm. For example, the median maximum dimension of the core of a population of nanoparticles or nanoparticle aggregates may be between about 40 and about 200 nm, preferably between about 45 and about 100 nm.

[0082] Organic nanoparticles made from conductive materials are usually used to have continuous sp 2The organic material is prepared from an organic material having a hybridized carbon center (i.e., a carbon double bond or an aromatic ring containing a heteroatom (usually N or S) within or outside the aromatic ring). Preferred organic materials are selected from polyaniline, polypyrrole, polyacetylene, polythiophene, polycarbazole, polypyrene, poly(3,4-ethylenedioxythiophene) and / or poly(3,4-ethylenedioxythiophene) polystyrene sulfonate. More preferably, the organic material is poly(3,4-ethylenedioxythiophene) or poly(3,4-ethylenedioxythiophene) polystyrene sulfonate. In another preferred aspect, the organic material is poly(3,4-ethylenedioxythiophene) (PEDOT) and / or poly(styrene sulfonate) (PSS).

[0083] Biocompatible coatings of nanoparticles or nanoparticle aggregates

[0084] In a preferred embodiment, the core of the nanoparticle or nanoparticle aggregate used to prepare the composition of interest in the context of the present invention can be coated with a biocompatible material that brings a negative charge on the surface of the nanoparticle or nanoparticle aggregate. The reagent that forms a negative charge on the surface of the nanoparticle or nanoparticle aggregate can be, for example, a phosphate (e.g., polyphosphate, metaphosphate, pyrophosphate, etc.), a carboxylate (e.g., citrate or dicarboxylic acid, particularly succinic acid) or a sulfate.

[0085] In a preferred embodiment, the core of the nanoparticle or aggregate of nanoparticles exhibits a hydrophilic neutral surface charge or is coated with a biocompatible material (ie, a coating agent) selected from hydrophilic agents that impart a neutral surface charge to the nanoparticle.

[0086] The hydrophilic reagent that imparts the core neutral surface charge of nanoparticles or nanoparticle aggregates can be a reagent that displays a functional group selected from alcohol (R-OH), aldehyde (R-COH), ketone (R-CO-R), ester (R-COOR), acid (R-COOH), thiol (R-SH), sugar (e.g., glucose, fructose, ribose), anhydride (RCOOOC-R) and pyrrole. The hydrophilic reagent that imparts the core neutral surface charge of nanoparticles or nanoparticle aggregates can be a monomer, dimer, oligomer, polymer or copolymer. When the reagent is an oligomer, it can be an oligosaccharide such as cyclodextrin. When the reagent is a polymer, it can be a polyester (e.g., poly(lactic acid) or polyhydroxyalkanoic acid), a polyether, polyethylene oxide, polyethylene glycol, polyvinyl alcohol, polycaprolactone, polyvinylpyrrolidone, a polysaccharide (e.g., cellulose), polypyrrole, etc.

[0087] In addition, the hydrophilic agent that imparts a core neutral surface charge to the nanoparticle or nanoparticle aggregate may be an agent that exhibits a specific group (X-) that can interact with the surface of the nanoparticle or nanoparticle aggregate. X is typically selected from thiol, silane, carboxyl and phosphate groups.

[0088] When the core of the nanoparticle or the aggregate of nanoparticles is a conductor and a metal nanoparticle, X is preferably a thiol, a thioether, a thioester, a dithiolane or a carboxyl group. Preferably, the hydrophilic neutral coating agent is selected from thioglucose, 2-mercaptoethanol, 1-thioglycerol, thiodiglycol, hydroxybutyric acid and mercaptopolyethylene glycol. Preferably, the hydrophilic agent that imparts a negative surface charge at physiological pH is dithiosuccinic acid.

[0089] When the core of the nanoparticle or aggregate of nanoparticles is an insulator, metal oxide or mixed metal oxide nanoparticle, X is preferably a silane or phosphate group. Preferably, the hydrophilic neutral coating agent is a silane-polyethylene glycol. Preferably, the hydrophilic agent that imparts a negative surface charge at physiological pH is a polyphosphate molecule, more preferably hexametaphosphate.

[0090] According to preferred aspects described herein, the core of the nanoparticle or nanoparticle aggregate consists of HfO2. Preferably, the core is coated with a biocompatible coating having a negative surface charge, such as a coating showing phosphate groups. In one aspect described herein, the core HfO2 is coated with a hexametaphosphate biocompatible coating.

[0091] According to one embodiment of the present invention, the core is coated with a biocompatible hydrophilic neutral coating agent selected from hydroxymethyltriethoxysilane, fructose 6-phosphate or glucose 6-phosphate compounds.

[0092] The hydrophilic agent that imparts a neutral surface charge to the core of the nanoparticle or nanoparticle aggregate may be a zwitterionic compound such as an amino acid, a peptide, a polypeptide, a vitamin or a phospholipid.

[0093] As is well known to those skilled in the art, the surface charge of nanoparticles or nanoparticle aggregates is typically determined by zeta potential measurements, typically at a concentration of nanoparticle or nanoparticle aggregate material in water (solution) between 0.01 and 10 g / L, a pH between 6 and 8, and an electrolyte concentration (in water) typically between 0.001 and 0.2 M, such as 0.01 M or 0.15 M. Under the above defined conditions, the surface charge of the nanoparticles or nanoparticle aggregates is typically comprised between -80 mV and +15 mV, between -60 mV and +10 mV, or between -45 mV and +10 mV. When neutral, the surface charge of the nanoparticle or aggregate of nanoparticles is typically comprised between -10 mV, -9 mV, -8 mV, -7 mV, -6 mV, -5 mV, -4 mV, -3 mV, -2 mV, or -1 mV and 1 mV, 2 mV, 3 mV, 4 mV, 5 mV, 6 mV, 7 mV, 8 mV, 9 mV, or 10 mV. When negative, the surface charge of the nanoparticle or aggregate of nanoparticles is typically below -11 mV, -12 mV, -13 mV, -14 mV -15 mV, -16 mV, -17 mV, -18 mV, -19 mV, -20 mV, -21 mV, -22 mV, -23 mV, -24 mV, -25 mV, -26 mV, -27 mV, -28 mV, -29 mV, -30 mV, -31 mV, -32 mV, -33 mV, -34 mV, -35 mV, -40 mV, or -45 mV.

[0094] In the context of the present invention, when the nanoparticles present a hydrophilic neutral surface charge, a complete biocompatible coating of the nanoparticles or aggregates may be advantageous in order to avoid any charge on the surface of the nanoparticles. "Complete coating" means the presence of very high density / compactness of biocompatible molecules capable of producing at least half a monolayer, or preferably at least a complete monolayer, on the surface of the particle.

[0095] The biocompatible coating specifically allows for the stability of the nanoparticles in fluids, such as physiological fluids (blood, plasma, serum, etc.) or any isotonic or physiological medium required for drug administration.

[0096] Stability can be confirmed by quantification of dry extracts using a drying oven and measured on the nanoparticle suspension before and after filtration, typically on a 0.45 µm filter.

[0097] Advantageously, the coating preserves the integrity of the particle in vivo, ensures or improves its biocompatibility, and facilitates its optional functionalization (eg with spacer molecules, biocompatible polymers, targeting agents, proteins, etc.).

[0098] The biocompatible nanoparticles or aggregates of nanoparticles of the present invention should neither dissolve, thereby releasing potentially toxic substances after in vivo administration (i.e., at physiological pH), nor exhibit redox behavior, and are generally considered to be biocompatible, i.e., safe for use in subjects, particularly in mammals, preferably in humans.

[0099] Another specific object described herein relates to a composition, in particular a pharmaceutical composition, comprising nanoparticles and / or nanoparticle aggregates as described above, preferably together with a pharmaceutically acceptable carrier or vehicle.

[0100] In certain aspects, the composition may comprise nanoparticles or nanoparticle aggregates of the invention and a therapeutic agent, for example for topical administration, such as an anti-inflammatory drug.

[0101] The composition may be in the form of a solid, liquid (suspended particles), an aerosol, a gel, a paste, etc. Preferred compositions are in the form of a liquid or a gel. Particularly preferred compositions are in the form of a liquid.

[0102] The pharmaceutically acceptable support or carrier used may be any classical support known to those skilled in the art, such as physiological saline, isotonic, sterile, buffered solution, non-aqueous vehicle solution, and the like.

[0103] The composition may also contain stabilizers, surfactants, polymers, and the like.

[0104] It can be formulated, for example, into an ampoule or a liquid for injection using techniques for pharmaceutical preparation known to those skilled in the art.

[0105] Subjects to be treated:

[0106] The nanoparticles are administered for treating at least one peripheral neuropathic pain disorder.

[0107] According to one embodiment of the present invention, the subject suffers from peripheral diabetic neuropathy (PDN).

[0108] According to one embodiment of the present invention, the subject suffers from postherpetic neuralgia.

[0109] According to one embodiment of the present invention, the subject suffers from CIPN.

[0110] According to one embodiment of the invention, the subject suffers from a painful radiculopathy.

[0111] According to one embodiment of the present invention, the subject suffers from peripheral nerve injury, including post-traumatic neuropathic pain, postoperative neuropathic pain or neuropathic pain caused by neuroma.

[0112] According to one embodiment of the invention, the patient suffers from (peripheral) neuropathic pain due to an autoimmune disease such as Guillain-Barré syndrome, human immunodeficiency virus (HIV), Fabry disease, sodium channel gene mutation, vasculitis, chronic inflammatory demyelinating polyneuropathy, amyloidosis, non-freezing frostbite, paraneoplastic syndrome or leprosy.

[0113] According to one embodiment of the invention, the subject suffers from focal (peripheral) neuropathic pain.

[0114] According to one embodiment of the invention, the subject suffers from refractory and / or chronic (peripheral) neuropathic pain.

[0115] According to a preferred embodiment of the present invention, the subject suffers from peripheral NP manifested by ectopic afferent discharges.

[0116] A subject with NP may preferably have preserved at least partial thermal sensation (as tested by cold or warm allodynia / hyperalgesia tests known to those skilled in the art).

[0117] Without being bound by any theory, the inventors believe that retaining at least some thermal sensation, meaning retaining at least some (cutaneous) afferent fibers, may be necessary for the treated subject to experience a sensation of pain relief in the subject.

[0118] Mode of administration:

[0119] The affected painful area can be delineated by a professional (i.e. a doctor or nurse) by drawing it on the skin with a pen and measuring it. This delineation can help determine the total dose of nanoparticles to be administered in the painful area. The delineated painful area should preferably be less than 15 cm 2 .

[0120] The nanoparticles or nanoparticle aggregates of the present invention can be administered to a subject using intradermal and / or intraepidermal injections. Intradermal injections can be performed with a syringe commonly used for intradermal injections (e.g., an insulin or tuberculin syringe) with a 25 to 30 gauge needle at an angle commonly used for intradermal injections (e.g., an angle of 5 to 15 degrees to the site). Intradermal injections can also be performed according to the Mantoux test. In another aspect, hollow, solid, or soluble microneedles can be used for intradermal and / or intraepidermal injections. Such microneedles can be in the form of a patch [Jung, JH, et al. (2021) Microneedle for transdermal drug delivery: current trends and fabrication, Journal of Pharmaceutical Investigation, 51, 503–517]. The nanoparticles or nanoparticle aggregates of the present invention can be administered by multiple intradermal and / or intraepidermal injections, and the affected pain area is divided into multiple checkerboard-shaped sites, with one dose per site, just as botulinum toxin A is commonly used to treat focal neuropathic pain.

[0121] Nanoparticles or nanoparticle aggregates can be administered as often as needed depending on the patient's pain. Nanoparticle administration may need to be once a month, or once every two months, or once every three months.

[0122] Preferably, nanoparticle administration only needs to be once every three months. More preferably, nanoparticle administration only needs to be once every four months. Even more preferably, nanoparticle administration only needs to be once every five or six months. Even more preferably, nanoparticle administration only needs to be once every seven or eight months. Most preferably, nanoparticles are administered only once and provide pain relief that lasts for more than one year. Even most preferably, nanoparticles are administered only once and provide pain relief that lasts for the remainder of the patient's life.

[0123] Nanoparticles and / or nanoparticle aggregates, once administered, typically interact with the subject's neurons / nerves. In preferred aspects, this interaction is a long-term interaction, i.e., an interaction of hours, days, weeks, or months. In specific aspects, nanoparticles or aggregates of nanoparticles remain in the subject.

[0124] The nanoparticles or nanoparticle aggregates and compositions comprising such nanoparticles or nanoparticle aggregates described herein are for use in a subject, typically a human patient.

[0125] A typical number of nanoparticles or nanoparticle aggregates to be administered in the dermis and / or epidermis of a subject is about 100 μg / cm 2 In 10 5Up to 10 17 Between 10 5 Up to 10 16 Between or within 10 5 Up to 10 15 Between, preferably between 10 7 Up to 10 14 between 10 and 20. 9 Up to 10 13 Most preferably, the typical number of nanoparticles or aggregates of nanoparticles to be administered in the dermis and / or epidermis of a subject is between 10 and 15 cm. 2 In 10 10 Up to 10 12 between.

[0126] According to one embodiment of the present invention, when the patient suffers from painful polyneuropathy associated with diabetes, the dose of the nanoparticles or aggregates thereof administered is preferably at least 60 μg per square centimeter of skin surface to be injected.

[0127] In one aspect, when the patient suffers from polyneuropathy associated with diabetes and when the material of the nanoparticles or their aggregates is a metal oxide or a mixed metal oxide, such as HfO2 and / or ZrO2, the dose of the nanoparticles or their aggregates administered is preferably at least 60 μg per square centimeter of skin surface to be injected.

[0128] In one aspect, when the patient suffers from CIPN and when the material of the nanoparticles or their aggregates is a metal oxide or a mixed metal oxide, such as HfO2 and / or ZrO2, the dose of the nanoparticles or their aggregates administered is preferably at least 250 μg per square centimeter of skin surface to be injected, more preferably at least 390 μg.

[0129] According to one embodiment, when the patient suffers from CIPN and when the material of the nanoparticles or aggregates thereof is a metal conductor selected from Ir, Pd, Pt, Au and any mixture thereof, the dose of the nanoparticles or aggregates thereof administered is preferably at least 70 μg, for example 78 μg, per square centimeter of skin surface to be injected.

[0130] Targeting

[0131] Aggregates of specific nanoparticles and / or nanoparticles as described herein further comprise targeting agents, which allow the recognition elements present on the target cells (usually neurons / nerve cells) to interact. Once the aggregates of nanoparticles and / or nanoparticles accumulate in the target site (usually in the skin, even more usually on neurons / nerves), this targeting agent will usually work. Targeting agents can be any biological or chemical structure that shows affinity to the molecules present in the human body or animal body. For example, it can be a peptide, oligopeptide or polypeptide, protein, nucleic acid (DNA, RNA, siRNA, tRNA, miRNA, etc.), antibody, hormone, vitamin, enzyme, ligand of a molecule / receptor expressed by neurons / nerve cells or by pathological cells, in particular a ligand of an intraepidermal nerve fiber receptor, a ligand of an intradermal nerve fiber receptor, a ligand of an axon receptor, a ligand of a neuronal soma receptor, a ligand of a Schwann cell receptor, a ligand of myelin, a ligand of an axonal transport vesicle / endosome receptor, a ligand of a signaling endosomal receptor, a ligand of a neurotrophic factor, a ligand of a semaphorin, a ligand of a nerve growth factor, a ligand of a growth cone receptor or a ligand of a netrin receptor complex, a ligand of a receptor protein tyrosine phosphatase, a ligand of a dynein or kinesin, or a ligand of a cytokine receptor. The targeting agent can be selected, for example, from the group of biomarkers for PGP 9.5, GTPase activating proteins (such as GAP-43), β-III tubulin, vesicular glutamate transporter (VGLUT1), tyrosine receptor kinases B and C (Trk B, C), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), calreticulin, and the targeting agent can be retinoic acid.

[0132] Composition

[0133] Also described herein are pharmaceutical compositions comprising the nanoparticles and / or aggregates of nanoparticles as described above, and a pharmaceutically acceptable carrier, vehicle, or support.

[0134] The pharmaceutical composition is suitable for treating neuropathic pain as described above.

[0135] Technical effects:

[0136] Experimental results using animal models of neuropathic pain, namely the CIPN model (Examples 5 and 6) and the diabetes-induced neuropathic pain model (Example 7) (see the Examples section for details) illustrate the therapeutic efficacy of the claimed nanoparticles.

[0137] In Example 5, several embodiments of the claimed nanoparticles were demonstrated in rats to have a lasting effect (at least 11 days) on pain relief due to CIPN, for example after a single intraplantar injection. In the experiments, animals could not be evaluated beyond 11 days.

[0138] Thus, according to one embodiment of the present invention, the claimed nanoparticles can be used to treat CIPN.

[0139] In Examples 6 and 7, a single intraplantar injection of hafnium dioxide nanoparticles with a negatively charged biocompatible coating (Example 3) produced a lasting effect on pain relief (at least 7 days for the diabetes-induced NP model and at least 11 days for the CIPN model). In contrast, the positive control pregabalin had to be injected once every 2 days 2 hours before the Von Frey assessment to achieve sustained pain relief during the test period. In addition, a dose effect was clearly observed in the experiment of Example 6 (i.e., increasing the dose of the administered nanoparticles had an increased pain relief effect).

[0140] Therefore, according to one embodiment of the present invention, the claimed nanoparticles can be used to treat diabetic neuropathic pain.

[0141] According to one embodiment of the present invention, increasing the concentration of nanoparticles can result in increased therapeutic efficacy.

[0142] The two animal models used to demonstrate the efficacy of the present nanoparticles are considered clinically relevant.

[0143] Based on the in vivo data from two different animal models provided herein, the inventors believe that the nanoparticle compositions of the present invention may be useful for treating all neuropathic pain disorders, preferably peripheral neuropathic pain disorders.

[0144] Thus, the inventors have shown that the claimed nanoparticles can be used as a topical treatment for peripheral neuropathic pain for sustained pain relief. Topical administration is advantageous because the negative side effects of systemic treatments as detailed above are avoided. In addition, patient compliance is improved because the nanoparticles are not administered frequently compared to other topically applied neuropathic pain treatments.

[0145] Other aspects and advantages of the present invention will become apparent from the following examples, which are given for purposes of illustration only and not by way of limitation. Example

[0146] Example 1. Nanoparticles prepared from conductive materials: Synthesis of gold nanoparticles coated with a biocompatible coating exhibiting a negative surface charge

[0147] Gold nanoparticles are synthesized by reducing gold chloride salt (HAuCl4) with a capping agent (sodium citrate) (protocol adapted from G. Frens, (1973) Nature Physical Science 241, 21)). In a typical experiment, the HAuCl4 solution is heated to boiling. Subsequently, the sodium citrate solution is added. The resulting solution is boiled for another 5 minutes and then filtered. The gold concentration in the suspension is determined by UV-visible spectroscopy at 530 nm.

[0148] The resulting nanoparticles were coated with a biocompatible surface coating, namely meso-2,3-dimercaptosuccinic acid (DMSA). Sufficient DMSA was added to the nanoparticle suspension to achieve at least half monolayer coverage (2.5 molecules / nm) on the surface. 2 ).

[0149] The hydrodynamic diameter (measured as intensity) was determined by dynamic light scattering (DLS) with a laser emitting at 633 nm at a scattering angle of 173° using a Nano-Zetasizer (Malvern) by diluting the nanoparticle suspension in water (final concentration 0.1 g / L). The hydrodynamic diameter of the nanoparticles in the suspension thus obtained was equal to 81 nm, and the polydispersity index (dispersity of the population of nanoparticles in size) was 0.49.

[0150] The zeta potential was determined by measuring the electrophoretic mobility of the nanoparticles (Nano-Zetasizer, Malvern) by diluting the nanoparticle suspension in a NaCl solution at 1 mM at pH 7 (final concentration 0.1 g / L). The zeta potential at pH 7 was found to be equal to -32 mV.

[0151] Gold concentration was determined using inductively coupled plasma-optical emission spectroscopy (ICP-OES).

[0152] Example 2. Nanoparticles prepared from insulator materials with low relative dielectric constant (equal to or lower than 100): Synthesis of zirconium oxide nanoparticles coated with a biocompatible coating exhibiting a negative surface charge

[0153] Zirconium oxide (ZrO2) nanoparticles were synthesized by precipitation of zirconium chloride (ZrCl4) with tetramethylammonium hydroxide (TMAOH) at alkaline pH. The resulting suspension was autoclaved at temperatures above 110°C and, after cooling, washed with deionized water, acidified and filtered (0.22µm PES membrane filter). The nanoparticle (ZrCL) concentration was determined as dry mass concentration

[0154] Coating was performed as follows. Sufficient mass of sodium hexametaphosphate was added to the nanoparticle suspension to achieve at least half monolayer coverage (2.5 molecules / nm) on the surface. 2 ).

[0155] The hydrodynamic diameter of the nanoparticles was measured by DLS to be 66 nm and the polydispersity index (dispersity of the nanoparticle population in size) was 0.10.

[0156] The zeta potential was determined to be -40 mV at pH 7.

[0157] Zirconium concentration was determined using inductively coupled plasma-optical emission spectroscopy (ICP-OES).

[0158] Example 3. Nanoparticles prepared from insulator materials with low relative dielectric constant (equal to or lower than 100): Synthesis of hafnium dioxide nanoparticles coated with a biocompatible coating exhibiting a negative surface charge

[0159] Hafnium dioxide (HfO2) nanoparticles were synthesized by precipitation of hafnium chloride (HfCl4) with tetramethylammonium hydroxide (TMAOH) at alkaline pH. The resulting suspension was treated with high pressure steam at above 110°C, cooled, washed with water and acidified.

[0160] As in Example 2, sodium hexametaphosphate was used for surface functionalization.

[0161] The hydrodynamic diameter was measured by DLS to be 73 nm and the polydispersity index (dispersion of the population of nanoparticles in size) was 0.09. At pH 7, the zeta potential was determined to be equal to -39 mV.

[0162] Hafnium concentration was determined using inductively coupled plasma-optical emission spectroscopy (ICP-OES).

[0163] Example 4. Nanoparticles prepared from insulator materials with low relative dielectric constant (equal to or lower than 100): Synthesis of hafnium dioxide nanoparticles coated with a biocompatible coating exhibiting a neutral surface charge

[0164] Hafnium dioxide (HfO2) nanoparticles were synthesized by precipitation of hafnium chloride (HfCl4) with tetramethylammonium hydroxide (TMAOH) at alkaline pH. The resulting suspension was autoclaved at above 110°C, cooled, washed with deionized water and acidified.

[0165] Biocompatible coating was performed using silane-polyethylene glycol 2 kDa ("Si-PEG 2 kDa"). Sufficient mass of Si-PEG 2 kDa was added to the nanoparticle suspension to achieve at least half monolayer coverage (2.5 molecules / nm) on the surface.2 ).

[0166] The hydrodynamic diameter of the nanoparticles was found to be equal to 81 nm and the polydispersity index (dispersity of the population of nanoparticles in size) was 0.15.

[0167] At pH 7, the zeta potential was determined to be equal to -5 mV.

[0168] Hafnium concentration was determined using inductively coupled plasma-optical emission spectroscopy (ICP-OES).

[0169] Example 5: Efficacy of a single administration of nanoparticles for the symptomatic treatment of mechanical allodynia in a chemotherapy-induced peripheral neuropathy model in rats (oxaliplatin)

[0170] The aim of this study was to investigate the effect of a single intraplantar treatment with nanoparticles from Example 1 at a dose of 11 g / L (NP1B), 53 g / L (NP2B), 57 g / L (NP20B), and 59 g / L (NP20A) (each injection volume of 20 µL) on mechanical allodynia (as assessed using von Frey) occurring after systemic administration of oxaliplatin in rats.

[0171] Study Design

[0172] The experimental design of the CIPN model is shown in Table 1.

[0173]

[0174] Table 1: Experimental design of CIPN study from Example 5

[0175] Materials and Methods

[0176] All experiments were performed in accordance with the ethical guidelines of the International Association for the Study of Pain ( Zimmerman, 1983 ).

[0177] Experimental Subjects: Seventy-two (72) adult male Sprague-Dawley rats were used in this study. The animals were housed in groups of four in intra-ventilated cages in a controlled environment with constant temperature and humidity (temperature: 21 ± 1°C, light: dark cycle of 12:12 h) with ad libitum access to food and water. The animals were allowed to recover from transportation for at least one week before starting the experiment.

[0178] Static mechanical (tactile) allodynia assessment: Paw withdrawal threshold (PWT) measurements were achieved using a calibrated (force; g) von-Frey monofilament (Touch-Test Sensory Evaluator; Scientific Marketing Associates) applied to the plantar surface of the hind paw. Withdrawal thresholds were determined by increasing and decreasing stimulus intensity and estimated using Dixon's up-down method.

[0179] The animal was placed in a 0.5 cm 2 The rats were placed on an elevated mesh-bottom platform of a grid to provide access to the ventral side of the hind paw. An inverted plexiglass container was placed on top of each rat and tested after an initial 15-20 minute adaptation / habituation period. The von Frey filament was placed vertically on the plantar surface of the hind paw from underneath the mesh floor. The monofilament was held in this position for approximately 5 seconds with sufficient force to induce a slight bend in the filament. Only a vigorous withdrawal response (or flinching) occurring within a maximum of five seconds from the start of the stimulus was considered to represent a positive response.

[0180] Research Plan:

[0181] Baseline readings of withdrawal latency (sec) were assessed for three consecutive days (Day -3, Day -2, and Day -1). The average of Day -2 and Day -1 was considered the baseline before oxaliplatin administration, and Day 0 (D0) was the day of oxaliplatin injection. Neuropathic baseline recordings were performed on Day 5 (D5) and Day 6 (D6) after oxaliplatin.

[0182] On D7 after oxaliplatin, nanoparticle-treated animals were injected intraplantarly into the left paw using a microneedle device. Throughout A single injection of nanoparticles was performed during the experiment. Pregabalin treated animals (positive control) were dosed orally (po) and tested 2 hr after dosing. Nanoparticle treated animals were also tested 2 hr after dosing on D7. Pregabalin was administered on each day of the von Frey test.

[0183] Mechanical allodynia was subsequently reassessed 2-3 times per week after injection until D26 post-oxaliplatin. Testing days (post-oxaliplatin) were D7 (test compound dosing day), D10, D14, D18, D22, and D26.

[0184] Data analysis

[0185] Two-way repeated measures ANOVA was used with 'treatment' as the between-subject effect and 'day' as the within-subject effect (using GraphPad Prism version 9.0 for Windows, GraphPad Software, San Diego California USA), followed by Dunnett's multiple comparison test. Data are presented as mean ± SEM.

[0186] result

[0187] Figure 1 Shown are the values ​​of paw withdrawal threshold (PWT) of rats following oxaliplatin-induced mechanical allodynia. Figure 2 Shown are pictures of rat paws immediately after intraplantar administration of nanoparticles from Example 1 (D0) and immediately after the rats were sacrificed (D26).

[0188] in conclusion

[0189] Oxaliplatin administration induced consistent mechanical allodynia responses as indicated by paw withdrawal threshold (PWT) levels ( Figure 1 ). Systemic pregabalin treatment, as a positive control, rescued the allodynic response and restored PWT to healthy baseline levels.

[0190] The nanoparticles from Example 1 (NP1B) showed a significant increase in PWT when compared to their neuropathological baseline ( Figure 1 ), especially on day 14 and beyond. The nanoparticles from Example 2 (NP2B) showed an increase in PWT when compared to their neuropathic baseline values ​​(at D7, D14, and D18). The nanoparticles from Example 3 (NP20B) were particularly effective on D18 and beyond, with significant differences from their neuropathic baseline. The nanoparticles from Example 4 (NP20A) were consistently the most effective nanoparticle compounds for reversing mechanical allodynia on D14 and beyond, with significant increases in PWT values ​​relative to their neuropathic baseline. Figure 2 It was shown that the nanoparticles from Example 1 remained at the site where they were injected for at least 26 days with minimal elimination.

[0191] Example 6: Efficacy of a single administration of nanoparticles from Example 3 for the symptomatic treatment of mechanical allodynia in a chemotherapy-induced peripheral neuropathy model in rats (oxaliplatin): dose effect

[0192] The aim of this study was to investigate the effect of a single intraplantar administration of nanoparticles from Example 3 at different doses on mechanical allodynia in the rat oxaliplatin model of chemotherapy-induced neuropathic pain.

[0193] Study Design

[0194] The experimental design of the CIPN model study is shown in Table 2.

[0195]

[0196] Table 2: Experimental design of CIPN study from Example 6 - Note: In this study, each animal constituted its own neuropathic control, as the 'treatment' had been injected into the left paw by intraplantar injection, while the 'vehicle' had been injected into the right paw by intraplantar injection, so the paw withdrawal threshold (PWT) measurements on the right paw constituted the 'neuropathic control group'. A 'vehicle / vehicle' group ('healthy animals') was also included.

[0197] Materials and Methods

[0198] All experiments were performed in accordance with the ethical guidelines of the International Association for the Study of Pain ( Zimmerman, 1983 ).

[0199] Experimental Subjects: Sixty (60) adult male Sprague-Dawley rats (180–210 g) were used in this study. The animals were housed in groups of four in a controlled environment with constant temperature and humidity (temperature: 21 ± 1°C, light:dark cycle of 12:12 h) in internally ventilated cages with ad libitum access to food and water. The animals were allowed to recover from transportation for at least one week before starting the experiment.

[0200] Static mechanical (tactile) allodynia: Withdrawal threshold measurements were achieved using a calibrated (force; g) von-Frey monofilament (Touch-Test Sensory Evaluator; Scientific Marketing Associates) applied to the plantar surface of the hind paw. Withdrawal thresholds were determined by increasing and decreasing stimulus intensity and estimated using Dixon's up-and-down method.

[0201] The animal was placed in a 0.5 cm 2 The rats were placed on an elevated mesh-bottom platform of a grid to provide access to the ventral side of the hind paw. An inverted plexiglass container was placed on top of each rat and tested after an initial 15-20 minute adaptation / habituation period. The von-Frey filament was placed vertically on the plantar surface of the hind paw from underneath the mesh floor. The monofilament was held in this position for approximately 4 seconds with sufficient force to induce a slight bend in the filament. Only vigorous withdrawal reactions (or withdrawal) occurring within a maximum of five seconds from the onset of stimulation were considered to represent positive responses.

[0202] Study schedule: Baseline readings of withdrawal latency (sec) were assessed on three consecutive days (Day -3, Day -2, and Day -1). The average of Day -2 and Day -1 was considered the baseline before oxaliplatin administration, and Day 0 (D0) was the day of oxaliplatin injection. Neuropathic baseline recordings were performed on Day 5 (D5) after oxaliplatin.

[0203] On day 6 (D6) after oxaliplatin, nanoparticle-treated animals were injected intraplantarly into one paw using a microneedle device (the contralateral paw served as a control by injecting the same volume of vehicle-saline using a microneedle device). Throughout the experiment A single injection of nanoparticles was performed during the procedure. Pregabalin treated animals (positive control) were dosed orally (po) and tested for mechanical allodynia 2 hr post-dose. Nanoparticle treated animals were also tested 2 hr post-dose on D6. Pregabalin was administered daily for von Frey testing.

[0204] Mechanical allodynia was subsequently reassessed 2-3 times per week after injection until day 24 (D24) after oxaliplatin.Test days (after oxaliplatin) were D6 (test compound dosing day), D9, D13, D16, D20, and D24.

[0205] Data analysis

[0206] Two-way repeated measures ANOVA was used with 'treatment' as the between-subject effect and 'day' as the within-subject effect (using GraphPad Prism version 9.0 for Windows, GraphPad Software, San Diego California USA), followed by Dunnett's multiple comparison test. Data are presented as mean ± SEM.

[0207] result

[0208] The paw withdrawal threshold (PWT) values ​​of rats after oxaliplatin-induced mechanical allodynia are shown in Figure 3 , 4 , 5, 6 and 7, and the significance of the results is evaluated in Tables 3, 4, 5, 6 and 7 below.

[0209] Sources of variation P-value P-value summary Time × Group 0.9418 ns time 0.1317 ns Group (left paw vs. right paw) 0.7654 ns Subjects <0.0001 ****

[0210] Table 3: CIPN study from Example 6: Summary of mixed effects analysis of 'Vehicle / Vehicle' group (Dunnett's multiple comparison test) ("ns": not significant; *: P value < 0.05; **: P value < 0.01; ***: P value < 0.001; ****: P value < 0.0001).

[0211] Sources of variation P-value P-value summary Time × Group 0.4155 ns time <0.0001 **** Group (left paw vs. right paw) 0.0326 * Subjects 0.0612 ns

[0212] Table 4: Summary of mixed effects analysis (Dunnett's multiple comparison test) for CIPN study from Example 6: 'Nanoparticles from Example 3 - 61 g / L-20 µL' group ("ns": not significant; *: P value < 0.05; **: P value < 0.01; ***: P value < 0.001; ****: P value < 0.0001).

[0213] Sources of variation P-value P-value summary Time × Group 0.5784 ns time <0.0001 **** Group (left paw vs. right paw) 0.0678 ns Subjects 0.0058 **

[0214] Table 5: Summary of mixed effects analysis (Dunnett's multiple comparison test) for CIPN study from Example 6: 'Nanoparticles from Example 3 - 18 g / L-20 µL' group ("ns": not significant; *: P value < 0.05; **: P value < 0.01; ***: P value < 0.001; ****: P value < 0.0001).

[0215] Sources of variation P-value P-value summary Time × Group 0.5997 ns time <0.0001 **** Group (left paw vs. right paw) 0.4304 ns Subjects 0.0001 ***

[0216] Table 6: Summary of mixed effects analysis (Dunnett's multiple comparison test) for CIPN study from Example 6: 'Nanoparticles from Example 3 - 18 g / L-10 μL' group ("ns": not significant; *: P value < 0.05; **: P value < 0.01; ***: P value < 0.001; ****: P value < 0.0001).

[0217] Sources of variation P-value P-value summary Time × Group 0.317 ns time <0.0001 **** Group (left paw vs. right paw) 0.3211 ns Subjects 0.0003 ***

[0218] Table 7: Summary of mixed effects analysis (Dunnett's multiple comparison test) for the CIPN study from Example 6: 'Pregabalin / oxaliplatin' group ("ns": not significant; *: P value < 0.05; **: P value < 0.01; ***: P value < 0.001; ****: P value < 0.0001).

[0219] in conclusion

[0220] Administration of oxaliplatin induced consistent mechanical allodynia responses on days after administration until assessment on day 20, as indicated by paw withdrawal threshold (PWT) levels in the right paw. As known from the literature (WH Xiao, H. Zheng, andG. J. Bennett, Neuroscience. 2012, 203: 194–206 : Characterization ofoxaliplatin-induced chronic painful peripheral neuropathy in the rat andcomparison to the neuropathy induced by paclitaxel), and as observed from the PWT of the untreated (right) paw in all groups at baseline levels (before neuropathy) on day 24, the mechanical allodynia side effect of oxaliplatin began to decrease after 4 weeks due to oxaliplatin washout. Systemic pregabalin treatment served as a positive control, as PWT levels were not significantly different from the 'vehicle / vehicle' group (non-neuropathic) for both left and right paws on any test day.

[0221] The nanoparticles from Example 3 at a concentration of 61 g / L and an applied volume of 20 μL resulted in a reduction in the pain response of the treated (left) paw, as the data showed a higher paw withdrawal threshold (PWT) value on the left paw when compared to the right paw, and because statistical analysis showed a significant effect of side (left paw relative to right paw), p value <0.05 (p value = 0.0326; see Table 4), while statistical analysis did not show a significant effect of side of the nanoparticles from Example 3 at 18 g / L, in a volume of 20 μL (p value = 0.0678) and 10 μL (p value = 0.4304) (see Tables 5 and 6). This result indicates that the minimum dose threshold of the nanoparticles from Example 3 is significantly effective in reducing mechanical allodynia caused by oxaliplatin-induced peripheral neuropathy in rats. A single injection of nanoparticles from Example 3 at a concentration of 61 g / L (20 µL) induced pain relief from day 9 to day 20, meaning that pain relief lasted for at least 11 days, whereas the positive control pregabalin had to be injected every 2 days (2 hr before Von Frey assessment).

[0222] Example 7: Efficacy of a single administration of nanoparticles for the symptomatic treatment of mechanical allodynia in a diabetes-induced peripheral neuropathy model in rats (streptozotocin)

[0223] The main cause of neuropathic pain observed clinically is caused by diabetes. In rodents, this is simulated by injection of streptozotocin (STZ) to induce diabetes. STZ is an antibiotic that interferes with insulin production by destroying pancreatic islet cells, and as a result, rats develop diabetes and diabetes-induced neuropathic pain. The rat STZ model of diabetes has been successfully used to simulate neuropathic pain caused by type 1 diabetes and provided key decision-making allodynia efficacy data for the development of pregabalin, which is one of the very few treatments that has successfully translated preclinical neuropathic pain results into clinical success.

[0224] Diabetes was confirmed by measuring blood glucose levels. Neuropathic pain symptoms, such as mechanical allodynia (measured using von-Frey filaments), usually appeared between 2 and 6 weeks after STZ injection.

[0225] The aim of this study was to investigate the effect of a single intraplantar treatment with nanoparticles from Example 3 (at doses of 117 g / L in 20 µL injection volume, 58 g / L in 20 µL injection volume, and 18 g / L in 10 µL injection volume) on mechanical allodynia (assessed using von Frey) following systemic administration of streptozotocin in rats.

[0226] Study Design

[0227] The experimental design of the STZ-induced diabetic neuropathy model is shown in Table 8.

[0228] Group ID STZ treatment (day 0) Dose level and route Test article administration day Test article (left hind paw) Nanoparticle concentration Volume / Route of administration Number of animals A vehicle 10 mL / kg IP D14 vehicle n / a 20 µl intraplantar 6 B Streptozotocin 55 mg / kg IP D14 vehicle n / a 20 µl intraplantar 12 C Streptozotocin 55 mg / kg IP D14 Nanoparticles from Example 3 117 g / L 20 µl intraplantar 12 D Streptozotocin 55 mg / kg IP D14 Nanoparticles from Example 3 58 g / L 20 µl intraplantar 12 E Streptozotocin 55 mg / kg IP D14 Nanoparticles from Example 3 18 g / L 10 µl intraplantar 12 F Streptozotocin 55 mg / kg IP D14 Pregabalin 30 mg / kg po 12

[0229] Table 8: Experimental design for STZ-induced diabetic NP study (Example 7)

[0230] Materials and Methods

[0231] All experiments were performed in accordance with the ethical guidelines of the International Association for the Study of Pain (Zimmerman, 1983). All behavioral tests were approved by the UK Home Office Animals (Scientific Procedures) Act (1986).

[0232] Experimental Subjects: Sixty-six (66) adult male Sprague-Dawley rats (180–210 g) were used in this study. The animals were housed in groups of two in a controlled environment with constant temperature and humidity (temperature: 21 ± 1°C, light:dark cycle of 12:12 h) in internally ventilated cages with ad libitum access to food and water. The animals were allowed to recover from transportation for at least one week before starting the experiment.

[0233] Streptozotocin-induced diabetes model: Animals were injected with STZ (day 0) (55 mg / kg, i.p., 10 mL / kg, single injection) or its vehicle solution (20 mM citrate buffer, i.p., 10 mL / kg, single injection). Forty-eight hours after STZ injection, animals were given 2% sucrose in their drinking water (provided with a choice of 1 bottle of water and 1 bottle of 2% sucrose) to manage the transient hypoglycemic period that typically occurs between 4 - 8 hours after STZ injection. After STZ injection, all animals were switched to a slightly higher protein diet (Labdiet 5LF5; 22% protein).

[0234] Body weight was monitored daily throughout the study. STZ rats typically lose between 5 - 10% of their baseline body weight and usually start to gain weight back to baseline levels within 4 weeks. Observable STZ-induced toxicity occurred 3 - 4 days after injection (< 5% of the total n). Typical symptoms of diabetic animals include polydipsia, polyuria, glycosuria, and hyperglycemia. To minimize distress, diabetic animals were provided with extra drinking water as they were polydipsic and, due to polyuria, their home cages were changed more frequently (daily). Rats were cleaned daily after i.p. STZ and after behavioral testing.

[0235] Confirmation of hyperglycemia: On day 7 (D7), a drop of tail vein blood was obtained from awake rats by needle prick. The blood glucose level in a drop of blood was measured using an Exactive Vital (MictoTech Medical) blood glucose monitor. Only STZ-injected rats with a blood glucose concentration higher than 16 mmol / L were considered diabetic and included in this study (expected > 90%).

[0236] Static mechanical (tactile) allodynia: Measurement of withdrawal threshold was achieved using a calibrated (force; g) von-Frey monofilament (Touch-Test Sensory Evaluator; Scientific Marketing Associates) applied to the plantar surface of the hind paw. The withdrawal threshold was determined by increasing and decreasing the stimulus intensity and estimated using Dixon's up-and-down method (Dixon, 1980; Chaplan et al., 1994).

[0237] Animals were placed on a surface with 0.5 cm 2The rats were placed on an elevated mesh-bottom platform of a grid to provide access to the ventral side of the hind paw. An inverted plexiglass container was placed on top of each rat and tested after an initial 15-20 minute adaptation / habituation period. The von-Frey filament was placed vertically on the plantar surface of the hind paw from underneath the mesh floor. The monofilament was held in this position for approximately 4 seconds with sufficient force to induce a slight bend in the filament. Only vigorous withdrawal reactions (or withdrawal) occurring within a maximum of five seconds from the onset of stimulation were considered to represent positive responses.

[0238] Study schedule: Nanoparticle treated animals were topically dosed with a microneedle device as an intraplantar injection into a single paw. Pregabalin was orally administered 2 hr prior to each Von Frey test. Nanoparticles were administered only once on day 14 (D14). Control groups ('Vehicle / Vehicle' and 'STZ / Vehicle') were injected with saline once in a single paw using a microneedle (on D14).

[0239] Von Frey readings were performed at baseline (pre-STZ), D9 and D11 after STZ (neuropathic / allodynia baseline), and 2 hours post-dose on day 14. Von-Frey readings were repeated twice weekly until 3 weeks post-STZ (1 week after nanoparticle administration).

[0240] Data analysis

[0241] Two-way repeated measures ANOVA was used with 'treatment' as the between-subject effect and 'day' as the within-subject effect (using GraphPad Prism version 9.0 for Windows, GraphPad Software, San Diego California USA), followed by Dunnett's multiple comparison test. Data are presented as mean ± SEM.

[0242] result

[0243] Figure 8 The values ​​of paw withdrawal threshold (PWT) of rats after STZ-induced mechanical allodynia are shown in , and the significance of the results is assessed in Table 9 below.

[0244]

[0245] Table 9: STZ-induced diabetic NP study (Example 7): Summary of mixed effects analysis (Dunnett's multiple comparison test) ("ns": not significant; *: P value < 0.05; **: P value < 0.01; ***: P value < 0.001; ****: P value < 0.0001)

[0246] in conclusion

[0247] Blood glucose levels: All STZ-treated animals had elevated blood glucose levels on day 7 (D7), with levels above 16 mmol / L (data not shown). This increase was statistically significant when comparing the means of the different groups on day 0 (D0) (STZ administration day and day 7).

[0248] It is noteworthy that the model was run until D38, but due to the abnormal behaviors induced in the animals by the side effects of STZ (diarrhea, increased behavioral signs of stress during the treatment period), although the animals from the untreated (naïve) group did not show any clinical symptoms as expected, they also showed some behavioral signs of stress, such as restlessness when being handled, which led to uninterpretable results from D24 to D38.

[0249] Mechanical allodynia: STZ-treated animals were scored for neuropathic mechanical allodynia on day 9 (D9) and day 11 (D11). All animals showed increased levels of mechanical allodynia.

[0250] Systemic pregabalin treatment served as a positive control. On all tested days, PWT levels were significantly different from the 'STZ / Vehicle' group.

[0251] Treatment with different doses of nanoparticles resulted in statistically significantly higher PWT levels at D14, D17 and D21 for the group treated with 58 g / L concentration when compared to the 'STZ / Vehicle' group ( Figure 7 ). Notably, the lowest dose of the nanoparticles from Example 3 (18 g / L-10 µL) gave significantly higher PWT levels relative to the 'STZ / Vehicle' group, with a p-value < 0.001 at D21, meaning that this dose is sufficient to have the efficacy of the nanoparticles from Example 3 for the symptomatic treatment of mechanical allodynia in the diabetic-induced neuropathic pain model in rats.

Claims

1. Nanoparticles or aggregates thereof for use in treating peripheral neuropathic pain in a subject without exposing the nanoparticles or nanoparticle aggregates to an electric field or any other external activation source, wherein i) the nanoparticle material is a metal conductor selected from Ir, Pd, Pt, Au and any mixture thereof; having a continuous sp 2 A hybrid carbon-centered organic material selected from poly(3,4-ethylenedioxythiophene) (PEDOT), poly(styrene sulfonate) (PSS), and mixtures thereof; or having a dielectric constant ε equal to or lower than 100 ijk The invention relates to an insulator material which is a metal oxide or a mixed metal oxide, wherein the metal is Zr and / or Re, ii) when the nanoparticle material is a metal conductor, the median population core size of the nanoparticles or nanoparticle aggregates is at least 45 nm, and iii) the cores of the nanoparticles or nanoparticle aggregates are coated with a biocompatible coating, which provides a neutral or negative surface charge when measured in an aqueous solution with an electrolyte concentration between 0.001 and 0.2 M, a nanoparticle or nanoparticle aggregate material concentration between 0.01 and 10 g / L and a pH between 6 and 8.

2. The nanoparticle or aggregate thereof for use according to claim 1, wherein the subject to be treated suffers from trigeminal neuralgia, neuropathic pain after peripheral nerve injury including post-traumatic neuropathic pain, postoperative neuropathic pain or neuropathic pain caused by neuroma, painful polyneuropathy associated with diabetes, human immunodeficiency virus (HIV), Fabry disease, sodium channel gene mutation, autoimmune diseases such as Guillain-Barré syndrome, vasculitis, chronic inflammatory demyelinating polyneuropathy, amyloidosis, non-freezing frostbite, paraneoplastic syndrome or leprosy, chemotherapy-induced peripheral neuropathy (CIPN), postherpetic neuralgia or painful radiculopathy.

3. The nanoparticle or aggregate thereof for use according to claim 2, wherein the subject to be treated suffers from peripheral nerve damage including post-traumatic neuropathic pain, postoperative neuropathic pain or neuropathic pain caused by neuroma, post-herpetic neuralgia, painful polyneuropathy associated with diabetes, CIPN or HIV.

4. The nanoparticle or aggregate thereof for use according to claim 3, wherein the subject to be treated suffers from neuropathic pain after peripheral nerve injury, including post-traumatic neuropathic pain, postoperative neuropathic pain or neuropathic pain caused by neuroma.

5. The nanoparticle or aggregate thereof for use according to claim 3, wherein the subject to be treated suffers from painful polyneuropathy associated with diabetes or painful polyneuropathy arising from CIPN.

6. The nanoparticle or aggregate thereof for use according to any one of claims 1 to 5, wherein the subject suffers from focal neuropathic pain.

7. The nanoparticle or aggregate thereof for use according to any one of claims 1 to 5, wherein the subject suffers from refractory and / or chronic neuropathic pain.

8. The nanoparticles or aggregates thereof for use according to any one of claims 1 to 7, wherein the nanoparticles or aggregates are administered by intradermal and / or intraepidermal injection.

9. Nanoparticles or aggregates thereof for use according to any one of claims 1 to 8, wherein the dose of nanoparticles or aggregates to be administered is at least 60 μg per square centimeter of injected skin surface.

10. Nanoparticles or aggregates thereof for use according to any one of claims 1 to 9, wherein the nanoparticle material is ZrO2.

11. The nanoparticle or aggregate thereof for use according to any one of claims 1 to 9, wherein the nanoparticle material is selected from Ir, Au, Pd, Pt and any mixture thereof.

12. The nanoparticles or aggregates thereof for use according to claim 10, wherein the patient suffers from diabetic neuropathy and the dose of the nanoparticles or aggregates administered is at least 60 μg per square centimeter of skin surface to be injected.

13. The nanoparticles or aggregates thereof for use according to claim 10, wherein the patient suffers from CIPN and the dose of the nanoparticles or aggregates administered is at least 390 μg per square centimeter of skin surface to be injected.

14. The nanoparticles or aggregates thereof for use according to claim 11, wherein the patient suffers from CIPN and the dose of the nanoparticles or aggregates administered is at least 70 μg per square centimeter of skin surface to be injected.

15. The nanoparticles or aggregates thereof for use according to any one of claims 1 to 14, wherein the nanoparticles or aggregates thereof are administered using a dissolvable microneedle patch.

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