Treating pain associated with chemotherapy-induced peripheral neuropathy

Abstract

The invention features methods of preventing and / or treating neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN).

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 192,246, filed May 24, 2021, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0002] The present invention relates to compounds and their use in the treatment of neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN). Background Art

[0003] Neuropathy is a disease or abnormality of the nervous system that afflicts more than 20 million Americans. In fact, according to recent studies, neuropathic pain is observed to affect approximately 1 in 10 adults, and the economic burden of treating this pain is increasing.

[0004] Neuropathy is associated with the development of neuropathic pain. Neuropathic pain can occur due to damage to the peripheral or central nervous system. Peripheral neuropathic pain is caused by damage to neural structures (such as peripheral nerve endings or nociceptors), which become extremely sensitive to stimulation and can generate impulses in the absence of stimulation. Damage can occur for many reasons, such as chemotherapy treatment (i.e. CIPN), diseases such as diabetes and advanced cancer, viruses (e.g., herpes zoster or HIV) and physical injuries (e.g., accidents or surgical operations).

[0005] Peripheral nerve damage can lead to a pathological state characterized by the presence of persistent spontaneous pain that is often associated with hyperalgesia (increased response to noxious stimuli) and allodynia (pain caused by non-painful stimuli). Hyperalgesia and allodynia are associated with central sensitization, in which CNS nociceptive neurons exhibit increased excitability due to a lowered threshold for stimulation triggered by persistent input or peripheral injury. Central sensitization has been implicated in the generation and maintenance of neuropathic pain associated with peripheral neuropathy.

[0006] From a symptom perspective, peripheral neuropathy can cause sharp pain, dull pain, painful burning or cold sensations, paresthesias, loss of proprioception, numbness, or even loss of pain perception.

[0007] There is a worldwide need for additional pain therapies, and neuropathic pain has evolved into a major health problem for a large population.

[0008] Neuropathic pain is often tried with so-called unconventional analgesics, such as antidepressants like duloxetine and amitriptyline, or antiepileptic drugs like gabapentin or pregabalin. In addition, local anesthetics including lidocaine have been used to treat and control neuropathic pain. Despite evidence to the contrary, nonsteroidal anti-inflammatory drugs (NSAIDs) are still widely used to control neuropathic pain. However, according to a recent review of clinical trials, there is no evidence that NSAIDs significantly reduce pain in patients with neuropathic pain (Moore et al. Cochrane Database of Systematic Reviews (2015); 10: 1–25), nor are there clinical results showing a statistically significant difference between NSAIDs and placebo. The Cochrane Library concluded that NSAIDs should not be recommended for the treatment of neuropathic pain.

[0009] CIPN and related neuropathic pain are common, dose-dependent side effects in conventional chemotherapy. Peripheral nerve damage represents most of the nerve damage associated with chemotherapy toxicity, and represents the most common limiting factor of chemotherapy after hematological toxicity. It has always been believed that the pain is due to direct toxic effects on sensory axons, demyelination or calcium metabolism disorders. The neuropathic pain associated with CIPN is particularly difficult to treat. It is currently managed and controlled with antidepressants (such as duloxetine) and / or antiepileptic drugs (such as gabapentin and pregabalin). Unfortunately, pain control is not very satisfactory, and these systemic treatments induce major side effects, resulting in poor treatment compliance. In fact, to date, there is no satisfactory way to prevent or even treat the pain associated with CIPN: the only approved drug (duloxetine) is generally considered to be ineffective.

[0010] Therefore, there is a strong need for compounds that treat and / or prevent pain associated with peripheral neuropathies, in particular CIPN. Summary of the invention

[0011] The present inventors have unexpectedly discovered that sulindac phosphate (PS) is effective in treating and preventing pain associated with CIPN.

[0012] PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike its parent compound, the NSAID sulindac, PS does not inhibit COX-1 and COX-2 expression and is therefore not a typical NSAID. PS has previously been shown to have anticancer and anti-inflammatory properties through its inhibition of NF-κB activation and changes in the MAPK signaling branch, as well as activity in treating rheumatoid arthritis in inflammatory mouse models by inhibiting key pro-inflammatory signaling pathways (Mackenzie et al. (2010) Gastroenterology 139(4):1320–32 and Mattheolabakis et al. (2013) Pharm Res 30(6):1471–82). WO 2019 / 067919 shows that PS has anti-inflammatory activity in an acute model of dry eye disease (DED). In addition, in this model, PS was observed to restore suppressed ocular sensitivity in DED, indicating that the effect of PS is to increase rather than reduce nociception. Although, as mentioned above, PS is not a typical NSAID, it exhibits activity similar to that of NSAIDs when administered to normal eyes in the DED model. However, these observations fail to suggest a role for PS in the treatment of neuropathic pain associated with CIPN. Furthermore, clinical guidelines in the field recommend avoiding the use of NSAIDs to treat all types of neuropathic pain, and therefore anti-inflammatory activity alone is considered insufficient for treatment.

[0013] However, the inventors considered the activity of PS in a specific animal model of neuropathic pain and demonstrated unexpected therapeutic efficacy, equivalent to direct-acting nerve block anesthetics such as lidocaine and pregabalin. Specific animal models are important in the development of therapies for the treatment of neuropathic pain. In fact, in view of the pathogenesis of pain associated with peripheral neuropathy, the efficacy of specific compounds observed in alternative pain models does not indicate the utility of the compounds in the treatment of neuropathic pain. Consistent with this, even if the clinical syndrome is similar, it is impossible to extrapolate the use of effective drugs from other forms of neuropathic pain to the neuropathic pain of particular interest. For example, gabapentin shows different efficacy in the treatment of different forms of neuropathic pain. Therefore, the animal model used in early testing before further clinical development is crucial. Based on a specific animal model of CIPN neuropathic pain, the observations herein demonstrate that PS has unprecedented efficacy in the treatment and / or prevention of neuropathic pain associated with CIPN.

[0014] Therefore, in a first aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with CIPN, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with CIPN is treated and / or prevented.

[0015] In some embodiments, PS is a sulfoxide form of PS. Thus, PS may have Formula I (PS-I):

[0016]

[0017] In other embodiments, PS is a sulfide form of PS. Thus, PS may have Formula II (PS-II):

[0018]

[0019] Herein, reference to "sulindac phosphate" or "PS" encompasses both PS-I and PS-II. The sulfide form of the compound is preferred. Compounds of Formula I and II are described in U.S. Pat. No. 8,236,820, which is hereby incorporated by reference in its entirety.

[0020] As described above, nerve damage associated with CIPN can lead to excessive activation of pain signaling pathways, thereby causing peripheral neurons and / or central neurons to be sensitive, and the neurons show a reduced threshold for stimulation. Therefore, subjects with CIPN may experience pain due to this sensitization, for example, experience pain caused by non-painful stimuli (allodynia) or experience pain (hyperalgesia) in response to aggravated noxious stimuli. Based on the observations herein, PS may have a direct analgesic effect, such as by reducing the neuronal signaling involved in pain sensation. In addition, PS can alleviate the pain produced by peripheral sensitization or by central sensitization. Therefore, PS can reduce or prevent pain signaling occurring in the center. PS can reduce or prevent pain signaling occurring in the sciatic nerve. PS can reduce or prevent pain signaling occurring in the dorsal root ganglion. In view of the fact that PS shows that peripheral neurons are promoted to the spinal cord, PS can reduce or prevent pain signaling occurring in the spinal cord. In some embodiments, neuropathic pain is allodynia. Allodynia can be a response to mechanical and / or thermal stimuli. In addition, in some embodiments, neuropathic pain is hyperalgesia.

[0021] PS can be formulated into a pharmaceutical composition for use in the present invention. In some embodiments, the pharmaceutical composition comprises PS and one or more pharmaceutically acceptable excipients. PS can be formulated for topical administration, particularly topical administration to the upper and lower extremities of a subject (i.e., covered with stockings and gloves for distribution). BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 - Schematic overview of neuropathic pain associated with CIPN prevention studies. PWT is the paw withdrawal threshold test.

[0023] Figure 2 – Effect of PS compared with vehicle on the prevention of neuropathic pain associated with CIPN.

[0024] Figure 3 – Schematic overview of neuropathic pain relevant to CIPN treatment research.

[0025] Figure 4 – Effect of PS in the treatment of neuropathic pain associated with CIPN.

[0026] Figure 5 - Effect of PS on the treatment of neuropathic pain associated with paclitaxel-induced CIPN. Compared with its vehicle control, the effect of PS was significant from day 5 and increased thereafter ( & , p = 1.7x10 -7 ,*,p=2.2x10 -7 ).

[0027] Figure 6 - Effect of PS on the treatment of neuropathic pain associated with vincristine-induced CIPN. The effect of PS was significant at day 16 compared to its vehicle control (*p=8.6x10 -6 ).

[0028] Figure 7 - Effect of PS on the treatment of neuropathic pain associated with oxaliplatin-induced CIPN. The effect of PS was significant at day 22 compared to its vehicle control (*p=0.004).

[0029] Figure 8 - Effect of PS on the prevention of neuropathic pain associated with paclitaxel-induced CIPN. The effect of PS was significant compared to its vehicle control (*, p=3.0x10 -8 , **, p = 2.3x10 -6 ).

[0030] Fig. 9 – Schematic outline of PS metabolism.

[0031] Fig.10 - Biodistribution of PS in different tissues after topical application. SN = sciatic nerve. DRG = dorsal root ganglion.

[0032] Fig.11– Biodistribution of PS metabolites in different tissues after topical administration of PS. SN = sciatic nerve. DRG = dorsal root ganglion.

[0033] Figure 12 – Effect of PS compared with sulindac, lidocaine, and pregabalin in the treatment of neuropathic pain associated with CIPN. Fig. 12A Involving mechanical allodynia (*, statistically significant difference; NS, not statistically significant). Fig. 12B Involvement in cold allodynia (values: mean ± SEM; *, p < 0.0001). DETAILED DESCRIPTION

[0034] definition

[0035] The following definitions of pain types are based on the definitions of the International Association for the Study of Pain (IASP). "Pain" is an unpleasant sensory and emotional experience associated with or similar to actual or potential tissue damage. "Neuropathic pain" is caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain is a clinical description (not a diagnosis) that requires a lesion or disease that clearly meets established neurological diagnostic criteria. Neuropathic pain patients may experience one or more sensations described as heat, burning, throbbing, shooting, tingling, sharp, cramping, soreness, tingling, numbness or pins and needles. When diagnostic tests (e.g., imaging, neurophysiology, biopsy, laboratory tests) reveal abnormalities or when there is obvious trauma, the term "lesions of the somatosensory nervous system" is often used. When the underlying cause of the lesion is known (e.g., stroke, vasculitis, diabetes, genetic abnormalities), the term "disease of the somatosensory nervous system" is often used. "Peripheral neuropathic pain" is pain caused by a lesion or disease of the peripheral somatosensory nervous system. “Central neuropathic pain” is pain caused by a lesion or disease of the central somatic sensory nervous system. “Central sensitization” refers to the increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input. “Peripheral sensitization” refers to the increased responsiveness and lowered threshold of nociceptive neurons in the periphery to stimulation of their receptive fields. “Allodynia” is pain caused by stimuli that do not normally cause pain. “Hyperalgesia” refers to the exacerbation of pain caused by stimuli that normally cause pain.

[0036] In general, the term "disease" refers to a state or condition in a patient or subject that can be treated using the methods provided herein.

[0037] The term "therapeutically effective amount" refers to an amount of a compound or combination of compounds as described herein sufficient to achieve the intended application, including but not limited to treating and / or preventing disease.

[0038] "Pharmaceutically acceptable excipients" are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients contained in a pharmaceutical composition. The use of such pharmaceutically acceptable excipients for formulating active pharmaceutical ingredients is well known in the art. Unless any conventional pharmaceutically acceptable excipient is incompatible with PS, its use in the therapeutic compositions of the present invention is contemplated.

[0039] The use of the term "about" when referring to numbers is optional and means that the number referred to is an approximation within typical experimental variability (or within statistical experimental error), and thus the number may vary accordingly.

[0040] The term "comprising" encompasses "including" as well as "consisting of," for example, a composition "comprising" X may consist of X alone, or may include additional substances (eg, X+Y).

[0041] Pain associated with chemotherapy-induced peripheral neuropathy

[0042] As described above, chemotherapy can cause neuronal damage, leading to peripheral neuropathy and associated neuropathic pain. Pain may occur during or after a patient undergoes chemotherapy, and may manifest as, for example, shooting pain, burning pain, or tingling associated with other sensory symptoms. Therefore, in some embodiments, the present invention provides a method for preventing neuropathic pain associated with CIPN, the method comprising administering a therapeutically effective amount of PS to a subject in need, so that neuropathic pain associated with CIPN is prevented. In other embodiments, the present invention provides a method for treating neuropathic pain associated with CIPN, the method comprising administering a therapeutically effective amount of PS to a subject in need, so that neuropathic pain associated with CIPN is treated. The subject may experience neuropathic pain caused by one or more previous doses of chemotherapy before one or more subsequent doses, and therefore the subject will benefit from an analgesic that can both treat existing neuropathic pain and prevent the generation of further neuropathic pain. Therefore, in some embodiments, PS can be used to treat and prevent neuropathic pain associated with CIPN. According to the above, the present invention provides PS for treating and / or preventing neuropathic pain associated with CIPN. Furthermore, the present invention provides the use of PS for the manufacture of a medicament for the treatment and / or prevention of neuropathic pain associated with CIPN.

[0043] Since CIPN develops in response to chemotherapy, the subject may be a human patient with cancer who is about to be treated, is currently being treated, or has previously been treated with one or more chemotherapeutic compounds. In general, a chemotherapeutic compound refers to an agent that has anti-tumor properties or the ability to inhibit the growth or proliferation of cells. The prevalence of CIPN is drug-dependent, with reported prevalence ranging from 19% to over 85% in patients receiving different drug treatments, and is highest in the case of platinum-based drugs, taxanes, immunomodulatory drugs, and epothilones, although CIPN is also observed in patients receiving other common cancer chemotherapies, including vinca alkaloids and proteasome inhibitors. Thus, the one or more chemotherapeutic compounds may be a platinum-based antineoplastic drug (e.g., oxaliplatin, cisplatin, or carboplatin), a taxane (e.g., paclitaxel, docetaxel, or cabazitaxel), a vinca alkaloid (e.g., vincristine, vinblastine, vinorelbine, or vindesine), or a proteasome inhibitor (e.g., bortezomib). The one or more chemotherapeutic compounds may be one or more immunomodulatory drugs, including thalidomide and / or its analogs. The one or more chemotherapeutic compounds may be platinum-based antineoplastic agents, such as oxaliplatin, taxanes (e.g., paclitaxel), and vinca alkaloids (e.g., vincristine). The subject may suffer from any cancer treated with chemotherapeutic compounds associated with the occurrence of CIPN and associated neuropathic pain. In some embodiments, the subject suffering from CIPN suffers from solid tumor cancer. The subject may suffer from ovarian cancer, breast cancer, lung cancer (e.g., non-small cell lung cancer), Kaposi's sarcoma, and / or pancreatic cancer. Alternatively, the subject may suffer from melanoma, esophageal cancer, prostate cancer (e.g., hormone-refractory prostate cancer), head and neck cancer, gastric cancer, and / or cervical cancer.

[0044] Based on the observations herein, PS has a direct analgesic effect on neuropathic pain associated with CIPN. Neuropathic pain associated with CIPN can be burning pain. Subjects undergoing chemotherapy or after chemotherapy may experience persistent and symmetrical neuropathic pain in the lower and upper limbs. When treating neuropathic pain associated with CIPN, PS can reduce or eliminate neuropathic pain. When treating neuropathic pain associated with CIPN, PS can also reduce or eliminate one or more sensory symptoms associated with CIPN. When preventing neuropathic pain associated with CIPN, PS can reduce the incidence of neuropathic pain. When preventing neuropathic pain associated with CIPN, PS can also reduce the incidence of one or more sensory symptoms associated with CIPN.

[0045] Patients with CIPN describe a range of sensory, bilateral symptoms, such as in the hands and feet (also described as a "stocking and glove" distribution). Sensory symptoms include paresthesias (e.g., numbness, tingling, tingling, and / or forking), burning, or shooting sensations (i.e., electric shock-like). Even if the sensory symptoms experienced by a subject undergoing or post-chemotherapy are not considered painful (or do not reach the threshold necessary to be considered pain per se), the PS may reduce, eliminate, or reduce the incidence of any one or more sensory symptoms (including those listed above) experienced by a subject undergoing or post-chemotherapy. The PS may be used to reduce, eliminate, or reduce the incidence of stocking and glove distribution in subjects undergoing or post-chemotherapy.

[0046] As described above, neuropathic pain associated with CIPN may be the result of central sensitization, resulting in allodynia and / or hyperalgesia. PS can reduce, eliminate or reduce the incidence of neuronal signaling involved in pain sensation in subjects undergoing chemotherapy or after chemotherapy. PS can reduce, eliminate or reduce the incidence of pain produced by peripheral sensitization or by central sensitization. Therefore, PS can reduce, eliminate or reduce the incidence of pain signaling occurring in the center. PS can reduce, eliminate or reduce the incidence of pain signaling occurring in the sciatic nerve. PS can reduce, eliminate or reduce the incidence of pain signaling occurring in the dorsal root ganglion. In view of the fact that PS shows that peripheral neurons are promoted to the spinal cord, PS can reduce, eliminate or reduce the incidence of pain signaling occurring in the spinal cord. Neuropathic pain CIPN in subjects undergoing chemotherapy or after chemotherapy can be allodynia (e.g., mechanical or thermal allodynia). Additionally or alternatively, neuropathic pain in subjects undergoing chemotherapy or after chemotherapy can be hyperalgesia.

[0047] Neuropathic pain in patients undergoing or following chemotherapy can be measured according to a visual analog pain scale or using any other appropriate method known in the art.

[0048] Pharmaceutical composition

[0049] The PS used in the methods of the present invention can be formulated into a suitable pharmaceutical composition for administration to a subject suffering from CIPN. The pharmaceutical composition is generally formulated to provide a therapeutically effective amount of the PS and may further comprise a pharmaceutically acceptable excipient.

[0050] Neuropathic pain associated with CIPN can occur in multiple locations of the body. However, as outlined above, CIPN tends to affect peripheral nerves in the upper and lower extremities, and therefore affects the extremities, explaining the "stocking and glove" distribution experienced by these patients. Therefore, particularly useful pharmaceutical compositions comprising PS are those that can be applied directly to peripheral locations experiencing neuropathic pain, such as the upper and lower extremities of a subject. In addition, pharmaceutical compositions comprising PS can be applied to those locations experiencing one or more sensory symptoms of CIPN. Therefore, pharmaceutical compositions comprising PS can be formulated for topical administration. In particular, pharmaceutical compositions comprising PS can be formulated for skin administration, particularly to the skin of the upper and / or lower extremities of a subject.

[0051] In some embodiments, pharmaceutical compositions comprising PS can be formulated as semisolids or liquids. Thus, pharmaceutical compositions comprising PS can be formulated as creams, gels (e.g., hydrogels), lotions, ointments, foams, and / or sprays. These compositions have different relative concentrations of oil and water, which results in compositions having different densities. Changing the density of the formulation is one way in which the exposure of the affected area to the pharmaceutical composition can be controlled. For example, a formulation with a lower density needs to be rubbed in until absorbed, possibly resulting in a shorter exposure time. Alternatively, a denser formulation that is less easily absorbed can allow the area to be exposed to the pharmaceutical composition for an extended period of time. The skilled artisan is aware of formulating topical pharmaceutical compositions to change the relative exposure of the area to the active pharmaceutical ingredient.

[0052] In other embodiments, the pharmaceutical composition comprising PS can be formulated as a patch that can be applied to the skin. The patch can be manufactured in such a way as to ensure controlled release of the PS to the affected area.

[0053] Formulations suitable for topical administration and appropriate pharmaceutically acceptable excipients are well known in the art. Exemplary formulations for topical administration are provided in WO 2019 / 067919, which is hereby incorporated by reference in its entirety.

[0054] In some embodiments, a PS formulation suitable for topical administration may include a concentration of PS of about 0.5% w / w to about 15% w / w of the pharmaceutical composition. Thus, the concentration of PS may be 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1% or 0.5% w / w of the pharmaceutical composition. As an illustrative example, when formulated as a topical cream, the concentration of PS may be less than or equal to 8% w / w of the pharmaceutical composition, such as about 5% w / w of the pharmaceutical composition, and particularly about 3% w / w of the pharmaceutical composition. As a further illustrative example, when formulated as a gel, the concentration of PS may be less than or equal to 8% w / w of the pharmaceutical composition, such as less than or equal to 5% w / w of the pharmaceutical composition, particularly less than or equal to 3% w / w of the pharmaceutical composition, such as about 2% or about 1% w / w of the pharmaceutical composition. In certain formulations, such as when formulated as a hydrogel or an ointment, the concentration of PS may be 5% w / w of the pharmaceutical composition.

[0055] A single application to both hands (i.e., gloves) may require less than about 5 ml of the pharmaceutical composition, such as about 3 ml of the pharmaceutical composition (i.e., about 1.5 ml of the pharmaceutical composition per hand). A single application to both feet (i.e., stockings) may require less than about 6 ml of the pharmaceutical composition, such as about 4 ml of the pharmaceutical composition (i.e., about 2 ml of the pharmaceutical composition per foot).

[0056] The pharmaceutical composition comprising PS may alternatively be formulated for any other form of administration suitable for the treatment and / or prevention of neuropathic pain associated with CIPN. For example, the composition may be formulated for transdermal administration or injection, such as subcutaneous injection.

[0057] Dosage regimen

[0058] The appropriate dosage regimen of PS for the treatment and / or prevention of CIPN will depend on variables such as the type and degree of pain progression (e.g., as determined according to the World Health Organization's "Pain Ladder" guidelines), the severity of the pain (e.g., acute, subacute, or chronic), the age, weight, and general condition of the particular patient, the formulation of the excipient, the route of administration, and the judgment of the attending clinician.

[0059] For topical administration, PS can be applied to cover one or more affected areas, such as the upper and lower extremities of a subject. In some embodiments, about 0.01 to about 5 g of PS can be applied to the affected area. With respect to the size of the affected area, about 0.005–0.25 g / 10 cm 2PS can be applied to the affected area. Therefore, about 0.005 g / 10 cm 2 , 0.01g / 10cm 2 , 0.05g / 10cm 2 , 0.1g / 10cm 2 , 0.15g / 10cm 2 , 0.2g / 10cm 2 or 0.25g / 10cm 2 Apply PS to the affected area.

[0060] In some cases, the PS for topical application may be applied and then removed from the affected area (e.g., by washing off) before reapplication. In some cases, the PS is washed off after a period of time. Alternatively, since the analgesic effect may weaken over time and may need to be reapplied, in some cases, the PS is not washed off, but simply reapplied to the affected area after an appropriate administration period. For example, the PS may be applied to the affected area and left on the affected area (before removal or reapplication) for between about 0.5 hours and about 5 hours. Thus, the PS may be topically applied and left on the affected area (before removal or reapplication) for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours.

[0061] Because the neuropathic pain associated with CIPN is chronic, repeated topical applications of PS are necessary. Thus, PS may be applied topically 1 to 4 times per day. Thus, PS may be applied once per day, twice per day, three times per day, or four times per day. For a particular PS formulation, such as a hydrogel or ointment having a PS concentration of about 5% w / w of the pharmaceutical composition, the formulation may be applied topically three times per day. In more severe cases, further applications of PS may be applied about 0.5 hours after each application.

[0062] PS may have a long-lasting analgesic effect and may therefore be administered less frequently. For example, PS may be topically applied less than once a day, such as once every other day. In fact, for those patients who experience long-term analgesia with a single administration, PS may be topically applied less than once a week, such as once every two weeks.

[0063] For topical application of some pharmaceutical compositions, it is useful to cover the affected area with a dressing (e.g., plastic wrap or film) after application of the pharmaceutical composition, e.g., to ensure that the appropriate amount of composition can be applied for an appropriate period of time. Thus, after topical application of the PS, the affected area may be bandaged.

[0064] In some embodiments, the PS can be topically administered in the form of a patch (e.g., plaster). The use of a patch can allow for a reduction in dosing intervals and / or dosing frequency, for example, because the patch ensures controlled release of the PS. Thus, the patch can be applied to the affected area once a day, less than twice a day, less than three times a day, or less than four times a day.

[0065] PS can be administered continuously for as long as necessary. For example, PS can be administered for more than 1, 2, 3, 4, 5, 6, 7, 14, 28, 56, or 84 days. As described above, PS can be administered continuously for a long period of time to treat chronic effects, for example, for at least 3 months. Thus, in some cases, continuous dosing is achieved and maintained for as long as necessary. PS can be administered intermittently based on the recurrence of neuropathic pain and / or related sensory symptoms.

[0066] PS can be used to treat and / or prevent CIPN in mammals. For example, the subject can be a human.

[0067] As described above, PS can be formulated into a suitable pharmaceutical composition for administration to a subject suffering from CIPN. Thus, PS can be administered in the form of a suitable pharmaceutical composition according to the above-described dosing regimen.

[0068] One of ordinary skill in the art understands that in certain embodiments, the dosage of such compounds may be adjusted according to the mammal to be treated. For example, treatment of mice is described herein, and such dosages may or may not be modified when administering PS to humans. However, if necessary, one of ordinary skill in the art may convert the dosages provided herein as described in Guidance for Industry: Estimation of Maximum Safe Starting Dose in Initial Clinical Trials of Therapeutic Agents in Adult Healthy Volunteers, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2005. The human equivalent dose (HED) may be determined based on the animal dose, which may be multiplied by the following conversion factors to provide units in mg / kg: mouse = 0.08, hamster = 0.13, rat = 0.16, ferret = 0.19, guinea pig = 0.22, rabbit = 0.32, dog = 0.54, monkey = 0.32, marmoset = 0.16, squirrel monkey = 0.19, baboon = 0.54, mini pig = 0.73, mini pig = 0.95.

[0069] Pharmaceutically acceptable forms of PS

[0070] Pharmaceutical compositions comprising PS may contain PS in a pharmaceutically acceptable form. The pharmaceutically acceptable form may be a solvate, a derivative and / or a prodrug.

[0071] Solvate

[0072] As used herein, the term "solvate" refers to a compound that also contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. In the case where the solvent is water, the solvate is a hydrate. Pharmaceutically acceptable forms of PS may include solvates of PS, such as solvates of PS-I and / or PS-II. In some embodiments, the solvate contains at least 1 solvent molecule. In some embodiments, the solvate contains less than 1 solvent molecule. In some embodiments, the solvate is a hydrate.

[0073] isotope

[0074] Pharmaceutically acceptable forms of PS may include isotopically labeled PS-I derivatives. Pharmaceutically acceptable forms of PS may include isotopically labeled PS-II derivatives. Isotopically labeled derivatives are compounds identical to PS except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. In some embodiments, isotopically labeled PS derivatives include one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine. In some embodiments, isotopically labeled PS derivatives include 2 H. 3 H. 13 C. 14 C. 18 O. 17 O. 31 P. 32 P. 35 S and 18 In some embodiments, the isotope-labeled PS derivative comprises 2 One or more isotopes of H (e.g., deuterium). In some embodiments, the isotope-labeled PS derivative comprises 3 In some embodiments, the isotope-labeled PS derivative comprises 14 One or more isotopes of C.

[0075] Derivatives and prodrugs

[0076] The pharmaceutically acceptable form of PS may include a derivative of PS-I. The pharmaceutically acceptable form of PS may include a derivative of PS-II. In some embodiments, the derivative of PS (e.g., PS-I or PS-II) is a metabolite. In other embodiments, the pharmaceutically acceptable form of PS is a prodrug of PS, such as a prodrug of PS-I or a prodrug of PS-II.

[0077] The sulfone group can be represented structurally as: RS(=O) 2-R'. In some embodiments, the derivative of PS is a sulfoxide form of PS.

[0078] PS contains an organic phosphate functional group. The organic phosphate functional group can be represented structurally as O=P(OR) 3 、O=P(OR) 2 (OR') or O = P (OR) (OR') (OR"). For example, if R = CH 2 CH 3 and R' = the rest of the molecule is PS according to formula I or II (eg, PS-I, PS-II or a derivative thereof), then O = P (OR) 2 (OR') can represent PS.

[0079] In some embodiments, the derivative of PS is one in which the ethoxy group (e.g., -OCH 2 CH 3 ) groups is a PS or a pharmaceutically acceptable salt thereof. In some embodiments, the PS derivative is a PS in which two ethoxy groups (e.g., -OCH 2 CH 3 ) groups are all OH groups, PS or a pharmaceutically acceptable salt thereof.

[0080] The activities of PS demonstrated herein will be shared by its pharmaceutically acceptable form. Accordingly, the present invention provides a pharmaceutically acceptable form of PS for use in the methods of the present invention.

[0081] While preferred embodiments of the invention are shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be used to practice the invention.

[0082] Example

[0083] Embodiments encompassed herein are now described with reference to the following examples. These examples are provided for illustrative purposes only, and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations that become apparent as a result of the teachings provided herein.

[0084] Example 1 : Role of PS in preventing neuropathic pain in a CIPN mouse model

[0085] CIPN was induced in a mouse population using paclitaxel. This is a well-established CIPN model (Hidaka et al. (2012) European Journal of Pain 13(1):22–27) and is relevant to human therapy, especially since paclitaxel is widely used in cancer chemotherapy to treat solid tumors, including breast, ovarian, and lung cancers. The experiments herein demonstrate the efficacy of PS in preventing pain associated with CIPN.

[0086] method

[0087] To establish CIPN, paclitaxel was administered intraperitoneally at 10 mg / kg to C57 / BL mice. Paclitaxel was administered once daily to all study groups (except the group that was naive) for 5 days. This paclitaxel dosing regimen produced pain associated with CIPN, and its time course was similar to the time course of pain after paclitaxel administration in cancer patients.

[0088] PS (as 8% hydrogel) or vehicle control was applied topically to both hind paws of mice 3 times daily for 7 days.The first dose was administered 2 days before the first administration of paclitaxel.

[0089] The experimental groups are as follows:

[0090] 1. Group 1: Mice that were naive (i.e., without paclitaxel)

[0091] 2. Group 2: Paclitaxel only (n=6)

[0092] 3. Group 3: Paclitaxel plus vehicle (n=7)

[0093] 4. Group 4: Paclitaxel plus PS (n=7)

[0094] To determine the outcome of treatment, pain threshold responses were measured using the well-established von Frey filament method. In particular, a simplified up-and-down method (as described in Bonin et al., Molecular Pain (2014); 10(26): 1–10) for estimating paw withdrawal threshold (PWT) using von Frey filaments was used. The results of the PWT test are expressed as the force applied (gm). The PWT test was performed at baseline (i.e., 4 days before paclitaxel administration (day -4)) and then one day after the final treatment with PS or vehicle (i.e., day 6 after the first administration of paclitaxel).

[0095] Table 1 provides a summary of the studies.

[0096] result

[0097] like Figure 2As shown in Figure 1, administration of paclitaxel resulted in a significant decrease in PWT (p<0.01 compared to naive mice), as expected. Thus, the model establishes pain associated with chemotherapy. Additional administration of vehicle had no significant effect on PWT compared to treatment with paclitaxel alone, whereas administration of PS achieved a significant increase in PWT compared to vehicle (p<0.01 compared to vehicle). Table 1 provides the data for the comparison with the control group. Figure 2 The corresponding value.

[0098] Table 1-PWT in the 4 study groups

[0099]

[0100]

[0101] in conclusion

[0102] Topical administration of PS significantly increased PWT in mice exhibiting paclitaxel-induced neuropathic pain (i.e., CIPN). Thus, PS prevents pain associated with CIPN.

[0103] NSAIDs (such as loxoprofen sodium) have been shown to be ineffective in reducing pain signaling in this CIPN model (Hidaka et al. (2009) European Journal of Pain 13:22–27). This is consistent with the observations of Moore et al. (2015) Cochrane Database of Systematic Reviews 10:1–25, in which NSAIDs were shown to have no therapeutic efficacy in peripheral neuropathic pain.

[0104] In contrast to observations with typical NSAIDs, PS clearly exhibits a pain-relieving effect in CIPN. In fact, this surprising activity of PS in a specific animal model of CIPN supports the observation that, unlike typical NSAIDs, PS is effective in preventing neuropathic pain associated with chemotherapy-induced neuropathy.

[0105] Example 2 : Effect of PS in the treatment of neuropathic pain in the CIPN mouse model

[0106] method

[0107] CIPN was established by intraperitoneal administration of 10 mg / kg paclitaxel to C57 / BL mice. Paclitaxel was administered once daily to all study groups for 3 days. Figure 2 The results showed that paclitaxel caused a significant decrease in PWT compared with naive mice.

[0108] PS (as 8% hydrogel) or vehicle control was topically applied to both hind paws of mice 3 times daily for 10 days. The first dose was administered 2 days after the last administration of paclitaxel.

[0109] The experimental groups are as follows:

[0110] 1. Group 1: Paclitaxel only (n=9)

[0111] 2. Group 2: Paclitaxel plus vehicle (n=10)

[0112] 3. Group 3: Paclitaxel plus PS (n=10)

[0113] To determine the outcome of treatment, pain threshold responses were measured using the well-established von Frey filament method consistent with that performed in Example 1. PWT testing was performed at baseline (i.e., 4 days after the first dose of paclitaxel was administered (day -1), and then on the last day of treatment with PS or vehicle (i.e., day 10), approximately 30 minutes after the last application. Data are expressed as percent change relative to the corresponding baseline values.

[0114] Table 3 provides a summary of the studies.

[0115] result

[0116] like Figure 4 As shown in Table 2, administration of vehicle on a background of paclitaxel had limited effect on PWT compared to treatment with paclitaxel alone, whereas administration of PS achieved a significant increase in PWT compared to vehicle and paclitaxel alone. Figure 4 The corresponding value.

[0117] Table 2-3 PWT in the study groups

[0118]

[0119] in conclusion

[0120] Topical administration of PS significantly increased PWT in mice with established neuropathic pain (ie, CIPN) induced by paclitaxel. Thus, PS treats neuropathic pain associated with CIPN.

[0121] Consistent with the observations in Example 1 and in contrast to those observed with typical NSAIDs, PS exhibited pain relief in a therapeutic model of pain associated with CIPN. This surprising activity of PS in a specific animal model of CIPN supports the observation that, unlike typical NSAIDs, PS is effective in treating neuropathic pain associated with chemotherapy-induced neuropathy.

[0122] Example 3PS effectively treats neuropathic pain associated with CIPN induced by multiple different chemotherapeutic agents

[0123] method

[0124] animal

[0125] Adult male C57BL / 6J mice, 8 weeks old and weighing 20-30 g at the start of the experiment, were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice were housed in groups of four in an AAALAC-accredited facility. Food and water were available ad libitum. Mice in each cage were randomly assigned to treatment groups. All studies were performed by an experimenter who was unaware of the identity of the treatment groups. Experiments were performed during the light cycle (7:00 am to 7:00 pm) and were controlled by CO 2 Animals were euthanized by asphyxiation. The study was approved by the relevant institutional animal care and use committee and followed the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animal studies were reported in accordance with the ARRIVE guidelines.

[0126] Sulindac phosphate

[0127] PS is formulated as an 8% hydrogel ointment for topical application.

[0128] Induction of CIPN

[0129] CIPN was induced in mice using an established protocol with three different chemotherapeutic compounds (Carozzi et al., Exp Neurol (2010); 226: 301-309; Currie et al., PLoS Biol (2019); 17: e3000243; Eldridge et al., Toxicol Pathol (2020); 48: 190-201). Each of the three chemotherapeutic compounds was prepared and administered as follows.

[0130] Paclitaxel: Paclitaxel (purchased from MilliporeSigma (St. Louis, MO)) was dissolved in a mixture of 1 volume ethanol / 1 volume Cremophor EL (EMD Millipore Corp, Burlington, MA) / 18 volumes distilled water. Paclitaxel was administered as four intraperitoneal injections of 8 mg / kg paclitaxel (in a volume of 1 ml / 100 g body weight) every other day, resulting in a cumulative dose of 32 mg / kg.

[0131] Oxaliplatin: Dissolve oxaliplatin in ddH 2O. Oxaliplatin 3 mg / kg was injected intraperitoneally once a day for 5 days, followed by 5 days of no treatment, followed by 5 more days of oxaliplatin intraperitoneal injections once a day as before, for a total of ten injections, resulting in a cumulative dose of 30 mg / kg. All injections were administered intraperitoneally in a volume of 1 ml / 100 g body weight.

[0132] Vincristine: Vincristine was dissolved in PBS. Vincristine 1.5 mg / kg was injected intraperitoneally twice in one week, with a total cumulative dose of 3 mg / kg. All injections were administered intraperitoneally in a volume of 1 ml / 100 g body weight.

[0133] Established regimen for the treatment of neuropathic pain associated with CIPN using PS

[0134] Once CIPN was established by a reduction in the mechanical allodynia threshold, PS 8% or placebo hydrogel ointment was applied to the hind paws of mice three times daily for the duration of the assessment period (see Figure 5-7 ). Mechanical allodynia was measured at the time points noted in the graphs.

[0135] Assessment of mechanical allodynia (von Frey test)

[0136] According to established methods, mechanical allodynia thresholds were determined using von Frey filaments (Chaplan et al., J Neurosci Methods (1994); 53: 55-63; Bagdas et al., Biochem Pharmacol (2015); 97: 590-600). Briefly, mice were placed in a quiet room for 30 minutes, then placed in a Plexiglas cage with a mesh metal floor, and allowed to adapt for 30 minutes before testing. A series of calibrated von Frey filaments with incremental stiffness (Stoelting, WoodDale, IL) were applied vertically to the paw with sufficient force to cause a slight bend and held for 2-3 seconds. This process was repeated 5 times at each stiffness level, with a few seconds interval. Retracting, licking or shaking the paw was considered a positive response. The mechanical threshold (expressed in g) indicates the force with which the animal reacts to the von Frey filament.

[0137] Statistical analysis

[0138] Results are expressed as mean ± SEM. PK parameters were calculated by Microsoft Excel and PKSolver. Non-compartmental analysis was used. Analysis of variance (ANOVA) tests were performed, followed by Bonferroni post hoc tests. Differences were considered significant at P < 0.05.

[0139] result

[0140] The effects of PS were evaluated in mice with neuropathic pain associated with three different chemotherapeutic compounds. This mirrors the clinical situation already considered in Example 2, where patients develop neuropathic pain after starting or completing their chemotherapy.

[0141] like Figure 5-7 As shown, each of the three anticancer drugs studied induced significant neuropathic pain, as evidenced by changes in mechanical allodynia.After neuropathic pain was established, topical treatment with PS 8% ointment 3 times / day was initiated.

[0142] Each of the different chemotherapeutic compounds is discussed below.

[0143] Paclitaxel (See Figure 5 ):

[0144] At baseline, mice in all four study groups had essentially the same allodynia scores (range 2.24 ± 0.26 g to 2.49 ± 0.24 g; mean ± SEM for this and all subsequent values). Paclitaxel administered to the three study groups over 12 days significantly reduced (approximately 85%) their mechanical allodynia scores, indicating neuropathic pain associated with CIPN. In contrast, the control group (non-paclitaxel, non-PS) showed small, statistically insignificant changes in allodynia scores throughout the study.

[0145] When PS was applied to the paws of mice with paclitaxel-induced neuropathic pain, their allodynia scores showed a gradual improvement from the lowest point at the start of treatment, returning to baseline on day 16 (day 0 = 0.79 ± 0.08 g vs. day 16 = 2.49 ± 0.18 g; p = 1.6 x 10 -6 ). In contrast, the vehicle-treated group showed a mild worsening of allodynia (Day 0 = 0.79 ± 0.11 g vs. Day 16 = 0.56 ± 0.05 g; p = NS). Only the paclitaxel-treated group showed a similar change in allodynia scores as the vehicle group (Day 0 = 0.78 ± 0.08 g vs. Day 16 = 0.57 ± 0.05 g; p = NS).

[0146] The difference between the PS-treated group and its vehicle control first became statistically significant on day 5 (PS = 1.17 ± 0.07 g, vehicle = 0.7 ± 0.07 g; p = 0.002), after which their difference increased and became the largest on day 16 (PS = 2.49 ± 0.18 g, vehicle = 0.56 ± 0.05 g; p = 2.1×10 -7 ).

[0147] Vincristine (See Figure 6 ):

[0148] PS improved mechanical allodynia induced by the commonly used vincristine. In the three groups administered with it, vincristine reduced mechanical allodynia scores by 61%-65% (for all, scores on day -7 ranged from 1.8±0.18 g to 2.0±0.24 g, vs. day 0=0.7±0.07 g; p=3.2×10 -6 In contrast, the control group that received only the solvent showed no changes in allodynia during these 7 days. PS treatment of mice with vincristine-induced neuropathic pain for 16 days significantly improved allodynia scores (increase of 114% compared to day 0; p = 1.3 x 10 -6 ), which had the same score as the control group (without vincristine).

[0149] On day 16, the difference between the PS-treated group and its vehicle control was statistically significant (PS = 1.5 ± 0.09 g, vehicle = 0.8 ± 0.09 g; p = 8.6 x 10 -6 During the same time period, there was no significant change in allodynia scores for the vehicle group and the vincristine alone group (0.7±0.07 g vs. 0.8±0.09 g for both).

[0150] Oxaliplatin (See Figure 7 ):

[0151] As expected, during oxaliplatin administration, allodynia scores decreased by 65% ​​and 56% on Day 0 in both study groups, respectively.

[0152] PS treatment restored allodynia scores to the day -15 baseline (1.8 ± 0.09 g vs. 1.76 ± 0.13 g), while the vehicle group continued to show suppressed allodynia scores, which were reduced by 47% on day 22 compared to day -15. The difference between the PS-treated group and the vehicle-treated group became statistically significant on day 22 (p = 0.004).

[0153] Security of PS

[0154] In all studies, no local or systemic side effects were observed with PS ointment when applied three times daily to the hind paws of mice for up to 22 days. This finding is consistent with the known safety profile of PS.

[0155] in conclusion

[0156] Topical administration of PS significantly improved mechanical allodynia scores compared to those induced by three different chemotherapeutic compounds.Thus, PS treats neuropathic pain induced by a range of different chemotherapies.

[0157] Consistent with the observations in Example 2, PS demonstrated pain relief in a therapeutic model of neuropathic pain associated with CIPN induced by chemotherapeutic compounds from different therapeutic classes.

[0158] Example 4 PS effectively prevents neuropathic pain associated with CIPN induced by paclitaxel

[0159] Similar to the experiment discussed in Example 1, the ability of PS to prevent neuropathic pain associated with paclitaxel chemotherapy was evaluated. This experiment used a different paclitaxel dosing regimen than Example 1. As in Example 1, the relevant clinical situation is one in which neuropathic pain therapy is administered prior to or concurrently with chemotherapy. Mechanical allodynia was used as an endpoint to evaluate the effect on neuropathic pain associated with CIPN.

[0160] method

[0161] Methods concerning animals, induction of CIPN (with paclitaxel), assessment of mechanical allodynia and statistical analysis corresponded to those outlined in Example 3.

[0162] For prevention of neuropathic pain associated with CIPN, PS 8% or vehicle was administered to the hind paws of mice as described above starting two days before the start of administration of paclitaxel compounds as explained in Example 3. Mechanical allodynia was measured before PS administration and on day 10 after the start of PS treatment.

[0163] result

[0164] exist Figure 8 In the prevention study depicted, three of the four study groups of mice were treated with paclitaxel (injected every other day for a total of four times), while the fourth group received only the vehicle, serving as a control. The two paclitaxel-treated groups were topically treated with either PS ointment or vehicle (ointment alone) starting 2 days before the first dose of paclitaxel.

[0165] At the end of the study (day 10), the mechanical allodynia scores in the paclitaxel group were 53% lower than those in the control group (0.7±0.17 g vs. 1.5±0.19 g; p=3×10 -8The allodynia scores in the vehicle-treated group were the same as those in the paclitaxel-only group (0.7±0.12 vs. 0.7±0.17). However, the allodynia scores in the pre-treated PS group were significantly increased compared to the vehicle group (1.2±0.15 g vs. 0.7±0.12 g; p=2.3×10 -6 ), making it close to the allodynia score of the paclitaxel (solvent only) control (1.5±0.19 g).

[0166] In terms of safety, no local or systemic side effects of PS ointment were observed.

[0167] in conclusion

[0168] Similar to the conclusions of Example 1, topical administration of PS significantly increased the paw withdrawal threshold compared to its vehicle. Thus, PS prevented the development of neuropathic pain induced by paclitaxel administration. The study complemented the results of Example 1, demonstrating that the effects were observed regardless of the administration regimen used for paclitaxel.

[0169] Example 5 : Pharmacokinetics and biodistribution of PS

[0170] Given the potential for PS to treat and prevent neuropathic pain associated with CIPN, the site of action of PS has been investigated. Despite local administration, PS has been found to travel intraneurally from the periphery to the spinal cord.

[0171] method

[0172] 8% PS ointment was applied topically to each hind paw (50 μl per paw) and gently massaged. 2 Mice (n=4-5 mice / time point) were euthanized by inhalation. Blood was drawn immediately after death. Tissues, including paw skin, paw muscle, leg muscle, sciatic nerve, and bilateral lumbar DRG, were rapidly dissected, immediately frozen in liquid nitrogen and stored at -80°C until analysis.

[0173] In another experiment, we studied eight mice with paclitaxel-induced PN treated with PS 8% ointment 3 times / day for 2 weeks. Mice were euthanized as described above 30 minutes after the last administration of PS. We harvested two sciatic nerves from these mice, divided each sciatic nerve into proximal and distal halves, and combined the corresponding halves from every two animals for drug level determination.

[0174] As previously described (Wen et al., Int J Pharm (2019); 557:273-279), each plasma sample was mixed with double volume of acetonitrile and centrifuged at 13,200 rpm for 15 min. Tissue samples were weighed and ddHO was added.2 O (100-300 μL, depending on tissue weight) and homogenized. After adding acetonitrile (twice the volume of the homogenate), the mixture was sonicated for 10 minutes, centrifuged at 13,200 rpm for 15 minutes, and analyzed by HPLC as reported (Wen et al., 2019). The limit of quantification for PS was 0.1 μM, and the limit of quantification for sulindac, sulindac sulfone, sulindac sulfide and its glucuronidated derivatives was 0.05 μM.

[0175] result

[0176] PS can be rapidly metabolized in vitro and in vivo to a variety of metabolites, including PS sulfide, PS sulfone, sulindac, sulindac sulfide, and sulindac sulfone ( Fig. 9 ). Glucuronide of sulindac and its metabolites, which are mainly formed in the liver, have also been identified. Since the metabolism and PK / biodistribution of PS vary depending on its route of administration, we performed studies in normal mice in which PS was topically administered to their hind paws, with a particular focus on the sciatic nerve and dorsal root ganglia (DRG) affected in CIPN (Colvin, Pain (2019); 160 Suppl 1: S1-S10).

[0177] like Fig.10 PS was detected in the paw skin, its application site, subcutaneous muscle, leg muscle, sciatic nerve and DRG as shown in Table 3. As expected (Xie et al., Br J Pharmacol (2012a); 165:2152-2166), PS was not detected in the systemic circulation.

[0178] PS concentration decreases gradually from the skin to the most distant DRG, from C max (from 194.7±5.3μM to 0.3±0.1μM) and AUC 0-24h The corresponding values ​​of PS T (from 1,609.8 μM·h to 4.5 μM·h) were confirmed. max was the same in all tissues (0.5 h), except for DRG, which showed a prolonged T max (18 h), probably reflecting the way in which PS reaches it, as discussed below. Another interesting feature is the t 1 / 2 The difference, which was within a relatively narrow range (11.4-20.6 hours), compared to a much more prolonged value of 57.4 hours in the sciatic nerve, and probably an even more prolonged value in the DRG, which could not be determined with reasonable precision.

[0179] These differences suggest differential metabolic capacities of nerves and skin and muscle regarding PS.

[0180] Table 3-PK parameters of PS in mouse tissues and peripheral blood of normal mice

[0181]

[0182] *, cannot be determined. **, cannot be calculated because intact PS was not detectable. N = 4-5 mice / time point.

[0183] Only three PS metabolites were detected: sulindac, sulindac sulfone, and sulindac sulfide. Fig.11 and Table 4). No glucuronidation products were detected. Sulindac was the quantitatively dominant metabolite, with sulindac sulfide and sulindac sulfone levels being <20% of sulindac levels. Sulindac levels were approximately 25% of PS levels in all tissues except sciatic nerve (higher) and DRG (equal).

[0184] Table 4 - PK parameters of sulindac in mouse tissues and peripheral blood of normal mice

[0185]

[0186] *, cannot be determined. N = 4-5 mice / time point.

[0187] Sciatic nerve (C max =0.9±0.1μM; AUC 0-24h =12.0 μM·h) and DRG (C max =0.3±0.1μM; AUC 0-24h =4.5 μM·h) is of particular interest, as both are targets for chemotherapy associated with neuropathic pain. max The PS levels in DRG were very high, and were lower compared with those in sciatic nerve, suggesting that PS reaches DRG by passing through the sciatic nerve from the skin.

[0188] To further explore this conclusion, we compared the PS levels in the proximal and distal halves of the mouse sciatic nerve 30 minutes after it was applied to the hind paw. The two values ​​were significantly different, with the value of the distal half being 18.5 times higher than that of the proximal half (17 ± 5.1 μM vs. 0.9 ± 0.3 μM; Table 5). Compared with the proximal half, the concentrations of the three metabolites of PS (sulindac, sulindac sulfide, and sulindac sulfone) were higher in the distal half (4.5-8.5 times higher). These findings support the view that PS reaches DRG from its application site by direct tissue transfer or transport rather than by circulation.

[0189] Table 5 - PS and its metabolites in the proximal and distal halves of mouse sciatic nerve

[0190]

[0191]

[0192] *All differences between proximal and distal values ​​were statistically significant (p<0.001). N=8 mice / group.

[0193] in conclusion

[0194] These experiments demonstrate that topically applied PS can reach key sites of action (i.e., sciatic nerve and dorsal root ganglia) known to be involved in the generation of neuropathic pain associated with chemotherapy. In addition, given its rapid metabolism in the bloodstream, the results demonstrate that PS reaches these sites of action by passing through the central nervous system along peripheral neurons (e.g., sciatic nerve), with meaningful concentrations found in DRG. Thus, without wishing to be bound by theory, these observations demonstrate that PS may exert its analgesic activity directly on neurons and possibly within central sites of action, similar to the activity of centrally acting analgesics such as lidocaine and pregabalin.

[0195] Example 6 PS is as active as lidocaine and pregabalin, but not sulindac, in the treatment and prevention of neuropathic pain associated with CIPN

[0196] The effects of PS were compared with those of known centrally acting analgesics (lidocaine and pregabalin) and the parent compound of PS, sulindac, on neuropathic pain associated with CIPN. The treatment of neuropathic pain associated with the CIPN regimen corresponds to the treatment explained in Examples 2 and 3.

[0197] method

[0198] Methods concerning animals, induction of CIPN (with paclitaxel), assessment of mechanical allodynia and statistical analysis corresponded to those outlined in Example 3.

[0199] CIPN was established by administering paclitaxel to C57 / BL / 6J mice. Paclitaxel was administered to all of the following study groups:

[0200] 1. Group 1: Paclitaxel plus vehicle (n=8)

[0201] 2. Group 2: Paclitaxel plus PS 5% (n=8)

[0202] 3. Group 3: Paclitaxel plus PS 1.2% (n=8)

[0203] 4. Group 4: Paclitaxel plus 0.7% sulindac (n=8)

[0204] 5. Group 5: Paclitaxel plus 5% lidocaine cream (n=8)

[0205] 6. Group 6: Paclitaxel plus pregabalin (10 mg / kg) (n=8)

[0206] Regarding treatment with PS, sulindac, and vehicle: PS hydrogel 5%, PS 1.2%, 0.7% sulindac, or vehicle was applied to both hind paws 3 times a day starting on day 0 and continuing until day 15. 0.7% sulindac was the highest possible concentration and was equimolar to PS 1.2%.

[0207] Regarding treatment with lidocaine: 5% lidocaine cream (positive control) was applied once to both hind paws of mice 30 minutes before measuring PWT.

[0208] Regarding treatment with pregabalin: Pregabalin 10 mg / kg (positive control) was orally administered once one hour before measuring PWT.

[0209] To determine the treatment outcome, an assessment of mechanical allodynia was performed. In addition, in the groups of mice treated with vehicle or PS 5%, an assessment of cold allodynia (another manifestation of CIPN) was performed using the acetone test. Two methods for assessing allodynia are described in Toma W et al. Neuropharmacology 2017; 117: 305-15. In the same animal, mechanical allodynia and cold allodynia were measured at least one day apart.

[0210] Briefly, for mechanical allodynia, pain threshold responses were measured using the well-established von Frey filament method consistent with that performed in the previous examples. PWT testing was performed on day -8 (before the first dose of paclitaxel), on the day of treatment initiation (day 0, when CIPN was fully established), and on day 14 (treatment continued until day 15). Mechanical threshold (expressed in g) indicates the force with which the animal reacts to the von Frey filament.

[0211] For cold allodynia, mice with paclitaxel-induced CIPN were treated with 5% PS or vehicle for 15 days after CIPN was induced. An acetone test was used. In brief, acetone was applied to the plantar surface of each hind paw. The time spent licking, lifting and / or shaking the hind paw recorded in 60 seconds for each mouse was the score for cold allodynia. Measurements were performed on day -8 (before the first paclitaxel injection), the day of treatment (day 0), and the 15th day.

[0212] result

[0213] As expected, paclitaxel induced CIPN, as evidenced by a decrease in mechanical allodynia scores from 1.83±0.14 g (mean±SEM of this and all subsequent values) before paclitaxel administration to 0.55±0.05 g on study day 0 (after CIPN was fully established). Paclitaxel also sensitized mice to cold pain, as evidenced by the change in its scores before and after paclitaxel treatment (4.5±0.24 seconds vs. 7.1±0.4 seconds; p<0.0001).

[0214] Treatment with PS improved mechanical allodynia scores in a dose-dependent manner ( Fig. 12A ). Similarly, treatment with 5% PS improved the cold allodynia score. The cold allodynia score of the PS-treated group was significantly lower than that of the vehicle-treated group (3.1±0.4 vs. 9.3±0.7; p<0.0001) ( Fig. 12B ).

[0215] In contrast, administration of sulindac failed to demonstrate a significant effect on PWT, with scores similar to vehicle (0.62 ± 0.05 g vs. 0.56 ± 0.04 g; not statistically significant), whereas, as expected, both lidocaine and pregabalin positive controls achieved significant increases in PWT compared to vehicle ( Fig. 12A Importantly, PS 1.2% (equimolar concentration to sulindac 0.7%) significantly improved mechanical allodynia (p<0.0001). Table 6 provides the Fig. 12A Corresponding values ​​for mechanical allodynia.

[0216] Table 6 - PWT in the study groups

[0217]

[0218]

[0219] in conclusion

[0220] Although PS was shown to be effective in treating and preventing neuropathic pain associated with CIPN (see also Examples 1-3), unexpectedly, its non-phosphorylated "parent" sulindac (a typical NSAID) failed to achieve rescue in the PWT mouse model and therefore failed to treat neuropathic pain associated with CIPN. This was true even when sulindac was administered at the maximum non-toxic dose and in the same manner and formulation as PS. The positive controls lidocaine and pregabalin, known to have central sites of action for analgesia, demonstrated significant reduction in pain associated with CIPN as expected. Thus, the observed efficacy of topically applied PS was more similar to the centrally acting positive controls than to the closely related parent compound.

[0221] Thus, PS is mechanistically distinct from its parent NSAID and may work in a manner more similar to centrally acting agents. These observations of equivalent efficacy of PS and pregabalin and lidocaine in the treatment and prevention of neuropathic pain associated with CIPN reflect the central site of action of PS observed above (i.e., similar to the central site of action of pregabalin and lidocaine). These observations serve to demonstrate the potential of PS in the treatment of neuropathic pain associated with CIPN, similar to typical centrally acting analgesics (e.g., pregabalin and lidocaine).

[0222] Example 7 : Summary of observations

[0223] The observations herein show that PS has unprecedented analgesic activity in the prevention and treatment of neuropathic pain associated with CIPN using a well-established animal model. Therefore, the above experiments demonstrate that PS is able to reduce neuropathic pain signaling caused by CIPN produced by a series of chemotherapeutic compounds. The mechanistic action of PS for mechanical allodynia has been shown to affect the pathophysiology common to each chemotherapeutic compound-PS has a direct effect on neuronal pain signaling produced by nerve damage caused by chemotherapeutic compounds, thereby demonstrating the wide therapeutic applicability of PS in the treatment of neuropathic pain associated with chemotherapy. By topical administration, the therapeutic effect of PS on mechanical allodynia is very strong and quite fast. Indeed, after topical administration, PS is shown to follow an ascending trajectory along peripheral neurons (e.g., sciatic nerve) toward the spinal cord, and significant analgesia can be achieved in less than a week, and lasts for up to two weeks. The local route provides low systemic clearance, reduced drug interactions, improved patient tolerance, and is easy to use in combination with oral medications.

[0224] These observations demonstrate the previously unrecognized activity and therapeutic utility of PS, which is a compound belonging to the broader category of NSAIDs, but does not have all the characteristics of this family of compounds. In fact, in contrast to previous observations for NSAIDs, the data herein demonstrate that the activity of PS is more similar to an analgesic that directly targets neuronal activity, and has the potential to work at both peripheral and central sites. In fact, the above results confirm that PS can alleviate the pain caused by allodynia, which is known to include pain produced by peripheral and central sensitization. In the CIPN treatment model, pain was established five days before treatment randomization, thereby establishing central sensitization (compared to baseline) demonstrated by allodynia. Therefore, without wishing to be bound by theory, PS has a direct effect on neuronal pain signaling, similar to the established mechanism of action of anesthetics. In fact, the results show that PS can reduce pain signaling from peripheral and central sensitization, indicating the peripheral and central sites of action of the analgesic activity of this compound. Of course, this activity is different from the established effects of PS and typical NSAIDs as anti-inflammatory agents.

[0225] Early observations on the activity of PS were limited to its anti-inflammatory activity. For example, WO 2019 / 067919 proposed a role for PS in the treatment of DED using an acute DED model, in which concanavalin A (ConA) was administered to rabbit lacrimal glands simultaneously with PS. In this case, the anti-inflammatory activity of PS resulted in a limited inflammatory response to ConA, thereby preventing the formation of DED. These observations confirm the anti-inflammatory activity of PS and demonstrate its utility in preventing the establishment and maintenance of the inflammatory component of DED. The observations in this acute DED model failed to provide any evidence that PS was able to act directly on nerves to reduce neural signaling caused by neuropathic pain. Any reduction in pain in this acute DED model can only be considered a result of PS inhibiting the inflammatory response (i.e., the pathology responsible for triggering the activation of pain sensors). In fact, the results of the DED model showed that PS improved corneal sensitivity, suggesting an increase in nociception, which is contrary to the expected effect for analgesics. Of course, despite any suggestion of analgesic activity of PS, such activity observed in an acute DED model provides no indication of corresponding activity in neuropathic pain, and certainly not in neuropathic pain associated with CIPN.

[0226] The experiment herein is carried out in a specific animal model of neuropathic pain associated with CIPN. As mentioned above, the use of an appropriate animal model is essential for demonstrating the potential efficacy of a compound in a specific type of neuropathic pain. The efficacy of a drug for pain caused by peripheral neuropathy cannot be inferred from its efficacy for other forms of pain or even other forms of neuropathic pain. In fact, the pathogenesis of a specific form of neuropathic pain is different, and therefore therapeutic agents with different activities are required to carry out its treatment and / or prevention. It is necessary to design therapy according to the specific pathophysiology of neuropathic pain and test it in an appropriate model. For example, CIPN causes direct nerve damage, demyelination or calcium metabolism disorders of sensory axons due to the administration of toxic chemotherapeutic agents, while other neuropathy may occur due to extensive nerve damage caused by metabolic abnormalities (for example, as seen in diabetic peripheral neuropathy). Therefore, based on its specific pathophysiology, the impact on large and small fibers is different between CIPN and other forms of neuropathy. The only reliable determination of the efficacy of a compound in treating neuropathic pain caused by this pathophysiology is to test the compound in an appropriate CIPN neuropathic pain model, as shown above. Without these observations, any indication of the pain-relieving activity of PS in the context of neuropathic pain associated with CIPN is lacking.

[0227] The observations herein demonstrate that PS has therapeutic utility beyond that proposed for typical NSAIDs. Such NSAIDs (e.g., loxoprofen sodium) are ineffective in reducing pain signaling in paclitaxel-induced CIPN. In addition, Moore et al. (Cochrane Database of Systematic Reviews (2015); 10: 1–25) outline that NSAIDs have no therapeutic efficacy in peripheral neuropathic pain. The PS activity observed herein, corresponding to the activity of pregabalin and lidocaine, contrasts with the inability of typical NSAIDs observed in the prior art to provide direct analgesia to damaged neurons in neuropathic pain. In the above experiments, the unique activity of PS compared to typical NSAIDs was demonstrated by comparison with its parent compound, sulindac. Sulindac was unable to reduce established allodynia (i.e., caused by sensitization of peripheral and central neurons), indicating that, unlike PS, sulindac does not provide direct analgesia to damaged neurons in neuropathic pain caused by CIPN. Without wishing to be bound by theory, the reason for the lack of any reaction to typical NSAIDs in the prior art is likely that the pain is caused by neuropathic nerve damage, rather than by inflammation (i.e., any anti-inflammatory activity of typical NSAIDs is not enough to prevent or treat neuropathic pain). Therefore, the analgesic activity of PS observed herein is unique and is not shared by typical NSAIDs. Based on the observations of sulindac herein, any so-called NSAID analgesic activity observed in the prior art is a reflection of its anti-inflammatory activity (i.e., stopping the initial triggering factor causing pain), rather than the actual analgesic activity for nerve signal conduction (i.e., will result in alleviating the pain caused by nerve damage and allergy). In fact, if typical NSAIDs (e.g., sulindac) can act directly on neurons with analgesic activity, then sulindac will be expected to alleviate the hyperalgesia observed in the above-mentioned model.

[0228] Thus, the inventors have demonstrated that PS has new and unexpected activity in the treatment and / or prevention of neuropathic pain associated with CIPN. As described above, this activity exceeds the anti-inflammatory activity previously observed for PS and related NSAIDs. In fact, unlike typical NSAIDs, the observations herein demonstrate that PS has direct activity on peripheral and central nerves, which may be similar to the site and mechanism of action of established analgesics such as lidocaine and pregabalin. In addition, PS can be easily administered (e.g., topically), and its side effects are limited (Mackenzie et al. (2010) Gastroenterology 139 (4): 1320–32), making it an improved therapy for neuropathic pain associated with CIPN even compared to these centrally acting analgesics.

[0229] It will be understood that the foregoing describes the inventor's work by way of example only and that modifications may be made while remaining within the scope and spirit of the invention.

Claims

1. Use of sulindac phosphate (PS) for the preparation of a medicament for treating and / or preventing neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN) in a subject.

2. The method of claim 1, wherein a) treating the neuropathic pain including alleviating or eliminating the neuropathic pain; b) preventing the neuropathic pain includes reducing the incidence of the neuropathic pain; c) treating the neuropathic pain comprises reducing or eliminating one or more sensory symptoms associated with CIPN; and / or d) preventing said neuropathic pain comprises reducing the incidence of one or more of said sensory symptoms associated with CIPN.

3. The use of claim 2, wherein the one or more sensory symptoms are selected from paresthesia, burning sensation and shooting sensation.

4. The use of claim 3, wherein the paresthesia comprises one or more of numbness, tingling, prickling or forking sensation.

5. The use of claim 1, wherein: a) PS reduces, eliminates or reduces the incidence of neuronal signaling involved in pain perception; b) PS alleviates, eliminates or reduces the incidence of pain caused by peripheral sensitization; c) PS relieves or eliminates pain caused by central sensitization or reduces its incidence; d) PS reduces or eliminates pain signal transmission in the central nervous system or reduces its incidence; e) PS reduces, eliminates or reduces the incidence of pain signaling in the sciatic nerve; f) PS reduces, eliminates or reduces the incidence of pain signaling in the dorsal root ganglia; g) the neuropathic pain is allodynia; and / or h) The neuropathic pain is hyperalgesia.

6. Use according to claim 5, wherein the allodynia is mechanical allodynia and / or thermal allodynia.

7. The use of claim 1, wherein the subject has cancer and is currently being treated or has previously been treated with one or more chemotherapeutic compounds.

8. The use of claim 7, wherein the one or more chemotherapeutic compounds are selected from one or more of platinum-based drugs, taxanes, immunomodulatory drugs, epothilones, vinca alkaloids and proteasome inhibitors.

9. The use of claim 7, wherein the one or more chemotherapeutic compounds are selected from one or more of oxaliplatin, cisplatin, carboplatin, taxanes, paclitaxel, docetaxel, cabazitaxel, thalidomide, vincristine, vinblastine, vinorelbine, vindesine and bortezomib.

10. The use of claim 8, wherein the chemotherapeutic compound is a taxane.

11. The use according to claim 10, wherein the taxane is paclitaxel.

12. The use of claim 8, wherein the chemotherapeutic compound is a vinca alkaloid.

13. The use according to claim 12, wherein the vinca alkaloid is vincristine.

14. The use of claim 8, wherein the chemotherapeutic compound is a platinum-based anti-tumor agent.

15. The use of claim 14, wherein the platinum-based antitumor agent is oxaliplatin.

16. The use of claim 7, wherein the subject suffers from a solid tumor cancer.

17. The use of claim 7, wherein the subject suffers from ovarian cancer, breast cancer, lung cancer, Kaposi's sarcoma and / or pancreatic cancer.

18. The use of claim 1, wherein the subject is a human.

19. The use of claim 1, wherein the PS has formula I (PS-I):

20. The use of claim 1, wherein PS has formula II (PS-II):

21. The use of claim 1, wherein the PS is formulated in a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

22. The use of claim 21, wherein the pharmaceutical composition comprising PS is formulated for topical administration.

23. The use of claim 22, wherein: a) the pharmaceutical composition comprising PS is formulated as a semisolid; b) the pharmaceutical composition comprising PS is formulated as a liquid; c) the pharmaceutical composition comprising PS is a cream; d) the pharmaceutical composition comprising PS is a gel; e) the pharmaceutical composition comprising PS is a lotion; f) the pharmaceutical composition comprising PS is an ointment; g) the pharmaceutical composition containing PS is a spray; or h) The pharmaceutical composition comprising PS is formulated as a patch.

24. The use according to claim 23, wherein the gel is a hydrogel.

25. The use of claim 21, wherein the pharmaceutical composition comprises PS at a concentration of 0.5% to 15% w / w of the pharmaceutical composition.

26. The use of claim 25, wherein the pharmaceutical composition comprises PS at a concentration of 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1% or 0.5% w / w of the pharmaceutical composition.

27. The use of claim 25, wherein the pharmaceutical composition comprises PS at a concentration less than or equal to 8% w / w of the pharmaceutical composition.

28. The use of claim 27, wherein the pharmaceutical composition comprises PS at a concentration of 5% or 3% w / w of the pharmaceutical composition.

29. The use of claim 25, wherein the pharmaceutical composition comprises PS at a concentration less than or equal to 3% w / w of the pharmaceutical composition.

30. The use of claim 29, wherein the pharmaceutical composition comprises PS at a concentration of 2% or 1% w / w of the pharmaceutical composition.

31. The method of claim 21, wherein the PS is 0.005 g / 10 cm 2 Up to 0.25g / 10cm 2 Apply to the affected area.

32. The method of claim 31, wherein the PS is administered at a dose of: I) 0.005 g / 10 cm 2 affected areas; II) 0.01g / 10cm 2 affected areas; II) 0.05g / 10cm 2 affected areas; III) 0.1g / 10cm 2 affected areas; IV) 0.15g / 10cm 2 affected areas; V) 0.2g / 10cm 2 the affected area; or VI) 0.25g / 10cm 2 affected areas.

33. The use of claim 21, wherein the PS is applied to the affected area and left on the affected area for between 1 hour and 5 hours.

34. The use according to claim 33, I) wherein the PS is applied to the affected area and left on the affected area for 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours or 5 hours and / or II) In which: A) removing the PS from the affected area after the administration period; or B) applying a second or further application of PS to the affected area following the dosing period.

35. The use of claim 21, wherein: a) the PS is applied once a day; b) the PS is applied twice daily; c) the PS is applied three times daily; or d) The PS was applied four times daily.

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