Treatment of pain associated with chemotherapy-induced peripheral neuropathy

Abstract

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

Description

[Technical field]

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

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

[0003] Neuropathy is a disease or abnormality of the nervous system that affects over 20 million Americans. In fact, recent studies have observed that approximately 1 in 10 adults suffers from neuropathic pain, and the economic burden of treating this pain is increasing.

[0004] Neuropathy is associated with the development of neuropathic pain. Neuropathic pain may occur as a result of damage to the peripheral or central nervous system. Peripheral neuropathic pain is caused by damage to nerve structures, such as peripheral nerve endings or nociceptors, which become highly sensitive to stimuli and may generate pulses in the absence of stimuli. This damage can occur for many reasons, including chemotherapy treatments (i.e., CIPN), diseases such as diabetes, as well as advanced cancer, viruses (e.g., shingles or HIV), and physical injuries (e.g., accidents or surgery).

[0005] Peripheral nerve lesions can result in a pathological condition characterized by the presence of persistent spontaneous pain, often associated with hyperalgesia (increased response to noxious stimuli) and allodynia (pain induced by non-painful stimuli). Hyperalgesia and allodynia are associated with central sensitization, in which CNS nociceptive neurons exhibit hyperexcitability due to a lowered stimulation threshold in response to persistent input or peripheral injury. Central sensitization is involved in the generation and maintenance of neuropathic pain associated with peripheral neuropathy.

[0006] In terms of symptoms, peripheral neuropathy may cause sharp pain, dull pain, painful burning or cold sensations, paresthesias, loss of proprioception, numbness, and even loss of pain sensation.

[0007] There is currently a worldwide need for additional pain therapies, and neuropathic pain has evolved into a significant health problem for large segments of the population.

[0008] Treatment of neuropathic pain is often attempted using so-called non-conventional analgesics, e.g. antidepressants such as duloxetine and amitriptyline, or antiepileptic drugs such as gabapentin or pregabalin. In addition, local anesthetics, including lidocaine, are used to treat and manage neuropathic pain. Despite evidence to the contrary, nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to manage neuropathic pain. However, a review of recent clinical trials showed no indication of significant pain relief with NSAIDs in patients with neuropathic pain (Moore et al. Cochrane Database of Systematic Reviews (2015);10: 1-25), and there were no clinical outcomes 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 its associated neuropathic pain are frequent, dose-dependent side effects of commonly used chemotherapy. Peripheral nerve damage accounts for the majority of neurological damage associated with chemotherapy toxicity and is the most frequent chemotherapy-limiting factor after hematological toxicity. The pain is thought to be due to direct toxic effects on sensory axons, demyelination, or impaired calcium metabolism. Neuropathic pain associated with CIPN is particularly difficult to treat. Currently, CIPN-related neuropathic pain is managed with antidepressants (e.g., duloxetine) and / or antiepileptic drugs (e.g., gabapentin and pregabalin). Unfortunately, pain management is not very satisfactory and these systemic treatments induce significant side effects that lead to poor treatment adherence. Indeed, to date, there are no satisfactory means of preventing or even treating CIPN-related pain: the only approved drug (duloxetine) is generally considered ineffective.

[0010] Thus, there is a great need for compounds that treat and / or prevent pain associated with peripheral neuropathy, particularly CIPN. Summary of the Invention

[0011] The present inventors have surprisingly found that phosphosulindac (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 is not a typical NSAID because it does not inhibit the expression of COX-1 and COX-2. PS has previously been shown to have anti-cancer and anti-inflammatory properties, as well as activity in treating rheumatoid arthritis in inflammatory mouse models through inhibition of NF-κB activation and alteration of MAPK signaling branches, as well as suppression of 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). WO2019 / 067919 suggests anti-inflammatory activity of PS in an acute model of dry eye disease (DED). Furthermore, in this model, PS was seen to restore suppressed ocular sensitivity in DED, suggesting a role for PS in increasing rather than decreasing nociception. As mentioned above, PS is not a typical NSAID, but showed similar activity to NSAIDs when administered to normal eyes in the DED model. However, these observations do not suggest a role for PS in treating neuropathic pain associated with CIPN. Furthermore, clinical guidance in this field recommends avoiding the use of NSAIDs for the treatment of all types of neuropathic pain, and anti-inflammatory activity alone is not considered sufficient as a treatment.

[0013] Nevertheless, the inventors have considered the activity of PS in certain animal models of neuropathic pain and have demonstrated surprising therapeutic effects comparable to those of direct-acting neuroleptic anesthetics, such as lidocaine and pregabalin. Specific animal models are important in the development of therapies for the treatment of neuropathic pain. Indeed, given the pathogenesis of pain associated with peripheral neuropathy, the observation of the efficacy of a particular compound in an alternative pain model cannot indicate the utility of that compound in the treatment of neuropathic pain. Similarly, it is not possible to extrapolate the use of an effective drug from other forms of neuropathic pain to a particular neuropathic pain of interest, even when the clinical symptoms are similar. For example, gabapentin shows different efficacies in the treatment of different forms of neuropathic pain. Thus, it is important for animal models to be used for early testing before further clinical development. Based on a specific animal model of CIPN neuropathic pain, the observations herein show unprecedented efficacy for PS in the treatment and / or prevention of neuropathic pain associated with CIPN.

[0014] Thus, in a first aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with CIPN, 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 the sulfoxide form of PS. Thus, PS has the formula I (PS-I): [ka] may have:

[0016] In other embodiments, the PS is a sulfide form of PS. Thus, the PS has the formula II (PS-II): [ka] may have:

[0017] As used herein, reference to "phosphosulindac" or "PS" includes 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. Patent No. 8,236,820, which is incorporated herein by reference in its entirety.

[0018] As mentioned above, nerve damage associated with CIPN leads to overactivation of pain signaling pathways, resulting in sensitization of peripheral and / or central neurons, which exhibit a lowered stimulation threshold. Thus, subjects with CIPN may experience pain as a result of this sensitization, for example, experiencing pain induced by non-painful stimuli (allodynia) or experiencing increased pain in response to noxious stimuli (hyperalgesia). Based on the observations herein, PS may have a direct analgesic effect, for example, by reducing intraneuronal signaling involved in pain sensation. Furthermore, PS may reduce pain caused by peripheral sensitization or by central sensitization. Thus, PS may reduce or prevent pain signaling that occurs centrally. PS may reduce or prevent pain signaling that occurs in the sciatic nerve. PS may reduce or prevent pain signaling that occurs in the dorsal root ganglion. Given that PS has been shown to ascend peripheral neurons toward the spinal cord, PS can reduce or prevent pain signaling that occurs within the spinal cord. In some embodiments, the neuropathic pain is allodynia. Allodynia may occur in response to mechanical and / or thermal stimuli. Additionally, in some embodiments, the neuropathic pain is hyperalgesia.

[0019] PS can be formulated into pharmaceutical compositions for use in the present invention.In some embodiments, the pharmaceutical compositions comprise PS and one or more pharma-ceutically acceptable excipients.PS can be formulated for local administration, particularly for local administration to the upper and lower extremities of a subject (i.e., for targeting stocking and glove type distribution). [Brief description of the drawings]

[0020] [Figure 1] Schematic diagram of neuropathic pain relevant to CIPN prevention studies. PWT is the paw withdrawal threshold test. [Diagram 2] Effect of PS compared to vehicle on preventing neuropathic pain associated with CIPN. [Diagram 3] FIG. 1 is a schematic diagram of neuropathic pain associated with CIPN treatment studies. [Figure 4] Effect of PS on the treatment of neuropathic pain associated with CIPN. [Diagram 5] Effect of PS on the treatment of neuropathic pain associated with paclitaxel-induced CIPN. The effect of PS compared to vehicle control was significant from day 5 and increased thereafter (†, p<0.002; ‡, p=4.9x10-5; &, p=1.7x10-7; *, p=2.2x10-7). [Figure 6] Effect of PS on the treatment of neuropathic pain associated with vincristine-induced CIPN. The effect of PS compared to vehicle control was significant at day 16 (*p=8.6×10-6). [Figure 7] Effect of PS on the treatment of neuropathic pain associated with oxaliplatin-induced CIPN. The effect of PS compared to vehicle control was significant at day 22 (*p=0.004). [Figure 8] Effect of PS on preventing neuropathic pain associated with paclitaxel-induced CIPN. The effect of PS compared to vehicle control was significant (*, p=3.0x10-8; **, p=2.3x10-6). [Figure 9] FIG. 1 is a schematic diagram of PS metabolism. [Figure 10] Biodistribution of PS in various tissues upon local administration. SN=sciatic nerve. DRG=dorsal root ganglion. [Figure 11-1] Biodistribution of PS metabolites in various tissues upon local administration of PS. SN=sciatic nerve. DRG=dorsal root ganglion. [Figure 11-2]Biodistribution of PS metabolites in various tissues upon local administration of PS. SN=sciatic nerve. DRG=dorsal root ganglion. [Figure 12] A shows the effect of PS compared to sulindac, lidocaine, and pregabalin on treating neuropathic pain associated with CIPN for mechanical allodynia (*, statistically significant difference; NS, statistically not significant). B shows the effect of PS compared to sulindac, lidocaine, and pregabalin on treating neuropathic pain associated with CIPN for cold allodynia (values: mean ± SEM; *, p<0.0001). Detailed Description of the Invention

[0021] definition The following definitions of pain types are from the International Association for the Study of Pain (IASP): "Pain" is an unpleasant sensory and emotional experience associated with, or that appears to be associated with, 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 clear lesion or disease that meets established neurological diagnostic criteria. Patients with neuropathic pain may experience one or more sensations described as hot, burning, throbbing, electric, stabbing, sharp, cramping, tingling, prickling, numbness, or a numb, pins and needles sensation. The term "lesion of the somatosensory nervous system" is commonly used when diagnostic tests (e.g., imaging, neurophysiology, biopsy, clinical trials) reveal abnormalities or when there has been clear trauma. The term "disease of the somatosensory nervous system" is commonly used when the underlying cause of the lesion is known (e.g., stroke, vasculitis, diabetes mellitus, genetic abnormalities). "Peripheral neuropathic pain" is pain caused by lesion or disease of the peripheral somatosensory nervous system. "Central neuropathic pain" is pain caused by lesion or disease of the central somatosensory nervous system. "Central sensitization" refers to increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input. "Peripheral sensitization" refers to 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" is the augmentation of pain by stimuli that normally cause pain.

[0022] In general, the term "disease" refers to a condition or state of a patient or subject that can be treated using the methods provided herein.

[0023] The term "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein sufficient to achieve its intended use, including but not limited to the treatment and / or prevention of a disease.

[0024] "Pharmaceutically acceptable excipient" is intended to include any solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic and absorption retarding agents, and inactive ingredients contained in pharmaceutical compositions.The use of such pharmaceutically acceptable excipients to formulate active pharmaceutical ingredients is well known in the art.Unless conventional pharmaceutically acceptable excipients are incompatible with PS, their use in the therapeutic compositions of the present invention is contemplated.

[0025] Use of the term "about" when referring to a numerical value is arbitrary and means that the numerical value referred to is an approximation within typical experimental variation (or within statistical experimental error), and therefore the numerical value may vary accordingly.

[0026] The term "comprising" encompasses "including" and "consisting." For example, a composition "comprising" X may consist of only X or may include some additional elements, e.g., X+Y.

[0027] Treatment of pain associated with chemotherapy-induced peripheral neuropathy As outlined above, chemotherapy can cause damage to neurons, resulting in peripheral neuropathy and associated neuropathic pain. Pain can occur during or after a patient is receiving chemotherapy, and can manifest as, for example, shooting, burning, or stabbing pain associated with other sensory symptoms. Thus, in some embodiments, the present invention provides a method for preventing neuropathic pain associated with CIPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with CIPN is prevented. In other embodiments, the present invention provides a method for treating neuropathic pain associated with CIPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with CIPN is treated. The subject may experience neuropathic pain caused by one or more prior doses of chemotherapy before one or more subsequent doses, and therefore the subject would benefit from an analgesic that can both treat existing neuropathic pain and prevent the development of further neuropathic pain. Thus, in some embodiments, PS can be used to treat and prevent neuropathic pain associated with CIPN. In accordance with the above, the present invention provides PS for use in the treatment and / or prevention of 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.

[0028] Since CIPN develops in terms of chemotherapy, the subject may be a human patient with cancer who is about to undergo treatment, is undergoing treatment, or has previously been treated with one or more chemotherapy compounds. Generally, chemotherapy compounds refer to drugs that have antitumor properties or the ability to inhibit cell growth or proliferation. The prevalence of CIPN is drug-dependent, with reported rates varying from 19% to over 85% in patients taking different drugs, and the prevalence is highest in the case of platinum-based drugs, taxanes, immunomodulators, and epothilones, but is also observed in patients receiving other common cancer chemotherapy drugs, including vinca alkaloids and proteasome inhibitors. Thus, the one or more chemotherapeutic compounds may be platinum-based antineoplastic agents (e.g., oxaliplatin, cisplatin, or carboplatin), taxanes (e.g., paclitaxel, docetaxel, or cabazitaxel), vinca alkaloids (vincristine, vinblastine, vinorelbine, or vindesine), or proteasome inhibitors (e.g., bortezomib). The one or more chemotherapeutic compounds may be one or more immunomodulatory agents, including thalidomide and / or analogs thereof. The one or more chemotherapeutic compounds may be platinum-based antineoplastic agents, such as oxaliplatin, taxanes, such as paclitaxel, and vinca alkaloids, such as vincristine. The subject may have any cancer that is treated with a chemotherapeutic compound associated with the development of CIPN and associated neuropathic pain. In some embodiments, the subject with CIPN has a solid tumor cancer. The subject may have ovarian cancer, breast cancer, lung cancer (e.g., non-small cell lung cancer), Kaposi's sarcoma, and / or pancreatic cancer. Alternatively, the subject may have melanoma, esophageal cancer, prostate cancer (e.g., hormone refractory prostate cancer), head and neck cancer, gastric cancer, and / or cervical cancer.

[0029] Based on the observations herein, PS has a direct analgesic effect on the neuropathic pain associated with CIPN. The neuropathic pain associated with CIPN can be burning pain. The control undergoing chemotherapy or after chemotherapy may experience neuropathic pain that always exists symmetrically in the lower and upper limbs. In the treatment of neuropathic pain associated with CIPN, PS may reduce or eliminate neuropathic pain. In the treatment of neuropathic pain associated with CIPN, PS may reduce or eliminate one or more sensory symptoms associated with CIPN. In the prevention of neuropathic pain associated with CIPN, PS may reduce the incidence of neuropathic pain. In the prevention of neuropathic pain associated with CIPN, PS may reduce the incidence of one or more sensory symptoms associated with CIPN.

[0030] Patients suffering from CIPN describe a variety of sensory, bilateral symptoms, for example in the hands and feet (also described as a "sock-and-glove" distribution). Sensory symptoms include paresthesia (e.g., numbness, tingling, pins and needles, and / or formication), burning, or electric shock sensations (i.e., like electric shocks). Even if the sensory symptoms experienced by a subject undergoing or following chemotherapy are not considered painful (or do not reach the threshold required to be considered painful per se), PS can reduce, eliminate, or reduce the incidence of any one or more sensory symptoms experienced by a subject undergoing or following chemotherapy, including those listed above. PS can be used to reduce, eliminate, or reduce the incidence of stocking-and-glove distribution in subjects undergoing or following chemotherapy.

[0031] As mentioned above, neuropathic pain associated with CIPN may be the result of central sensitization resulting in allodynia and / or hyperalgesia. PS may reduce, eliminate, or reduce the incidence of intraneuronal signaling associated with the sensation of pain in subjects undergoing or after chemotherapy. PS may reduce, eliminate, or reduce the incidence of pain caused by peripheral or central sensitization. Thus, PS may reduce, eliminate, or reduce the incidence of centrally generated pain signaling. PS may reduce, eliminate, or reduce the incidence of pain signaling generated in the sciatic nerve. PS may reduce, eliminate, or reduce the incidence of pain signaling generated in the dorsal root ganglion. Given that PS has been shown to ascend peripheral neurons toward the spinal cord, PS may reduce, eliminate, or reduce the incidence of pain signaling generated within the spinal cord. Neuropathic pain in subjects undergoing or after chemotherapy CIPN may be allodynia (e.g., mechanical allodynia or thermal allodynia). Additionally or alternatively, the neuropathic pain in a subject undergoing or following chemotherapy CIPN can be hyperalgesia.

[0032] Neuropathic pain in patients undergoing or following chemotherapy can be measured using a visual analog pain scale or other suitable methods in the art.

[0033] Pharmaceutical Compositions The PS for use in the method of the present invention can be formulated into a suitable pharmaceutical composition for administering to a subject using CIPN.The pharmaceutical composition is typically formulated to provide a therapeutically effective amount of PS, and can further include a pharma- ceutical acceptable excipient.

[0034] Neuropathic pain associated with CIPN can occur in various parts of the body. However, as outlined above, CIPN tends to affect the peripheral nerves of the upper and lower limbs, and thus the extremities, explaining the "sock and glove" distribution experienced by these patients. Therefore, a particularly useful pharmaceutical composition comprising PS is one that can be directly applied to peripheral sites experiencing neuropathic pain, such as the upper and lower limbs of a subject. In addition, a pharmaceutical composition comprising PS can be applied to these sites experiencing one or more sensory symptoms of CIPN. Thus, a pharmaceutical composition comprising PS can be formulated for topical administration. In particular, a pharmaceutical composition comprising PS can be formulated for dermal administration, particularly to the skin of the upper and / or lower limbs of a subject.

[0035] In some embodiments, the pharmaceutical composition comprising PS can be formulated as a semi-solid or liquid. Thus, the pharmaceutical composition comprising PS can be formulated as a cream, gel (e.g., hydrogel), lotion, ointment, foam, and / or spray. These compositions have different densities because of the different relative concentrations of oil and water. Modifying the density of the formulation is a way to control the exposure of the affected area to the pharmaceutical composition. For example, a less dense formulation may require rubbing until absorbed, resulting in a shorter exposure time. Alternatively, a more dense formulation that is less absorbed may allow the area to be exposed to the pharmaceutical composition for a longer period of time. Those skilled in the art will recognize that topical pharmaceutical compositions can be formulated to modify the relative exposure of an area to the active pharmaceutical ingredient.

[0036] In other embodiments, pharmaceutical compositions containing PS can be formulated as patches that can be applied to the skin. The patches can be manufactured in a manner that ensures controlled release of PS to the affected area.

[0037] Formulations suitable for topical administration and suitable pharma- ceutically acceptable excipients are well known in the art. Exemplary formulations for topical administration are provided in WO2019 / 067919, the entirety of which is incorporated herein by reference.

[0038] In some embodiments, a formulation of PS suitable for topical administration may contain PS at a concentration of about 0.5% w / w to about 15% w / w of the pharmaceutical composition. Thus, PS may be 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. As an illustrative example, when formulated as a topical cream, PS may be at a concentration of 8% w / w or less of the pharmaceutical composition, such as about 5% w / w of the pharmaceutical composition, particularly about 3% w / w of the pharmaceutical composition. As a further illustrative example, when formulated as a gel, the PS may be at a concentration of 8% w / w or less of the pharmaceutical composition, such as 5% w / w or less of the pharmaceutical composition, particularly 3% w / w or less of the pharmaceutical composition, such as about 2% w / w or about 1% w / w of the pharmaceutical composition. In certain formulations, for example when formulated as a hydrogel or ointment, the PS may be at a concentration of 5% w / w of the pharmaceutical composition.

[0039] 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., socks) 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).

[0040] The pharmaceutical composition comprising PS can alternatively be formulated for any other administration form suitable for treating and / or preventing neuropathic pain associated with CIPN.For example, the composition can be formulated for transdermal administration or injection, such as subcutaneous injection.

[0041] Dosing regimen The appropriate dosing regimen of PS to treat and / or prevent CIPN will depend on variables such as the type and progression of pain (e.g., as determined by 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, excipient formulation, route of administration, and the clinician's judgment.

[0042] For local administration, PS can be administered to target 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 administered to the affected area. In terms of the size of the affected area, PS can be administered in an amount of about 0.005 to 0.25 g / 10 cm. 2 Therefore, PS can be administered at the affected area at a dose of 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 Administer at the affected area.

[0043] PS for use in topical administration may optionally be applied and then removed (e.g., by washing) from the affected area and then reapplied. In some cases, the PS is washed off after a certain time. Alternatively, since the analgesic effect may decrease over time and reapplication may be necessary, in some cases, the PS is not washed off, but instead is simply reapplied to the affected area after the appropriate administration period has elapsed. For example, the PS may be applied to the affected area and left (before removal or reapplication) for about 0.5 hours to about 5 hours. Thus, the PS may be applied topically to the affected area and left (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.

[0044] Because the neuropathic pain associated with CIPN is chronic, repeated local administration of PS is necessary. Thus, PS can be applied topically one to four times per day. Thus, PS can be applied once per day, twice per day, three times per day or four times per day. When using certain formulations of PS, such as hydrogels or ointments with a PS concentration of about 5% w / w of the pharmaceutical composition, the formulation can be applied topically three times per day. In more severe cases, further applications of PS can be performed about 0.5 hours after each application.

[0045] PS may provide long-lasting analgesic effects, and therefore may be administered less frequently. For example, PS may be administered topically less than once a day, for example, once every other day. Indeed, for patients who experience long-term analgesia with a single dose, PS may be administered topically less than once a week, for example, once every two weeks.

[0046] In the case of topical administration of some pharmaceutical compositions, it may be useful to cover the affected area with, for example, a bandage (e.g., plastic wrap or film) after applying the pharmaceutical composition, for example, to ensure that an appropriate amount of the composition is applied for an appropriate time. Thus, after topical application of PS, the affected area may be bandaged.

[0047] In some embodiments, PS can be administered locally in the form of a patch, for example a medicinal patch.By using a patch, for example, the patch can reduce the administration interval and / or administration frequency, by ensuring that the release of PS is controlled.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.

[0048] Administration of PS can be continued 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 mentioned above, PS can be administered continuously and chronically for long-term effects of treatment, for example, at least 3 months. Thus, in some cases, continuous administration is achieved and maintained as long as necessary. PS can be administered intermittently depending on the recurrence of neuropathic pain and / or associated sensory symptoms.

[0049] The PS can be used to treat and / or prevent CIPN in a mammal. For example, the subject may be a human.

[0050] As mentioned above, PS can be formulated into a suitable pharmaceutical composition for administering to subjects using CIPN.Therefore, PS can be administered in a suitable pharmaceutical composition according to the above-mentioned administration regimen.

[0051] Those skilled in the art understand that in certain embodiments, the dosage of such compounds can be adjusted depending on the mammal being treated.For example, the treatment of mice is described herein, and such dosage may or may not be modified when administering PS to humans.However, those skilled in the art can convert the dosage provided herein as necessary, as described in Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2005. The human equivalent dose (HED) can be determined from the animal dose by multiplying the animal dose 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, micropig = 0.73, minipig = 0.95.

[0052] Pharmaceutically acceptable forms of PS A pharmaceutical composition comprising PS can include a pharma- ceutically acceptable form of PS, which may be a solvate, derivative, and / or prodrug.

[0053] solvate As used herein, the term "solvate" refers to a compound that further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate. A pharma- ceutical acceptable form of PS can include a solvate of PS, such as a solvate of PS-I and / or PS-II. In some embodiments, the solvate comprises at least one molecule of solvent. In some embodiments, the solvate comprises less than one molecule of solvent. In some embodiments, the solvate is a hydrate.

[0054] Isotopes Pharmaceutically acceptable forms of PS may include isotopically labeled derivatives of PS-I. Pharmaceutically acceptable forms of PS may include isotopically labeled derivatives of PS-II. Isotopically labeled derivatives are compounds identical to PS except that one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. In some embodiments, isotopically labeled derivatives of PS include one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine. In some embodiments, isotopically labeled derivatives of PS include one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine, respectively. 2 H, 3 H, 13 C. 14 C. 18 O. 17 O. 31 P, 32 P, 35 S, and 18 In some embodiments, the isotopically labeled derivative of PS comprises one or more isotopes of F. 2 In some embodiments, the isotopically labeled derivative of PS comprises one or more isotopes of H (e.g., deuterium). 3 H. In some embodiments, the isotopically labeled derivative of PS comprises one or more isotopes of H (e.g., tritium). 14 Contains one or more isotopes of C.

[0055] Derivatives and Prodrugs The pharma- ceutically acceptable form of PS may include a derivative of PS-I. The pharma- ceutically 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 pharma- ceutically acceptable form of PS is a prodrug of PS, e.g., a prodrug of PS-I or a prodrug of PS-II.

[0056] The sulfone group can be structurally represented as RS(=O)2-R'. In some embodiments, the derivative of PS is the sulfone form of PS.

[0057] PS contains an organophosphate functional group, which can be structurally represented as O=P(OR)3, O=P(OR)2(OR'), or O=P(OR)(OR')(OR"). For example, O=P(OR)2(OR') can represent PS (e.g., PS-I, PS-II, or derivatives thereof) where R=CH2CH3 and R'=the remainder of the molecule conforms to PS in formula I or II.

[0058] In some embodiments, the derivative of PS is PS in which one of the ethoxy (e.g., -OCH2CH3) groups is an OH group, or a pharma- ceutically acceptable salt thereof. In some embodiments, the derivative of PS is PS in which both ethoxy (e.g., -OCH2CH3) groups are OH groups, or a pharma- ceutically acceptable salt thereof.

[0059] The activities of PS demonstrated herein will be shared by its pharma- ceutically acceptable forms, and thus the invention provides pharma- ceutically acceptable forms of PS for use in the methods of the invention.

[0060] 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 employed in practicing the invention. EXAMPLES

[0061] The embodiments encompassed herein will now be described with reference to the following examples, which 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 as encompassing any and all variations that are evident as a result of the teachings provided herein.

[0062] Example 1: Effect of PS in preventing neuropathic pain in a CIPN mouse model CIPN was induced in a mouse population using paclitaxel, a well-established model of CIPN (Hidaka et al. (2012) European Journal of Pain 13(1): 22-27) that is relevant to human therapy, especially since paclitaxel is widely used in cancer chemotherapy for the treatment of solid tumors, including breast, ovarian, and lung cancer. The experiments herein demonstrate the efficacy of PS in preventing pain associated with CIPN.

[0063] method To establish CIPN, paclitaxel was administered intraperitoneally to C57 / BL mice at 10 mg / kg. Paclitaxel was administered once daily for 5 days to all study groups (except the naïve group). This paclitaxel administration regimen produced CIPN-associated pain with a time course similar to that of pain following paclitaxel administration in cancer patients.

[0064] Mice were administered PS (as an 8% hydrogel) or vehicle control topically to both hind paws three times daily for 7 days, with the first dose administered 2 days prior to the first dose of paclitaxel.

[0065] The study groups were as follows: 1. Group 1: Naive mice (i.e., no paclitaxel) 2. Group 2: Paclitaxel only (n=6) 3. Group 3: Paclitaxel + vehicle (n = 7) 4. Group 4: Paclitaxel + PS (n = 7)

[0066] To determine the outcome of treatment, pain threshold responses were measured using the well-established method of Von Frey filaments. In particular, a simplified up-down method for estimating paw withdrawal threshold (PWT) using Von Frey filaments was used (as described in Bonin et al., Molecular Pain (2014);10(26):1-10)). The results of the PWT test are expressed as applied force (gm). The PWT test was performed at baseline (i.e., 4 days before paclitaxel administration (day -4)) and then 1 day after the final treatment with PS or vehicle (i.e., 6 days after the first dose of paclitaxel).

[0067] Figure 1 provides an overview of this study.

[0068] result As shown in FIG. 2, administration of paclitaxel significantly reduced PWT as expected (p<0.01 vs. naive mice). Thus, the model established chemotherapy-associated pain. Additional administration of vehicle did not significantly affect PWT compared to treatment with paclitaxel alone, whereas administration of PS achieved a significant increase in PWT compared to vehicle (p<0.01 vs. vehicle). Values ​​corresponding to FIG. 2 are provided in Table 1. [Table 1]

[0069] conclusion Local administration of PS significantly increased PWT in mice exhibiting paclitaxel-induced neuropathic pain (i.e., CIPN). Thus, PS prevents pain associated with CIPN.

[0070] NSAIDs, such as rofecoxib 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 in Moore et al. (2015) Cochrane Database of Systematic Reviews 10: 1-25, which showed that NSAIDs have no therapeutic effect in peripheral neuropathic pain.

[0071] In contrast to observations with typical NSAIDs, PS clearly demonstrates analgesic effects in CIPN. Indeed, this surprising activity of PS in a specific animal model of CIPN supports the observation that, unlike typical NSAIDs, PS can effectively prevent neuropathic pain associated with chemotherapy-induced neuropathy.

[0072] Example 2: Effect of PS in treating neuropathic pain in a mouse model of CIPN method CIPN was established by intraperitoneally administering 10 mg / kg paclitaxel to C57 / BL mice. Paclitaxel was administered once daily for 3 days to all study groups. The results in Figure 2 demonstrate that paclitaxel causes a significant decrease in PWT compared to naive mice.

[0073] Mice were administered PS (as an 8% hydrogel) or vehicle control topically to both hind paws three times daily for 10 days, with the first dose administered 2 days after the last dose of paclitaxel.

[0074] The study groups were as follows: 1. Group 1: Paclitaxel only (n=9) 2. Group 2: Paclitaxel + vehicle (n = 10) 3. Group 3: Paclitaxel + PS (n = 10)

[0075] To determine treatment outcomes, pain threshold responses were measured using the well-established method of Von Frey filaments, consistent with that performed in Example 1. PWT testing was performed at baseline (i.e., 4 days (day -1) after the first administration of paclitaxel) 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 from the respective baseline values.

[0076] Figure 3 provides an overview of this study.

[0077] result As shown in Figure 4, administration of vehicle in a background of paclitaxel had limited effect on PWT compared to treatment with paclitaxel alone, while administration of PS achieved a significant increase in PWT compared to vehicle and paclitaxel alone. Values ​​corresponding to Figure 4 are shown in Table 2. [Table 2]

[0078] conclusion Local administration of PS significantly increased PWT in mice with established paclitaxel-induced neuropathic pain (i.e., CIPN), thus PS treats pain associated with CIPN.

[0079] Consistent with the observations in Example 1 and in contrast to those observed with typical NSAIDs, PS demonstrates analgesic effects in a treatment 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 can effectively treat neuropathic pain associated with chemotherapy-induced neuropathy.

[0080] Example 3: PS effectively treats neuropathic pain associated with CIPN caused by multiple different chemotherapies method animal Adult male C57BL / 6J mice, 8 weeks of age at the start of the experiment and weighing 20–30 g, were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice were housed in groups of 4 in an AAALAC-accredited facility. Food and water were available ad libitum. Mice within each cage were randomly assigned to treatment groups. All studies were performed by experimenters blinded to the identity of the treatment groups. Experiments were performed during the light cycle (7 am–7 pm) and animals were euthanized by CO2 asphyxiation. Studies were approved by the relevant Institutional Animal Care and Use Committee and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Animal studies are reported in accordance with the ARRIVE guidelines.

[0081] Phosphosulindac PS was formulated as an 8% hydrogel ointment for topical administration.

[0082] Induction of CIPN CIPN was induced in mice with three different chemotherapeutic compounds using established protocols (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:

[0083] 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 by intraperitoneal injection of 8 mg / kg paclitaxel (volume of 1 ml / 100 g body weight) every other day for four doses, resulting in a cumulative dose of 32 mg / kg.

[0084] Oxaliplatin: Oxaliplatin was dissolved in ddH2O. Oxaliplatin was injected intraperitoneally at 3 mg / kg daily for 5 days, followed by 5 days of no treatment, followed by daily intraperitoneal injections of oxaliplatin as before for an additional 5 days, for a total of 10 injections, with a cumulative dose of 30 mg / kg. All injections were given intraperitoneally in a volume of 1 ml / 100 g body weight.

[0085] Vincristine: Vincristine was dissolved in PBS. Two intraperitoneal injections of 1.5 mg / kg of vincristine were given within one week, resulting in a total cumulative dose of 3 mg / kg. All injections were given intraperitoneally in a volume of 1 ml / 100 g body weight.

[0086] Protocol for the treatment of established neuropathic pain associated with CIPN with PS Once CIPN was established by a decrease in mechanical allodynia threshold, PS 8% or placebo hydrogel ointment was applied to the hind paws of mice three times per day for the evaluation period (see Figures 5-7). Mechanical allodynia was measured at the time points recorded in the figures.

[0087] Assessment of mechanical allodynia (von Frey test) Mechanical allodynia thresholds were determined using von Frey filaments according to established methods (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 min and then placed in a Plexiglas cage with a mesh metal floor and allowed to acclimate for 30 min before testing. A series of calibrated von Frey filaments with increasing stiffness (Stoelting, Wood Dale, IL) were applied perpendicular to the paw with enough force to cause a slight bend and held for 2-3 s. This process was repeated five times at each stiffness level with an interval of a few seconds. Paw withdrawal, licking, or shaking was considered a positive response. The mechanical threshold, expressed in g, indicates the force of the von Frey filaments to which the animal responded.

[0088] statistical analysis Results are expressed as mean ± SEM. PK parameters were calculated by Microsoft Excel and PKSolver. Non-compartmental analysis was employed. Analysis of variance (ANOVA) tests were performed followed by Bonferroni post-hoc tests. Differences were considered significant at P<0.05.

[0089] result The effect of PS in mice with neuropathic pain associated with three different chemotherapy compounds was evaluated, reflecting the clinical situation previously discussed in Example 2, where patients present with neuropathic pain following the initiation or completion of chemotherapy.

[0090] As shown in Figures 5-7, 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 was initiated three times per day.

[0091] Each of the different chemotherapeutic compounds is discussed individually below.

[0092] Paclitaxel (see Figure 5): At baseline, all four study groups of mice had essentially identical allodynia scores (range 2.24 ± 0.26 g to 2.49 ± 0.24 g; mean ± SEM for this and all subsequent values). Administration of paclitaxel over a 12-day period to the three study groups significantly reduced (approximately 85%) mechanical allodynia scores indicative of neuropathic pain associated with CIPN. In contrast, the control group (non-paclitaxel, non-PS) showed minor, non-statistically significant variation in allodynia scores throughout the study period.

[0093] When PS was applied to the paws of mice with paclitaxel-induced neuropathic pain, allodynia scores showed a gradual improvement from the nadir at the start of treatment, returning to baseline by day 16 (day 0 = 0.79 ± 0.08 g vs. day 16 = 2.49 ± 0.18 g; p = 1.6 × 10 -6 In contrast, the vehicle-treated group showed a mild worsening of allodynia scores (day 0 = 0.79 ± 0.11 g vs. day 16 = 0.56 ± 0.05 g; p = NS). The paclitaxel-only treated group showed a similar change in allodynia scores to the vehicle group (day 0 = 0.78 ± 0.08 g vs. day 16 = 0.57 ± 0.05 g; p = NS).

[0094] The differences between the PS-treated groups and their vehicle controls first became statistically significant on day 5 (PS=1.17±0.07g, vehicle=0.7±0.07g; p=0.002), and the differences increased thereafter, reaching a maximum on day 16 (PS=2.49±0.18g, vehicle=0.56±0.05g; p=2.1x10 -7 ).

[0095] Vincristine (see Figure 6): PS improved mechanical allodynia induced by the commonly used vincristine. In the three treated groups, vincristine reduced mechanical allodynia scores by 61%-65% (scores on day -7 ranged between 1.8±0.18g and 2.0±0.24g, compared with day 0 = 0.7±0.07g for all; p=3.2x10 -6 In contrast, the control group, which received vehicle alone, showed no change in allodynia over these 7 days. Mice with vincristine-induced neuropathic pain were treated with PS for 16 days, which significantly improved allodynia scores (114% increase compared to day 0; p=1.3x10 -6 ), whose scores were identical to those of the control group (without vincristine).

[0096] The difference between the PS-treated group and its vehicle control was statistically significant on day 16 (PS=1.5±0.09 g, Vehicle=0.8±0.09 g; p=8.6x10 -6 ). In the vehicle and vincristine alone groups, there was no significant change in allodynia scores over the same period (0.7±0.07 g vs. 0.8±0.09 g for both).

[0097] Oxaliplatin (see Figure 7): As expected, during oxaliplatin administration, allodynia scores decreased by 65% ​​and 56% in the two study arms, respectively, on day 0.

[0098] PS treatment restored allodynia scores to baseline on day -15 (1.8±0.09g vs. 1.76±0.13g), whereas the vehicle group continued to show suppressed allodynia scores, 47% lower on day 22 compared to day -15. The difference between PS- and vehicle-treated groups became statistically significant on day 22 (p=0.004).

[0099] Safety of PS During all studies, no local or systemic side effects were observed when PS ointment was applied to the hind paws of mice three times daily for up to 22 days, a finding consistent with the known safety profile of PS.

[0100] conclusion Local administration of PS significantly improved mechanical allodynia scores compared to those induced by three different chemotherapeutic compounds, thus treating neuropathic pain caused by a variety of chemotherapeutics.

[0101] Consistent with the observations in Example 2, PS demonstrates analgesic effects in treatment models of neuropathic pain associated with CIPN caused by chemotherapeutic compounds of various therapeutic classes.

[0102] Example 4: PS effectively prevents neuropathic pain associated with paclitaxel-induced CIPN Similar to the experiment discussed in Example 1, the ability of PS to prevent neuropathic pain associated with paclitaxel chemotherapy was evaluated. In this experiment, a different paclitaxel administration regimen is used than in Example 1. As in Example 1, the corresponding clinical situation is one in which neuropathic pain therapy is administered before or simultaneously with chemotherapy. Mechanical allodynia was used as the endpoint to evaluate the effect on neuropathic pain associated with CIPN.

[0103] method Methods for animals, induction of CIPN (with paclitaxel), assessment of mechanical allodynia, and statistical analysis correspond to those outlined in Example 3.

[0104] For prevention of neuropathic pain associated with CIPN, mice were administered PS 8% or vehicle in the hind paws as described above starting 2 days before administration of the paclitaxel compound as described in Example 3. Mechanical allodynia was measured before administration of PS and 10 days after initiation of PS treatment.

[0105] result In the prophylactic study shown in Figure 8, three of the four study groups of mice were treated with paclitaxel (one every other day for a total of four injections), while the fourth group received vehicle alone and served as a control. Two of the paclitaxel-treated groups began topical treatment with PS ointment or vehicle (ointment alone) two days prior to the first dose of paclitaxel.

[0106] At the end of the study (day 10), the mechanical allodynia scores in the paclitaxel group were 53% lower than their controls (0.7±0.17g vs. 1.5±0.19g, p=3×10 -8 ). The allodynia score in the vehicle-treated group was identical to the paclitaxel-only group (0.7±0.12 vs. 0.7±0.17). However, the allodynia score in the pre-treated PS group was significantly increased compared to the vehicle group (1.2±0.15g vs. 0.7±0.12g, p=2.3x10 -6 ), which approached the score for the paclitaxel (solvent alone) control (1.5±0.19 g).

[0107] Regarding safety, no local or systemic side effects were observed with PS ointment.

[0108] conclusion Similar to the conclusion of Example 1, local administration of PS significantly increases paw withdrawal threshold compared with its vehicle.Therefore, PS prevents the development of neuropathic pain caused by administration of paclitaxel.This study complements the findings of Example 1 and demonstrates that the effect is observed regardless of the administration regimen used for paclitaxel.

[0109] Example 5: Pharmacokinetics and biodistribution of PS Given the ability of PS to treat and prevent neuropathic pain associated with CIPN, the site of action of PS was investigated. Despite being administered locally, PS was found to traverse intraneurons from the periphery toward the spinal cord.

[0110] method PS 8% ointment was applied topically to each hind paw with gentle rubbing (50 μl per paw). At 0.5, 1, 3, 5, 12, 18, and 24 h, mice (n=4-5 mice / time point) were euthanized by CO2 inhalation. Blood was collected immediately after death. Tissues including paw skin, foot muscles, leg muscles, bilateral sciatic nerves, and lumbar DRG were quickly dissected, immediately frozen in liquid nitrogen, and stored at -80 °C until analysis.

[0111] In a separate experiment, eight mice with paclitaxel-induced PN were studied by treatment with PS 8% ointment 3x / day for 2 weeks. Mice were euthanized as described above 30 min after the last administration of PS. From these mice, both sciatic nerves were harvested and divided into proximal and distal halves, respectively, and the corresponding halves from each of the two animals were combined to assay for drug levels.

[0112] As previously described (Wen et al., Int J Pharm (2019);557:273-279), each plasma sample was mixed with 2 volumes of acetonitrile and centrifuged at 13,200 rpm for 15 min. Tissue samples were weighed, added with ddH2O (100–300 μL depending on tissue weight), and homogenized. After adding acetonitrile (2 volumes of homogenate), the mixture was sonicated for 10 min, centrifuged at 13,200 rpm for 15 min, and analyzed by HPLC, as reported (Wen et al., 2019). The limits of quantification are 0.1 μM for PS and 0.05 μM for sulindac, sulindac sulfone, sulindac sulfide, and their glucuronidated derivatives.

[0113] result PS can be rapidly metabolized both in vitro and in vivo to several metabolites, including PS sulfide, PS sulfone, sulindac, lindac sulfide, and sulindac sulfone (Figure 9). The glucuronide of sulindac and its metabolites, formed primarily in the liver, have also been identified. Because the metabolism and PK / biodistribution of PS differ depending on the route of administration, both were studied in normal mice administered PS locally to the hindpaw, with particular focus on the sciatic nerve and dorsal root ganglion (DRG), which are affected in CIPN (Colvin, Pain (2019);160 Suppl 1:S1-S10).

[0114] As shown in Figure 10 and Table 3, PS was detected in the foot skin, the application site, the muscle under the skin, the leg muscle, the sciatic nerve, and the DRG. As expected (Xie et al., Br J Pharmacol (2012a);165:2152-2166), PS was not detected in the systemic circulation.

[0115] The concentration of PS gradually decreased from the skin to its most distal DRG, which is consistent with the max (from 194.7±5.3μM to 0.3±0.1μM) and AUC 0-24h This is evidenced by the respective values ​​of both the T of PS (from 1,609.8 μM.hr to 4.5 μM.hr). max is a long-term T, possibly reflecting the way in which PS arrives at it, as discussed below. max The t values ​​for skin and muscle were the same (0.5 h) in all tissues, except for the DRG, which showed a t value of 18 h. Another interesting feature was the t values ​​for skin and muscle, which were within a relatively narrow range (11.4–20.6 h), in contrast to the very long-term value of 57.4 h in the sciatic nerve and the presumably even longer-term value in the DRG, which could not be determined with reasonable precision. 1 / 2 This is the difference.

[0116] These differences indicate different metabolic capacities between nerves and skin and muscle with respect to PS. [Table 3]

[0117] Only three metabolites of PS were detected: sulindac, sulindac sulfone, and sulindac sulfide (Figure 11 and Table 4). No glucuronidation products were detected. Sulindac was the quantitatively predominant metabolite, with sulindac sulfone and sulindac sulfone levels being <20% of the levels of sulindac. Sulindac levels were approximately 25% of the levels of PS in all tissues except sciatic nerve (higher) and DRG (equal). [Table 4]

[0118] Sciatic nerve (C max = 0.9 ± 0.1 μM; AUC 0-24h =12.0μM . time) and DRG(C max = 0.3 ± 0.1 μM; AUC 0-24h = 4.5 μM . The presence of PS, even in small amounts in the T cell of the DRG (times) is of particular interest, as both are targets of chemotherapy relevant to neuropathic pain. max The very high β-aspartate concentration in the sciatic nerve and the low PS levels in the DRG compared with the sciatic nerve suggest that PS reaches the DRG from the skin through the sciatic nerve.

[0119] To further explore this conclusion, we compared PS levels in the proximal and distal halves of mouse sciatic nerves 30 min after application to the hind paw. The two values ​​were significantly different, with the value in the distal half being 18.5-fold higher than that in the proximal half (17 ± 5.1 μM vs. 0.9 ± 0.3 μM; Table 5). Concentrations of three metabolites of PS (sulindac, sulindac sulfide, and sulindac sulfone) were also higher (4.5-8.5-fold higher) in the distal half compared to the proximal half. These findings support the notion that PS reaches the DRG from the application site by direct tissue transport or transport rather than via the circulation. [Table 5]

[0120] conclusion These experiments demonstrate that locally administered PS can reach key sites of action (i.e., the sciatic nerve and dorsal root ganglion) known to be involved in the development of chemotherapy-associated neuropathic pain. Furthermore, in view of its rapid metabolism in the bloodstream, the results demonstrate that PS reaches these sites of action by traversing along peripheral neurons (e.g., the sciatic nerve) toward the central nervous system and is detected at meaningful concentrations in the DRG. Thus, without wishing to be bound by theory, these observations confirm that PS likely exerts its analgesic activity directly on neurons and possibly within the central site of action, similar to the activity of centrally acting analgesics such as lidocaine and pregabalin.

[0121] Example 6: The activity of PS in the treatment and prevention of neuropathic pain associated with CIPN is comparable to that of lidocaine and pregabalin, but is not shared by sulindac The effect of PS was compared with that of known centrally acting analgesics (lidocaine and pregabalin) and the parent compound of PS, sulindac, on neuropathic pain associated with CIPN. Treatment of neuropathic pain associated with the CIPN protocol corresponds to that described in Examples 2 and 3.

[0122] method Methods for animals, induction of CIPN (with paclitaxel), assessment of mechanical allodynia, and statistical analysis correspond to those outlined in Example 3.

[0123] CIPN was established by administering paclitaxel to C57 / BL / 6J mice. Paclitaxel was administered to all study groups: 1. Group 1: Paclitaxel + vehicle (n = 8) 2. Group 2: Paclitaxel + PS 5% (n = 8) 3. Group 3: Paclitaxel + PS 1.2% (n=8) 4. Group 4: Paclitaxel + 0.7% sulindac (n=8) 5. Group 5: Paclitaxel + 5% lidocaine cream (n=8) 6. Group 6: Paclitaxel + Pregabalin (10 mg / kg) (n=8)

[0124] For treatment with PS, sulindac, and vehicle: PS hydrogel 5%, PS 1.2%, 0.7% sulindac, or vehicle was applied to both hind paws three times daily starting on day 0 through day 15. 0.7% sulindac was the highest concentration achievable and is equimolar to PS 1.2%.

[0125] For lidocaine treatment: 5% lidocaine cream (positive control) was applied once to both hind paws of mice 30 min prior to measurement of PWT.

[0126] Regarding pregabalin treatment: 10 mg / kg pregabalin (positive control) was administered orally once, 1 hour before PWT measurement.

[0127] To determine the outcome of the treatment, an evaluation of mechanical allodynia was performed. In addition, an evaluation of cold allodynia (another symptom of CIPN) was performed using the acetone test in groups of mice treated with vehicle or PS5%. Both methods of evaluating allodynia are described in Toma W, et al. Neuropharmacology 2017;117:305-15. Mechanical and cold allodynia are determined in the same animals with an interval of at least 1 day.

[0128] Briefly, pain threshold responses to mechanical allodynia were measured using the well-established method of von Frey filaments, consistent with that performed in the previous examples. PWT tests were performed on day -8 (before the first dose of paclitaxel), on the day treatment began (day 0, when CIPN was fully established), and on day 14 (treatment continued until day 15). Mechanical thresholds, expressed in g, indicate the force of the von Frey filaments to which the animals responded.

[0129] For cold allodynia, mice with paclitaxel-induced CIPN were treated with PS 5% or vehicle for 15 days after CIPN induction. The acetone test was used. Briefly, acetone was applied onto the plantar surface of each hind paw. The time each mouse licked, lifted and / or shook its hind paw, recorded over a period of 60 seconds, was the score for cold allodynia. Measurements were performed on day -8 (before the first paclitaxel injection), the day treatment began (day 0), and then on day 15.

[0130] result As expected, paclitaxel induced CIPN, as evidenced by a reduction in mechanical allodynia from a score of 1.83±0.14 g (mean±SEM of this and all subsequent values) before paclitaxel administration to 0.55±0.05 g on day 0 of the study (after CIPN was fully established). Paclitaxel also sensitized mice to cold allodynia, as evidenced by the change in scores before and after paclitaxel treatment (4.5±0.24 sec vs. 7.1±0.4 sec; p<0.0001).

[0131] Treatment with PS improved mechanical allodynia scores in a dose-dependent manner (Figure 12A). Similarly, treatment with PS 5% improved cold allodynia scores. The cold allodynia scores of the PS-treated group were significantly lower than those of the vehicle-treated group (3.1±0.4 vs. 9.3±0.7; p<0.0001) (Figure 12B).

[0132] In contrast, administration of sulindac failed to demonstrate a significant effect on PWT, with scores similar to those of vehicle (0.62±0.05 g vs. 0.56±0.04 g; not statistically significant), whereas, as expected, the positive controls lidocaine and pregabalin both achieved significant increases in PWT compared to vehicle (FIG. 12A). Importantly, mechanical allodynia was significantly improved (p<0.0001) by equimolar PS 1.2% with sulindac 0.7%. Values ​​for mechanical allodynia corresponding to FIG. 12A are provided in Table 6. [Table 6]

[0133] conclusion Although PS has been shown to be effective in treating and preventing neuropathic pain associated with CIPN (see also Examples 1-3), surprisingly, its non-phosphorylated "parent" sulindac (a typical NSAID) failed to achieve rescue of PWT in mouse models and therefore failed to treat neuropathic pain associated with CIPN. This was true even when sulindac was administered at its maximum non-toxic dose and in the same manner and formulation as PS. The positive controls lidocaine and pregabalin are known to have central sites of action in analgesia and, as expected, showed significant reduction in pain associated with CIPN. Thus, the efficacy observed for locally administered PS is more similar to the centrally acting positive controls than to its closely related parent compounds.

[0134] Thus, PS is mechanistically distinct from its parent NSAID and may act in a manner more similar to centrally acting drugs. These observations of comparable efficacy of PS with pregabalin and lidocaine in treating and preventing neuropathic pain associated with CIPN reflect the central site of action of PS observed above (i.e., similar to the site of action of pregabalin and lidocaine). These observations help demonstrate the potential of PS in treating neuropathic pain associated with CIPN, similar to typical centrally acting analgesics (e.g., pregabalin and lidocaine).

[0135] Example 7: Overview of Observations The observations herein demonstrate unprecedented analgesic activity of PS in the prevention and treatment of neuropathic pain associated with CIPN using a well-established animal model. Thus, the above experiments demonstrate that PS can reduce CIPN-induced neuropathic pain signaling produced by various chemotherapeutic compounds. The mechanism of action of PS on mechanical allodynia has been shown to affect a pathophysiology common to each of the chemotherapeutic compounds - PS directly affects neuronal pain signaling caused by nerve damage caused by the chemotherapeutic compounds, demonstrating the broad therapeutic applicability of PS in the treatment of chemotherapy-related neuropathic pain. The therapeutic effect of PS on mechanical allodynia is very potent and fairly rapid by local administration. Indeed, when administered locally, PS follows an ascending trajectory along peripheral neurons (e.g., sciatic nerve) toward the spinal cord and has been shown to achieve significant analgesic effects in less than one week, lasting up to two weeks. The local route results in lower systemic clearance, reduced drug interactions, improved patient tolerability, and easier combination with oral medications.

[0136] These observations demonstrate previously unrecognized activity and therapeutic utility of PS, a compound that falls into the broader class of NSAIDs, but does not share all the properties of this compound family. Indeed, in contrast to previous observations with NSAIDs, the data herein demonstrate that the activity of PS is more similar to analgesics that directly target neuronal activity and may act at both peripheral and central sites. Indeed, the above results confirm that PS can reduce pain from allodynia, which is known to include pain caused by peripheral and central sensitization. In the CIPN treatment model, pain was established for 5 days prior to treatment randomization, thereby establishing central sensitization as indicated by allodynia (compared to baseline). Thus, without wishing to be bound by theory, PS exerts a direct effect on neuronal pain signaling, similar to the established mechanism of action of anesthetic drugs. Indeed, these results demonstrate the ability of PS to reduce pain signaling from peripheral and central sensitization, engaging both peripheral and central sites of action for the analgesic activity of this compound. Of course, this activity is distinct from the established role of PS and typical NSAIDs as anti-inflammatory agents.

[0137] Previous observations on the activity of PS are limited to its anti-inflammatory activity. For example, WO2019 / 067919 suggests a role for PS in the treatment of DED using an acute DED model in which concanavalin A (ConA) is administered simultaneously with PS to the lacrimal glands of rabbits. In this context, the anti-inflammatory activity of PS results in a limited inflammatory response in response to ConA, thereby preventing the establishment of DED. These observations confirm the anti-inflammatory activity of PS and suggest its usefulness in preventing the establishment and maintenance of the inflammatory component of DED. The observations in this acute DED model have not been able to provide evidence of the ability of PS to act directly on nerves to reduce neural signaling caused by neuropathic pain. It can only be assumed that the reduction in pain in this acute DED model is the result of PS inhibiting the inflammatory response (i.e., the pathology responsible for causing the activation of pain sensors). Indeed, the results of the DED model suggest that PS improves corneal sensitivity, which implies an increase in pain sensation, i.e., the opposite effect to that desired for analgesics. Of course, regardless of any indication for analgesic activity of PS, such activity observed in acute DED models does not suggest a corresponding activity in neuropathic pain, certainly not in the neuropathic pain associated with CIPN.

[0138] The experiments herein were carried out in a specific animal model of neuropathic pain associated with CIPN. As outlined above, the use of an appropriate animal model is important to demonstrate the potential efficacy of a compound in a specific type of neuropathic pain. The efficacy of a drug on pain resulting from peripheral neuropathy cannot be extrapolated from its efficacy on other forms of pain, or even other forms of neuropathic pain. Indeed, certain forms of neuropathic pain differ in their etiology, and therefore require therapeutic agents with different activities for their treatment and / or prevention. Therapies need to be designed according to the specific pathophysiology of neuropathic pain and tested in appropriate models. For example, CIPN causes direct nerve damage to sensory axons by administration of toxic chemotherapeutic agents, demyelination or impaired calcium metabolism, while other neuropathies may occur as a result of widespread nerve damage due to metabolic abnormalities (e.g., as seen in diabetic peripheral neuropathy). Thus, the effects on both large and small fibers differ between CIPN and other forms of neuropathy based on their specific pathophysiology. The only definitive determination of a compound's efficacy in treating neuropathic pain caused by such pathophysiology is to test the compound in an appropriate neuropathic pain model of CIPN, as shown above. Without these observations, there is a lack of indication of the pain-relieving activity of PS in the context of neuropathic pain associated with CIPN.

[0139] The observations herein demonstrate that PS has therapeutic utility beyond that suggested for typical NSAIDs. Such NSAIDs, such as loxoprofen sodium, are ineffective in reducing pain signaling in paclitaxel-induced CIPN. Furthermore, Moore et al. (Cochrane Database of Systematic Reviews (2015);10: 1-25) have reviewed that NSAIDs have no therapeutic effect in peripheral neuropathic pain. The activity of PS observed herein corresponds to that of pregabalin and lidocaine, and contrasts with the inability of typical NSAIDs to provide direct analgesic effects to injured neurons in neuropathic pain, as observed in the prior art. The differential activity of PS compared to typical NSAIDs is confirmed by comparison with its parent compound, sulindac, in the above experiments. Sulindac fails to alleviate established allodynia (i.e., caused by sensitization of peripheral and central neurons), indicating that unlike PS, sulindac does not exert a direct analgesic effect on damaged neurons in neuropathic pain caused by CIPN. Without wishing to be bound by theory, the reason for the absence of response to typical NSAIDs in the prior art is that pain is likely caused by neuropathic nerve damage rather than inflammation (i.e., the anti-inflammatory activity of typical NSAIDs is not sufficient to prevent or treat neuropathic pain). Thus, the analgesic activity of PS observed herein is unique and not shared with typical NSAIDs. Based on the observations herein regarding sulindac, any purported analgesic activity of NSAIDs observed in the prior art is a reflection of their anti-inflammatory activity (i.e., stopping the initial trigger that causes pain) rather than actual analgesic activity directed at nerve signaling (i.e., which results in the reduction of pain caused by nerve damage and sensitization). Indeed, if typical NSAIDs, such as sulindac, could directly act on neurons with their analgesic activity, sulindac would have been expected to reduce the allodynia observed in the above model.

[0140] Thus, the inventors have demonstrated a new and surprising activity of PS in the treatment and / or prevention of neuropathic pain associated with CIPN. As outlined above, this activity exceeds the anti-inflammatory activity previously observed for PS and related NSAIDs. Indeed, unlike typical NSAIDs, the observations herein demonstrate that PS has direct activity on peripheral and central nerves, likely similar to the site and mechanism of action of established analgesics such as lidocaine and pregabalin. Furthermore, PS improves the therapy of neuropathic pain associated with CIPN, even compared to these centrally acting analgesics, because PS is easy to administer, for example locally, and has limited side effects (Mackenzie et al. (2010) Gastroenterology 139(4): 1320-32).

[0141] It will be understood that the inventors' work has been described above by way of example only and that modifications can be made whilst remaining within the scope and spirit of the invention.

Claims

1. A pharmaceutical composition comprising phosphothrinadine (PS) for treating and / or preventing neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN).

2. a) Treating the neuropathic pain includes reducing or eliminating the neuropathic pain, b) Preventing the neuropathic pain includes reducing the incidence of the neuropathic pain, c) Treating the neuropathic pain includes reducing or eliminating one or more of the sensory symptoms associated with CIPN, d) Preventing the neuropathic pain includes reducing the incidence of one or more of the sensory symptoms associated with CIPN, Optionally, the one or more sensory symptoms are selected from paresthesia, burning sensation, and electric shock sensation. For example, the paresthesia includes one or more of numbness, tingling, pricking sensation, or crawling sensation. The pharmaceutical composition according to claim 1.

3. a) PS reduces, eliminates, or reduces the incidence of intracellular signal transduction in nerve cells involved in pain sensation, b) PS reduces, eliminates, or reduces the incidence of pain caused through peripheral sensitization, c) PS reduces, eliminates, or reduces the incidence of pain caused through central sensitization, d) PS reduces, eliminates, or reduces the incidence of pain signal transduction occurring in the central nervous system, e) PS reduces, eliminates, or reduces the incidence of pain signal transduction occurring in the sciatic nerve, f) PS reduces, eliminates, or reduces the incidence of pain signal transduction occurring in the dorsal root ganglion, g) The neuropathic pain is allodynia, and the allodynia may be mechanical allodynia and / or thermal allodynia, and / or h) The neuropathic pain is hyperalgesia. The pharmaceutical composition according to claim 1.

4. The subject has cancer and has received or has been previously treated with one or more chemotherapy compounds. Optionally, the one or more chemotherapy compounds are selected from one or more of platinum-based drugs, taxanes, immunomodulators, epothilones, vinca alkaloids, and proteasome inhibitors. For example, the one or more chemotherapeutic compounds are selected from one or more of oxaliplatin, cisplatin, carboplatin, taxane, paclitaxel, docetaxel, cabazitaxel, thalidomide and its analogs, vincristine, vinblastine, vinorelbine, vindesine and bortezomib, the pharmaceutical composition according to claim 1.

5. The chemotherapeutic compound is a) a taxane, such as paclitaxel, b) the chemotherapeutic compound is a vinca alkaloid, such as vincristine, or c) the chemotherapeutic compound is a platinum-based anti-tumor drug, such as oxaliplatin, the pharmaceutical composition according to claim 4.

6. The subject is a) having solid tumor cancer, and / or b) having ovarian cancer, breast cancer, lung cancer, Kaposi's sarcoma and / or pancreatic cancer, the pharmaceutical composition according to claim 4.

7. The subject is human, the pharmaceutical composition according to claim 1.

8. PS has the formula I (PS-I): 【Chemical 1】 the pharmaceutical composition according to any one of claims 1 to 7.

9. PS has the formula II (PS-II): [Chemical Formula 2] the pharmaceutical composition according to any one of claims 1 to 7.

10. The pharmaceutical composition containing PS further comprises a pharmaceutically acceptable excipient, the pharmaceutical composition according to claim 1.

11. The pharmaceutical composition containing PS is formulated for topical administration, optionally, a) the pharmaceutical composition containing PS is formulated as a semi-solid, b) the pharmaceutical composition containing PS is formulated as a liquid, c) the pharmaceutical composition containing PS is a cream, d) the pharmaceutical composition containing PS is a gel, for example the gel is a hydrogel, e) the pharmaceutical composition containing PS is a lotion, f) the pharmaceutical composition containing PS is an ointment, g) the pharmaceutical composition containing PS is a spray, or h) the pharmaceutical composition containing PS is formulated as a patch, the pharmaceutical composition according to claim 10.

12. The pharmaceutical composition contains PS at a concentration of about 0.5% to about 15% w / w of the pharmaceutical composition, Optionally, the pharmaceutical composition comprises PS at a concentration of about 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, For example, a) the pharmaceutical composition comprises PS at a concentration of 8% w / w or less, for example about 5% w / w or about 3% w / w of the pharmaceutical composition, or b) the pharmaceutical composition comprises PS at a concentration of about 3% w / w or less, for example about 2% w / w or about 1% w / w of the pharmaceutical composition, The pharmaceutical composition according to claim 10.

13. a) said PS is from about 0.005 g / 10 cm ２ of the affected area to about 0.25 g / 10 cm ２ administered at the affected area, and optionally, said PS is I) about 0.005 g / 10 cm2 of the affected area, II) about 0.01 g / 10 cm2 of the affected area, III) about 0.05 g / 10 cm2 of the affected area, IV) about 0.1 g / 10 cm2 of the affected area, V) about 0.15 g / 10 cm2 of the affected area, VI) about 0.2 g / 10 cm2 of the affected area, or VII) about 0.25 g / 10 cm2 of the affected area and is administered; and / or b) the PS is applied to the affected area and left on the affected area for about 1 hour to about 5 hours, optionally, I) the PS is applied to the affected area and left on the affected area for about 0.5 hour, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours, and / or II) A) the PS is removed from the affected area after the administration period, for example by rinsing, or B) a second or further application of PS is made to the affected area after the administration period, The pharmaceutical composition according to claim 10.

14. a) The PS is applied once a day. b) The PS is applied twice a day. c) The PS is applied three times a day, or d) The PS is applied four times a day, The pharmaceutical composition according to claim 10.

15. The PS is administered in a pharmaceutical composition, The pharmaceutical composition according to claim 13 or 14.

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